Metabolism
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Reverted edits by [[Special:Contributions/75.31.139.180|75.31.139.180]] ([[User talk:75.31.139.180|talk]]) to last version by NickBush24
[[Image:ATP-3D-vdW.png|thumb|right|280px|Structure of the [[coenzyme]] [[adenosine triphosphate]], a central intermediate in energy metabolism.]]
'''Metabolism''' is the set of [[chemical reaction]]s that occur in living [[organism]]s in order to maintain [[life]]. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories. [[Catabolism]] breaks down large molecules, for example to harvest energy in [[cellular respiration]]. [[Anabolism]], on the other hand, uses energy to construct components of cells such as [[protein]]s and [[nucleic acid]]s.
The chemical reactions of metabolism are organized into [[metabolic pathway]]s, in which one chemical is transformed into another by a sequence of [[enzyme]]s. Enzymes are crucial to metabolism because they allow organisms to drive desirable but [[biological thermodynamics|thermodynamically]] unfavorable reactions by [[Coupling (physics)|coupling]] them to favorable ones. Enzymes also allow the [[Control theory|regulation]] of metabolic pathways in response to changes in the [[cell (biology)|cell's]] environment or [[cell signaling|signals]] from other cells.
The metabolism of an organism determines which substances it will find [[nutrition|nutritious]] and which it will find [[poison]]ous. For example, some [[prokaryote]]s use [[hydrogen sulfide]] as a nutrient, yet this gas is poisonous to animals.<ref name="Physiology1">{{cite journal |author=Friedrich C |title=Physiology and genetics of sulfur-oxidizing bacteria |journal=Adv Microb Physiol |volume=39 |issue= |pages=235–89 |year=1998 |pmid=9328649 |doi=10.1016/S0065-2911(08)60018-1}}</ref> The speed of metabolism, the metabolic rate, also influences how much food an organism will require.
A striking feature of metabolism is the similarity of the basic metabolic pathways between even vastly different species. For example, the set of [[carboxylic acid]]s that are best known as the intermediates in the [[citric acid cycle]] are present in all organisms, being found in species as diverse as the [[microorganism|unicellular]] [[bacteria]] ''[[Escherichia coli]]'' and huge [[multicellular organism|multicellular]] organisms like [[elephant]]s.<ref name=SmithE>{{cite journal |author=Smith E, Morowitz H |title=Universality in intermediary metabolism |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15340153 |journal=Proc Natl Acad Sci U S A |volume=101 |issue=36 |pages=13168–73 |year=2004 |pmid=15340153 |doi=10.1073/pnas.0404922101}}</ref> These striking similarities in metabolism are most likely the result of the high efficiency of these pathways, and of their early appearance in evolutionary history.<ref name=Ebenhoh>{{cite journal |author=Ebenhöh O, Heinrich R |title=Evolutionary optimization of metabolic pathways. Theoretical reconstruction of the stoichiometry of ATP and NADH producing systems |journal=Bull Math Biol |volume=63 |issue=1 |pages=21–55 |year=2001 |pmid=11146883 |doi=10.1006/bulm.2000.0197}}</ref><ref name=Cascante>{{cite journal |author=Meléndez-Hevia E, Waddell T, Cascante M |title=The puzzle of the Krebs citric acid cycle: assembling the pieces of chemically feasible reactions, and opportunism in the design of metabolic pathways during evolution |journal=J Mol Evol |volume=43 |issue=3 |pages=293–303 |year=1996 |pmid=8703096 |doi=10.1007/BF02338838}}</ref>
==Key biochemicals==
{{further|[[Biomolecule]], [[cell (biology)]] and [[biochemistry]]}}
[[Image:Trimyristin-3D-vdW.png|right|thumb|250px|Structure of a [[triacylglycerol]] lipid.]]
Most of the structures that make up animals, plants and microbes are made from three basic classes of [[molecule]]: [[amino acid]]s, [[carbohydrate]]s and [[lipid]]s (often called [[fat]]s). As these molecules are vital for life, metabolism focuses on making these molecules, in the construction of cells and tissues, or breaking them down and using them as a source of energy, in the digestion and use of food. Many important biochemicals can be joined together to make [[polymer]]s such as [[DNA]] and [[proteins]]. These [[macromolecules]] are essential parts of all living organisms. Some of the most common biological polymers are listed in the table below.
{| class="wikitable" style="margin-left: auto; margin-right: auto;"
!Type of molecule
!Name of [[monomer]] forms
!Name of [[polymer]] forms
!Examples of polymer forms
|-
|align="center" |[[Amino acid]]s
|align="center" |Amino acids
|align="center" |[[Protein]]s (also called polypeptides)
|align="center" |[[Fibrous protein]]s and [[globular protein]]s
|-
|align="center" |[[Carbohydrate]]s
|align="center" |[[Monosaccharide]]s
|align="center" |[[Polysaccharide]]s
|align="center" |[[Starch]], [[glycogen]] and [[cellulose]]
|-
|align="center" |[[Nucleic acid]]s
|align="center" |[[Nucleotide]]s
|align="center" |[[Polynucleotide]]s
|align="center" |[[DNA]] and [[RNA]]
|}
===Amino acids and proteins===
[[Protein]]s are made of [[amino acid]]s arranged in a linear chain and joined together by [[peptide bond]]s. Many proteins are the [[enzyme]]s that [[catalysis|catalyze]] the chemical reactions in metabolism. Other proteins have structural or mechanical functions, such as the proteins that form the [[cytoskeleton]], a system of [[scaffolding]] that maintains the cell shape.<ref>{{cite journal |author=Michie K, Löwe J |title=Dynamic filaments of the bacterial cytoskeleton |journal=Annu Rev Biochem |volume=75 |issue= |pages=467–92 |year=2006 |pmid=16756499 |doi=10.1146/annurev.biochem.75.103004.142452}}</ref> Proteins are also important in [[cell signaling]], [[antibody|immune responses]], [[cell adhesion]], [[active transport]] across membranes and the [[cell cycle]].<ref name=Nelson>{{cite book | last = Nelson | first = David L. | coauthors = Michael M. Cox | title = Lehninger Principles of Biochemistry | publisher = W. H. Freeman and company | date = 2005 | location = New York | pages = 841 | isbn = 0-7167-4339-6}}</ref>
===Lipids===
[[Lipid]]s are the most diverse group of biochemicals. Their main structural uses are as part of [[biological membrane]]s such as the [[cell membrane]], or as a source of energy.<ref name=Nelson/> Lipids are usually defined as [[hydrophobe|hydrophobic]] or [[amphiphiles|amphipathic]] biological molecules that will dissolve in [[organic solvent]]s such as [[benzene]] or [[chloroform]].<ref>{{cite journal |author=Fahy E, Subramaniam S, Brown H, Glass C, Merrill A, Murphy R, Raetz C, Russell D, Seyama Y, Shaw W, Shimizu T, Spener F, van Meer G, VanNieuwenhze M, White S, Witztum J, Dennis E |title=A comprehensive classification system for lipids |url=http://www.jlr.org/cgi/content/full/46/5/839 |journal=J Lipid Res |volume=46 |issue=5 |pages=839–61 |year=2005 |pmid=15722563 |doi=10.1194/jlr.E400004-JLR200}}</ref> The [[fat]]s are a large group of compounds that contain [[fatty acid]]s and [[glycerol]]; a glycerol molecule attached to three fatty acid [[ester]]s is a [[triglyceride|triacylglyceride]].<ref>{{cite web | title=Nomenclature of Lipids |publisher=IUPAC-IUB Commission on Biochemical Nomenclature (CBN) | url=http://www.chem.qmul.ac.uk/iupac/lipid/ |accessdate=2007-03-08}}</ref> Several variations on this basic structure exist, including alternate backbones such as [[sphingosine]] in the [[sphingolipid]]s, and [[hydrophile|hydrophilic]] groups such as [[phosphate]] in [[phospholipid]]s. [[Steroid]]s such as [[cholesterol]] are another major class of lipids that are made in cells.<ref>{{cite journal |author=Hegardt F |title=Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1220089&blobtype=pdf |journal=Biochem J |volume=338 (Pt 3) |issue= |pages=569–82 |year=1999 |pmid=10051425 |doi=10.1042/0264-6021:3380569}}</ref>
===Carbohydrates===
[[Image:Glucose Fisher to Haworth.gif|thumb|250px|right||[[Glucose]] can exist in both a straight-chain and ring form.]]
[[Carbohydrate]]s are straight-chain [[aldehyde]]s or [[ketone]]s with many [[hydroxyl]] groups that can exist as straight chains or rings. Carbohydrates are the most abundant biological molecules, and fill numerous roles, such as the storage and transport of [[energy]] ([[starch]], [[glycogen]]) and structural components ([[cellulose]] in plants, [[chitin]] in animals).<ref name=Nelson/> The basic carbohydrate units are called [[monosaccharide]]s and include [[galactose]], [[fructose]], and most importantly [[glucose]]. Monosaccharides can be linked together to form [[polysaccharide]]s in almost limitless ways.<ref>{{cite journal |author=Raman R, Raguram S, Venkataraman G, Paulson J, Sasisekharan R |title=Glycomics: an integrated systems approach to structure-function relationships of glycans |journal=Nat Methods |volume=2 |issue=11 |pages=817–24 |year=2005 |pmid=16278650 |doi=10.1038/nmeth807}}</ref>
===Nucleotides===
The polymers [[DNA]] and [[RNA]] are long chains of [[nucleotide]]s. These molecules are critical for the storage and use of genetic information, through the processes of [[transcription (genetics)|transcription]] and [[protein biosynthesis]].<ref name=Nelson/> This information is protected by [[DNA repair]] mechanisms and propagated through [[DNA replication]]. A few [[virus]]es have an RNA genome, for example [[HIV]], which uses [[reverse transcription]] to create a DNA template from its viral RNA genome.<ref>{{cite journal |author=Sierra S, Kupfer B, Kaiser R |title=Basics of the virology of HIV-1 and its replication |journal=J Clin Virol |volume=34 |issue=4 |pages=233–44 |year=2005 |pmid=16198625 |doi=10.1016/j.jcv.2005.09.004}}</ref> RNA in [[ribozyme]]s such as [[spliceosome]]s and [[ribosome]]s is similar to enzymes as it can catalyze chemical reactions. Individual [[nucleoside]]s are made by attaching a [[nucleobase]] to a [[ribose]] sugar. These bases are [[heterocyclic]] rings containing nitrogen, classified as [[purines]] or [[pyrimidines]]. Nucleotides also act as coenzymes in metabolic group transfer reactions.<ref name=Wimmer>{{cite journal |author=Wimmer M, Rose I |title=Mechanisms of enzyme-catalyzed group transfer reactions |journal=Annu Rev Biochem |volume=47 |issue= |pages=1031–78 |year=1978 |pmid=354490 |doi=10.1146/annurev.bi.47.070178.005123}}</ref>
===Coenzymes===
[[Image:Acetyl-CoA-2D.svg|thumb|right|300px|Structure of the [[coenzyme]] [[acetyl-CoA]].The transferable [[acetyl|acetyl group]] is bonded to the sulfur atom at the extreme left.]]
{{further|[[Coenzyme]]}}
Metabolism involves a vast array of chemical reactions, but most fall under a few basic types of reactions that involve the transfer of [[functional group]]s.<ref>{{cite journal |author=Mitchell P |title=The Ninth Sir Hans Krebs Lecture. Compartmentation and communication in living systems. Ligand conduction: a general catalytic principle in chemical, osmotic and chemiosmotic reaction systems |journal=Eur J Biochem |volume=95 |issue=1 |pages=1–20 |year=1979 |pmid=378655 |doi=10.1111/j.1432-1033.1979.tb12934.x}}</ref> This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions.<ref name=Wimmer/> These group-transfer intermediates are called [[coenzyme]]s. Each class of group-transfer reaction is carried out by a particular coenzyme, which is the [[substrate (biochemistry)|substrate]] for a set of enzymes that produce it, and a set of enzymes that consume it. These coenzymes are therefore continuously being made, consumed and then recycled.<ref name=Dimroth>{{cite journal |author=Dimroth P, von Ballmoos C, Meier T |title=Catalytic and mechanical cycles in F-ATP synthases. Fourth in the Cycles Review Series |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16607397 |journal=EMBO Rep |volume=7 |issue=3 |pages=276–82 |year=2006 |pmid=16607397 |doi=10.1038/sj.embor.7400646}}</ref>
One central coenzyme is [[adenosine triphosphate]] (ATP), the universal energy currency of cells. This [[nucleotide]] is used to transfer chemical energy between different chemical reactions. There is only a small amount of ATP in cells, but as it is continuously regenerated, the human body can use about its own weight in ATP per day.<ref name=Dimroth/> ATP acts as a bridge between catabolism and anabolism, with catabolic reactions generating ATP and anabolic reactions consuming it. It also serves as a carrier of phosphate groups in [[phosphorylation]] reactions.
A [[vitamin]] is an organic compound needed in small quantities that cannot be made in the cells. In human [[nutrition]], most vitamins function as coenzymes after modification; for example, all water-soluble vitamins are phosphorylated or are coupled to nucleotides when they are used in cells.<ref>{{Citation | last1 = Coulston | first1 = Ann | last2 = Kerner | first2 = John | last3 = Hattner | first3 = JoAnn | last4 = Srivastava | first4 = Ashini | contribution = Nutrition Principles and Clinical Nutrition | title = Stanford School of Medicine Nutrition Courses | publisher = SUMMIT | year = 2006 }}</ref> [[Nicotinamide adenine dinucleotide]] (NADH), a derivative of vitamin B<sub>3</sub> ([[niacin]]), is an important coenzyme that acts as a hydrogen acceptor. Hundreds of separate types of [[dehydrogenase]]s remove electrons from their substrates and [[redox|reduce]] NAD<sup>+</sup> into NADH. This reduced form of the coenzyme is then a substrate for any of the [[reductase]]s in the cell that need to reduce their substrates.<ref>{{cite journal |author=Pollak N, Dölle C, Ziegler M |title=The power to reduce: pyridine nucleotides—small molecules with a multitude of functions |journal=Biochem J |volume=402 |issue=2 |pages=205–18 |year=2007 |pmid=17295611 |doi=10.1042/BJ20061638}}</ref> Nicotinamide adenine dinucleotide exists in two related forms in the cell, NADH and NADPH. The NAD<sup>+</sup>/NADH form is more important in catabolic reactions, while NADP<sup>+</sup>/NADPH is used in anabolic reactions.
[[Image:1GZX Haemoglobin.png|thumb|300px|left|Structure of [[hemoglobin]]. The protein subunits are in red and blue, and the iron-containing [[heme]] groups in green. From {{PDB|1GZX}}.]]
===Minerals and cofactors===
{{further|[[Physiology]], [[bioinorganic chemistry]], [[Cofactor (biochemistry)|cofactor]] and [[Human iron metabolism|iron metabolism]]}}
Inorganic elements play critical roles in metabolism; some are abundant (e.g. [[sodium]] and [[potassium]]) while others function at minute concentrations. About 99% of mammals' mass are the elements [[carbon]], [[nitrogen]], [[calcium]], [[sodium]], [[chlorine]], [[potassium]], [[hydrogen]], [[phosphorus]], [[oxygen]] and [[sulfur]].<ref name=Heymsfield>{{cite journal |author=Heymsfield S, Waki M, Kehayias J, Lichtman S, Dilmanian F, Kamen Y, Wang J, Pierson R |title=Chemical and elemental analysis of humans in vivo using improved body composition models |journal=Am J Physiol |volume=261 |issue=2 Pt 1 |pages=E190–8 |year=1991 |pmid=1872381}}</ref> The [[organic compound]]s (proteins, lipids and carbohydrates) contain the majority of the carbon and nitrogen and most of the oxygen and hydrogen is present as water.<ref name=Heymsfield/>
The abundant inorganic elements act as [[ion]]ic [[electrolyte]]s. The most important ions are [[sodium]], [[potassium]], [[calcium]], [[magnesium]], [[chloride]], [[phosphate]], and the organic ion [[bicarbonate]]. The maintenance of precise [[ion gradient|gradients]] across [[cell membrane]]s maintains [[osmotic pressure]] and [[pH]].<ref>{{cite journal |author=Sychrová H |title=Yeast as a model organism to study transport and homeostasis of alkali metal cations |url=http://www.biomed.cas.cz/physiolres/pdf/53%20Suppl%201/53_S91.pdf |journal=Physiol Res |volume=53 Suppl 1 |issue= |pages=S91–8 |year=2004 |pmid=15119939}}</ref> Ions are also critical for [[nerve]]s and [[muscle]]s, as [[action potential]]s in these tissues are produced by the exchange of electrolytes between the [[extracellular fluid]] and the [[cytosol]].<ref>{{cite journal |author=Levitan I |title=Modulation of ion channels in neurons and other cells |journal=Annu Rev Neurosci |volume=11 |issue= |pages=119–36 |year=1988 |pmid=2452594 |doi=10.1146/annurev.ne.11.030188.001003}}</ref> Electrolytes enter and leave cells through proteins in the cell membrane called [[ion channels]]. For example, [[muscle contraction]] depends upon the movement of calcium, sodium and potassium through ion channels in the cell membrane and [[T-tubule]]s.<ref>{{cite journal |author=Dulhunty A |title=Excitation-contraction coupling from the 1950s into the new millennium |journal=Clin Exp Pharmacol Physiol |volume=33 |issue=9 |pages=763–72 |year=2006 |pmid=16922804 |doi=10.1111/j.1440-1681.2006.04441.x}}</ref>
The [[transition metal]]s are usually present as [[trace element]]s in organisms, with [[zinc]] and [[iron]] being most abundant.<ref>{{cite journal |author=Mahan D, Shields R |title=Macro- and micromineral composition of pigs from birth to 145 kilograms of body weight |url=http://jas.fass.org/cgi/reprint/76/2/506 |journal=J Anim Sci |volume=76 |issue=2 |pages=506–12 |year=1998 |pmid=9498359}}</ref><ref name=Husted>{{cite journal |author=Husted S, Mikkelsen B, Jensen J, Nielsen N |title=Elemental fingerprint analysis of barley (Hordeum vulgare) using inductively coupled plasma mass spectrometry, isotope-ratio mass spectrometry, and multivariate statistics |journal=Anal Bioanal Chem |volume=378 |issue=1 |pages=171–82 |year=2004 |pmid=14551660 |doi=10.1007/s00216-003-2219-0}}</ref> These metals are used in some proteins as [[Cofactor (biochemistry)|cofactors]] and are essential for the activity of enzymes such as [[catalase]] and oxygen-carrier proteins such as [[hemoglobin]].<ref>{{cite journal |author=Finney L, O'Halloran T |title=Transition metal speciation in the cell: insights from the chemistry of metal ion receptors |journal=Science |volume=300 |issue=5621 |pages=931–6 |year=2003 |pmid=12738850 |doi=10.1126/science.1085049}}</ref> These cofactors are bound tightly to a specific protein; although enzyme cofactors can be modified during catalysis, cofactors always return to their original state after catalysis has taken place. The metal micronutrients are taken up into organisms by specific transporters and bound to storage proteins such as [[ferritin]] or [[metallothionein]] when not being used.<ref>{{cite journal |author=Cousins R, Liuzzi J, Lichten L |title=Mammalian zinc transport, trafficking, and signals |url=http://www.jbc.org/cgi/content/full/281/34/24085 |journal=J Biol Chem |volume=281 |issue=34 |pages=24085–9 |year=2006 |pmid=16793761 |doi=10.1074/jbc.R600011200}}</ref><ref>{{cite journal |author=Dunn L, Rahmanto Y, Richardson D |title=Iron uptake and metabolism in the new millennium |journal=Trends Cell Biol |volume=17 |issue=2 |pages=93–100 |year=2007 |pmid=17194590 |doi=10.1016/j.tcb.2006.12.003}}</ref>
==Catabolism==
{{further|[[Catabolism]]}}
Catabolism is the set of metabolic processes that break down large molecules. These include breaking down and oxidising food molecules. The purpose of the catabolic reactions is to provide the energy and components needed by anabolic reactions. The exact nature of these catabolic reactions differ from organism to organism, with organic molecules being used as a source of energy in [[organotroph]]s, while [[lithotroph]]s use inorganic substrates and [[phototroph]]s capture [[sunlight]] as [[potential energy#Chemical energy|chemical energy]]. However, all these different forms of metabolism depend on [[redox]] reactions that involve the transfer of electrons from reduced donor molecules such as [[organic molecule]]s, [[water]], [[ammonia]], [[hydrogen sulfide]] or [[Ferrous|ferrous ions]] to acceptor molecules such as [[oxygen]], [[nitrate]] or [[sulfate]].<ref>{{cite journal |author=Nealson K, Conrad P |title=Life: past, present and future |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=10670014 |journal=Philos Trans R Soc Lond B Biol Sci |volume=354 |issue=1392 |pages=1923–39 |year=1999 |pmid=10670014 |doi=10.1098/rstb.1999.0532}}</ref> In animals these reactions involve complex [[organic molecule]]s being broken down to simpler molecules, such as [[carbon dioxide]] and water. In [[photosynthesis|photosynthetic]] organisms such as plants and [[cyanobacteria]], these electron-transfer reactions do not release energy, but are used as a way of storing energy absorbed from sunlight.<ref name=Nelson>{{cite journal |author=Nelson N, Ben-Shem A |title=The complex architecture of oxygenic photosynthesis |journal=Nat Rev Mol Cell Biol |volume=5 |issue=12 |pages=971–82 |year=2004 |pmid=15573135 |doi=10.1038/nrm1525}}</ref>
The most common set of catabolic reactions in animals can be separated into three main stages. In the first, large organic molecules such as [[protein]]s, [[polysaccharide]]s or [[lipid]]s are digested into their smaller components outside cells. Next, these smaller molecules are taken up by cells and converted to yet smaller molecules, usually [[coenzyme A|acetyl coenzyme A]] (CoA), which releases some energy. Finally, the acetyl group on the CoA is oxidised to water and carbon dioxide in the [[citric acid cycle]] and [[electron transport chain]], releasing the energy that is stored by reducing the coenzyme [[nicotinamide adenine dinucleotide]] (NAD<sup>+</sup>) into NADH.
===Digestion===
{{further|[[Digestion]] and [[gastrointestinal tract]]}}
Macromolecules such as starch, cellulose or proteins cannot be rapidly taken up by cells and need to be broken into their smaller units before they can be used in cell metabolism. Several common classes of enzymes digest these polymers. These digestive enzymes include [[protease]]s that digest proteins into amino acids, as well as [[glycoside hydrolase]]s that digest polysaccharides into monosaccharides.
Microbes simply secrete digestive enzymes into their surroundings,<ref>{{cite journal |author=Häse C, Finkelstein R |title=Bacterial extracellular zinc-containing metalloproteases |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=8302217 |journal=Microbiol Rev |volume=57 |issue=4 |pages=823–37 |year=1993 |pmid=8302217}}</ref><ref>{{cite journal |author=Gupta R, Gupta N, Rathi P |title=Bacterial lipases: an overview of production, purification and biochemical properties |journal=Appl Microbiol Biotechnol |volume=64 |issue=6 |pages=763–81 |year=2004 |pmid=14966663 |doi=10.1007/s00253-004-1568-8}}</ref> while animals only secrete these enzymes from specialized cells in their [[gut]]s.<ref>{{cite journal |author=Hoyle T |title=The digestive system: linking theory and practice |journal=Br J Nurs |volume=6 |issue=22 |pages=1285–91 |year=1997 |pmid=9470654}}</ref> The amino acids or sugars released by these extracellular enzymes are then pumped into cells by specific [[active transport]] proteins.<ref>{{cite journal |author=Souba W, Pacitti A |title=How amino acids get into cells: mechanisms, models, menus, and mediators |journal=JPEN J Parenter Enteral Nutr |volume=16 |issue=6 |pages=569–78 |year=1992 |pmid=1494216 |doi=10.1177/0148607192016006569}}</ref><ref>{{cite journal |author=Barrett M, Walmsley A, Gould G |title=Structure and function of facilitative sugar transporters |journal=Curr Opin Cell Biol |volume=11 |issue=4 |pages=496–502 |year=1999 |pmid=10449337 |doi=10.1016/S0955-0674(99)80072-6}}</ref>
[[Image:Catabolism schematic.svg|thumb|left|300px|A simplified outline of the catabolism of [[protein]]s, [[carbohydrate]]s and [[fat]]s.]]
===Energy from organic compounds===
{{further|[[Cellular respiration]], [[Fermentation (biochemistry)|fermentation]], [[carbohydrate catabolism]], [[fat catabolism]] and [[protein catabolism]]}}
Carbohydrate catabolism is the breakdown of carbohydrates into smaller units. Carbohydrates are usually taken into cells once they have been digested into [[monosaccharide]]s.<ref>{{cite journal |author=Bell G, Burant C, Takeda J, Gould G |title=Structure and function of mammalian facilitative sugar transporters |journal=J Biol Chem |volume=268 |issue=26 |pages=19161–4 |year=1993 |pmid=8366068}}</ref> Once inside, the major route of breakdown is [[glycolysis]], where sugars such as [[glucose]] and [[fructose]] are converted into [[pyruvic acid|pyruvate]] and some ATP is generated.<ref name=Bouche>{{cite journal |author=Bouché C, Serdy S, Kahn C, Goldfine A |title=The cellular fate of glucose and its relevance in type 2 diabetes |url=http://edrv.endojournals.org/cgi/content/full/25/5/807 |journal=Endocr Rev |volume=25 |issue=5 |pages=807–30 |year=2004 |pmid=15466941 |doi=10.1210/er.2003-0026}}</ref> Pyruvate is an intermediate in several metabolic pathways, but the majority is converted to [[acetyl-CoA]] and fed into the [[citric acid cycle]]. Although some more ATP is generated in the citric acid cycle, the most important product is NADH, which is made from NAD<sup>+</sup> as the acetyl-CoA is oxidized. This oxidation releases [[carbon dioxide]] as a waste product. In anaerobic conditions, glycolysis produces [[lactic acid|lactate]], through the enzyme [[lactate dehydrogenase]] re-oxidizing NADH to NAD+ for re-use in glycolysis. An alternative route for glucose breakdown is the [[pentose phosphate pathway]], which reduces the coenzyme [[NADPH]] and produces [[pentose]] sugars such as [[ribose]], the sugar component of [[nucleic acid]]s.
Fats are catabolised by [[hydrolysis]] to free fatty acids and glycerol. The glycerol enters glycolysis and the fatty acids are broken down by [[beta oxidation]] to release acetyl-CoA, which then is fed into the citric acid cycle. Fatty acids release more energy upon oxidation than carbohydrates because carbohydrates contain more oxygen in their structures.
[[Amino acid]]s are either used to synthesize proteins and other biomolecules, or oxidized to [[urea]] and carbon dioxide as a source of energy.<ref>{{cite journal |author=Sakami W, Harrington H |title=Amino acid metabolism |journal=Annu Rev Biochem |volume=32 |issue= |pages=355–98 |year=1963 |pmid=14144484 |doi=10.1146/annurev.bi.32.070163.002035}}</ref> The oxidation pathway starts with the removal of the amino group by a [[transaminase]]. The amino group is fed into the [[urea cycle]], leaving a deaminated carbon skeleton in the form of a [[keto acid]]. Several of these keto acids are intermediates in the citric acid cycle, for example the deamination of [[glutamate]] forms α-[[Ketoglutaric acid|ketoglutarate]].<ref>{{cite journal |author=Brosnan J |title=Glutamate, at the interface between amino acid and carbohydrate metabolism |url=http://jn.nutrition.org/cgi/content/full/130/4/988S |journal=J Nutr |volume=130 |issue=4S Suppl |pages=988S–90S |year=2000 |pmid=10736367}}</ref> The [[glucogenic amino acid]]s can also be converted into glucose, through [[gluconeogenesis]] (discussed below).<ref>{{cite journal |author=Young V, Ajami A |title=Glutamine: the emperor or his clothes? |url=http://jn.nutrition.org/cgi/content/full/131/9/2449S |journal=J Nutr |volume=131 |issue=9 Suppl |pages=2449S–59S; discussion 2486S–7S |year=2001 |pmid=11533293}}</ref>
==Energy transformations==
===Oxidative phosphorylation===
[[Image:ATPsynthase labelled.png|right|thumb|280px|Structure of [[ATP synthase]], the proton channel and rotating stalk are shown in blue and the synthase subunits in red.]]
{{further|[[Oxidative phosphorylation]], [[chemiosmosis]] and [[mitochondrion]]}}
In oxidative phosphorylation, the electrons removed from food molecules in pathways such as the citric acid cycle are transferred to oxygen and the energy released used to make ATP. This is done in [[eukaryote]]s by a series of proteins in the membranes of mitochondria called the [[electron transport chain]]. In [[prokaryote]]s, these proteins are found in the cell's [[bacterial cell structure|inner membrane]].<ref>{{cite journal |author=Hosler J, Ferguson-Miller S, Mills D |title=Energy transduction: proton transfer through the respiratory complexes |journal=Annu Rev Biochem |volume=75 |issue= |pages=165–87 |year=2006 |pmid=16756489 |doi=10.1146/annurev.biochem.75.062003.101730}}</ref> These proteins use the energy released from passing electrons from [[reducing agent|reduced]] molecules like NADH onto [[oxygen]] to pump [[proton]]s across a membrane.<ref>{{cite journal |author=Schultz B, Chan S |title=Structures and proton-pumping strategies of mitochondrial respiratory enzymes |journal=Annu Rev Biophys Biomol Struct |volume=30 |issue= |pages=23–65 |year=2001 |pmid=11340051 |doi=10.1146/annurev.biophys.30.1.23}}</ref>
Pumping protons out of the mitochondria creates a proton [[diffusion|concentration difference]] across the membrane and generates an [[electrochemical gradient]].<ref>{{cite journal |author=Capaldi R, Aggeler R |title=Mechanism of the F(1)F(0)-type ATP synthase, a biological rotary motor |journal=Trends Biochem Sci |volume=27 |issue=3 |pages=154–60 |year=2002 |pmid=11893513 |doi=10.1016/S0968-0004(01)02051-5}}</ref> This force drives protons back into the mitochondrion through the base of an enzyme called [[ATP synthase]]. The flow of protons makes the stalk subunit rotate, causing the [[active site]] of the synthase domain to change shape and phosphorylate [[adenosine diphosphate]] - turning it into ATP.<ref name=Dimroth/>
===Energy from inorganic compounds===
{{further|[[Microbial metabolism]] and [[nitrogen cycle]]}}
[[Chemolithotroph]]y is a type of metabolism found in [[prokaryote]]s where energy is obtained from the oxidation of [[inorganic compounds]]. These organisms can use [[hydrogen]],<ref>{{cite journal |author=Friedrich B, Schwartz E |title=Molecular biology of hydrogen utilization in aerobic chemolithotrophs |journal=Annu Rev Microbiol |volume=47 |issue= |pages=351–83 |year=1993 |pmid=8257102 |doi=10.1146/annurev.mi.47.100193.002031}}</ref> reduced [[sulfur]] compounds (such as [[sulfide]], [[hydrogen sulfide]] and [[thiosulfate]]),<ref name="Physiology1"/> [[Iron(II) oxide|ferrous iron (FeII)]]<ref>{{cite journal |author=Weber K, Achenbach L, Coates J |title=Microorganisms pumping iron: anaerobic microbial iron oxidation and reduction |journal=Nat Rev Microbiol |volume=4 |issue=10 |pages=752–64 |year=2006 |pmid=16980937 |doi=10.1038/nrmicro1490}}</ref> or [[ammonia]]<ref>{{cite journal |author=Jetten M, Strous M, van de Pas-Schoonen K, Schalk J, van Dongen U, van de Graaf A, Logemann S, Muyzer G, van Loosdrecht M, Kuenen J |title=The anaerobic oxidation of ammonium |journal=FEMS Microbiol Rev |volume=22 |issue=5 |pages=421–37 |year=1998 |pmid=9990725 |doi=10.1111/j.1574-6976.1998.tb00379.x}}</ref> as sources of reducing power and they gain energy from the oxidation of these compounds with electron acceptors such as [[oxygen]] or [[nitrite]].<ref>{{cite journal |author=Simon J |title=Enzymology and bioenergetics of respiratory nitrite ammonification |journal=FEMS Microbiol Rev |volume=26 |issue=3 |pages=285–309 |year=2002 |pmid=12165429 |doi=10.1111/j.1574-6976.2002.tb00616.x}}</ref> These microbial processes are important in global [[biogeochemical cycle]]s such as [[acetogenesis]], [[nitrification]] and [[denitrification]] and are critical for [[fertility (soil)|soil fertility]].<ref>{{cite journal |author=Conrad R |title=Soil microorganisms as controllers of atmospheric trace gases (H2, CO, CH4, OCS, N2O, and NO) |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=8987358 |journal=Microbiol Rev |volume=60 |issue=4 |pages=609–40 |year=1996 |pmid=8987358}}</ref><ref>{{cite journal |author=Barea J, Pozo M, Azcón R, Azcón-Aguilar C |title=Microbial co-operation in the rhizosphere |url=http://jxb.oxfordjournals.org/cgi/content/full/56/417/1761 |journal=J Exp Bot |volume=56 |issue=417 |pages=1761–78 |year=2005 |pmid=15911555 |doi=10.1093/jxb/eri197}}</ref>
===Energy from light===
{{further|[[Phototroph]], [[photophosphorylation]], [[chloroplast]]}}
The energy in sunlight is captured by [[plants]], [[cyanobacteria]], [[purple bacteria]], [[green sulfur bacteria]] and some [[protist]]s. This process is often coupled to the conversion of carbon dioxide into organic compounds, as part of photosynthesis, which is discussed below. The energy capture and carbon fixation systems can however operate separately in prokaryotes, as purple bacteria and green sulfur bacteria can use sunlight as a source of energy, while switching between carbon fixation and the fermentation of organic compounds.<ref>{{cite journal |author=van der Meer M, Schouten S, Bateson M, Nübel U, Wieland A, Kühl M, de Leeuw J, Sinninghe Damsté J, Ward D |title=Diel variations in carbon metabolism by green nonsulfur-like bacteria in alkaline siliceous hot spring microbial mats from Yellowstone National Park |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16000812 |journal=Appl Environ Microbiol |volume=71 |issue=7 |pages=3978–86 |year=2005 |pmid=16000812 |doi=10.1128/AEM.71.7.3978-3986.2005}}</ref><ref>{{cite journal |author=Tichi M, Tabita F |title=Interactive control of Rhodobacter capsulatus redox-balancing systems during phototrophic metabolism |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=11591679 |journal=J Bacteriol |volume=183 |issue=21 |pages=6344–54 |year=2001 |pmid=11591679 |doi=10.1128/JB.183.21.6344-6354.2001}}</ref>
The capture of solar energy is a process that is similar in principle to oxidative phosphorylation, as it involves energy being stored as a proton concentration gradient and this proton motive force then driving ATP synthesis.<ref name=Dimroth/> The electrons needed to drive this electron transport chain come from light-gathering proteins called [[photosynthetic reaction centre]]s. These structures are classed into two types depending on the type of [[photosynthetic pigment]] present, with most photosynthetic bacteria only having one type of reaction center, while plants and cyanobacteria have two.<ref>{{cite journal |author=Allen J, Williams J |title=Photosynthetic reaction centers |journal=FEBS Lett |volume=438 |issue=1–2 |pages=5–9 |year=1998 |pmid=9821949 |doi=10.1016/S0014-5793(98)01245-9}}</ref>
In plants, [[photosystem|photosystem II]] uses light energy to remove electrons from water, releasing oxygen as a waste product. The electrons then flow to the [[cytochrome b6f complex]], which uses their energy to pump protons across the [[thylakoid]] membrane in the [[chloroplast]].<ref>{{cite journal |author=Nelson N, Ben-Shem A |title=The complex architecture of oxygenic photosynthesis |journal=Nat Rev Mol Cell Biol |volume=5 |issue=12 |pages=971–82 |year=2004 |pmid=15573135 |doi=10.1038/nrm1525}}</ref> These protons move back through the membrane as they drive the ATP synthase, as before. The electrons then flow through [[photosystem|photosystem I]] and can then either be used to reduce the coenzyme NADP<sup>+</sup>, for use in the [[Calvin cycle]] which is discussed below, or recycled for further ATP generation.<ref>{{cite journal |author=Munekage Y, Hashimoto M, Miyake C, Tomizawa K, Endo T, Tasaka M, Shikanai T |title=Cyclic electron flow around photosystem I is essential for photosynthesis |journal=Nature |volume=429 |issue=6991 |pages=579–82 |year=2004 |pmid=15175756 |doi=10.1038/nature02598}}</ref>
==Anabolism==
{{further|[[Anabolism]]}}
'''Anabolism''' is the set of constructive metabolic processes where the energy released by catabolism is used to synthesize complex molecules. In general, the complex molecules that make up cellular structures are constructed step-by-step from small and simple precursors. Anabolism involves three basic stages. Firstly, the production of precursors such as [[amino acid]]s, [[monosaccharide]]s, [[Terpenoid|isoprenoids]] and [[nucleotide]]s, secondly, their activation into reactive forms using energy from ATP, and thirdly, the assembly of these precursors into complex molecules such as [[protein]]s, [[polysaccharide]]s, [[lipid]]s and [[nucleic acid]]s.
Organisms differ in how many of the molecules in their cells they can construct for themselves. [[Autotroph]]s such as plants can construct the complex organic molecules in cells such as polysaccharides and proteins from simple molecules like [[carbon dioxide]] and water. [[Heterotroph]]s, on the other hand, require a source of more complex substances, such as monosaccharides and amino acids, to produce these complex molecules. Organisms can be further classified by ultimate source of their energy: photoautotrophs and photoheterotrophs obtain energy from light, whereas chemoautotrophs and chemoheterotrophs obtain energy from inorganic oxidation reactions.
===Carbon fixation===
{{further|[[Photosynthesis]], [[carbon fixation]] and [[chemosynthesis]]}}
[[Image:Chloroplasten.jpg|frame|Plant cells (bounded by purple walls) filled with chloroplasts (green), which are the site of photosynthesis.]]
Photosynthesis is the synthesis of carbohydrates from sunlight, [[carbon dioxide]] (CO<sub>2</sub>) and water, with oxygen produced as a waste product. This process uses the ATP and NADPH produced by the [[photosynthetic reaction centre]]s, as described above, to convert CO<sub>2</sub> into [[glycerate 3-phosphate]], which can then be converted into glucose. This carbon-fixation reaction is carried out by the enzyme [[RuBisCO]] as part of the [[Calvin cycle|Calvin – Benson cycle]].<ref>{{cite journal |author=Miziorko H, Lorimer G |title=Ribulose-1,5-bisphosphate carboxylase-oxygenase |journal=Annu Rev Biochem |volume=52 |issue= |pages=507–35 |year=1983 |pmid=6351728 |doi=10.1146/annurev.bi.52.070183.002451}}</ref> Three types of photosynthesis occur in plants, [[C3 carbon fixation]], [[C4 carbon fixation]] and [[Crassulacean acid metabolism|CAM photosynthesis]]. These differ by the route that carbon dioxide takes to the Calvin cycle, with C3 plants fixing CO<sub>2</sub> directly, while C4 and CAM photosynthesis incorporate the CO<sub>2</sub> into other compounds first, as adaptations to deal with intense sunlight and dry conditions.<ref>{{cite journal |author=Dodd A, Borland A, Haslam R, Griffiths H, Maxwell K |title=Crassulacean acid metabolism: plastic, fantastic |url=http://jxb.oxfordjournals.org/cgi/content/full/53/369/569 |journal=J Exp Bot |volume=53 |issue=369 |pages=569–80 |year=2002 |pmid=11886877 |doi=10.1093/jexbot/53.369.569}}</ref>
In photosynthetic [[prokaryote]]s the mechanisms of carbon fixation are more diverse. Here, carbon dioxide can be fixed by the Calvin – Benson cycle, a [[Reverse Krebs cycle|reversed citric acid]] cycle,<ref>{{cite journal |author=Hügler M, Wirsen C, Fuchs G, Taylor C, Sievert S |title=Evidence for autotrophic CO2 fixation via the reductive tricarboxylic acid cycle by members of the epsilon subdivision of proteobacteria |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15838028 |journal=J Bacteriol |volume=187 |issue=9 |pages=3020–7 |year=2005 |pmid=15838028 |doi=10.1128/JB.187.9.3020-3027.2005}}</ref> or the carboxylation of acetyl-CoA.<ref>{{cite journal |author=Strauss G, Fuchs G |title=Enzymes of a novel autotrophic CO2 fixation pathway in the phototrophic bacterium Chloroflexus aurantiacus, the 3-hydroxypropionate cycle |journal=Eur J Biochem |volume=215 |issue=3 |pages=633–43 |year=1993 |pmid=8354269 |doi=10.1111/j.1432-1033.1993.tb18074.x}}</ref><ref>{{cite journal |author=Wood H |title=Life with CO or CO2 and H2 as a source of carbon and energy |url=http://www.fasebj.org/cgi/reprint/5/2/156 |journal=FASEB J |volume=5 |issue=2 |pages=156–63 |year=1991 |pmid=1900793}}</ref> Prokaryotic [[Chemotroph|chemoautotrophs]] also fix CO<sub>2</sub> through the Calvin – Benson cycle, but use energy from inorganic compounds to drive the reaction.<ref>{{cite journal |author=Shively J, van Keulen G, Meijer W |title=Something from almost nothing: carbon dioxide fixation in chemoautotrophs |journal=Annu Rev Microbiol |volume=52 |issue= |pages=191–230 |year=1998 |pmid=9891798 |doi=10.1146/annurev.micro.52.1.191}}</ref>
===Carbohydrates and glycans===
{{further|[[Gluconeogenesis]], [[glyoxylate cycle]], [[glycogenesis]] and [[glycosylation]]}}
In carbohydrate anabolism, simple organic acids can be converted into [[monosaccharide]]s such as [[glucose]] and then used to assemble [[polysaccharide]]s such as [[starch]]. The generation of [[glucose]] from compounds like [[pyruvate]], [[lactic acid|lactate]], [[glycerol]], [[glycerate 3-phosphate]] and [[amino acids]] is called [[gluconeogenesis]]. Gluconeogenesis converts pyruvate to [[glucose-6-phosphate]] through a series of intermediates, many of which are shared with [[glycolysis]].<ref name=Bouche/> However, this pathway is not simply [[glycolysis]] run in reverse, as several steps are catalyzed by non-glycolytic enzymes. This is important as it allows the formation and breakdown of glucose to be regulated separately and prevents both pathways from running simultaneously in a [[futile cycle]].<ref>{{cite journal |author=Boiteux A, Hess B |title=Design of glycolysis |journal=Philos Trans R Soc Lond B Biol Sci |volume=293 |issue=1063 |pages=5–22 |year=1981 |pmid=6115423 |doi=10.1098/rstb.1981.0056}}</ref><ref>{{cite journal |author=Pilkis S, el-Maghrabi M, Claus T |title=Fructose-2,6-bisphosphate in control of hepatic gluconeogenesis. From metabolites to molecular genetics |journal=Diabetes Care |volume=13 |issue=6 |pages=582–99 |year=1990 |pmid=2162755 |doi=10.2337/diacare.13.6.582}}</ref>
Although fat is a common way of storing energy, in [[vertebrate]]s such as [[human]]s the [[fatty acid]]s in these stores cannot be converted to glucose through [[gluconeogenesis]] as these organisms cannot convert acetyl-CoA into [[pyruvate]]; plants do, but animals do not, have the necessary enzymatic machinery.<ref name=Ensign>{{cite journal |author=Ensign S |title=Revisiting the glyoxylate cycle: alternate pathways for microbial acetate assimilation |journal=Mol Microbiol |volume=61 |issue=2 |pages=274–6 |year=2006 |pmid=16856935 |doi=10.1111/j.1365-2958.2006.05247.x}}</ref> As a result, after long-term starvation, vertebrates need to produce [[ketone bodies]] from fatty acids to replace glucose in tissues such as the brain that cannot metabolize fatty acids.<ref>{{cite journal |author=Finn P, Dice J |title=Proteolytic and lipolytic responses to starvation |journal=Nutrition |volume=22 |issue=7–8 |pages=830–44 |year=2006 |pmid=16815497 |doi=10.1016/j.nut.2006.04.008}}</ref> In other organisms such as plants and bacteria, this metabolic problem is solved using the [[glyoxylate cycle]], which bypasses the [[decarboxylation]] step in the citric acid cycle and allows the transformation of acetyl-CoA to [[oxaloacetate]], where it can be used for the production of glucose.<ref name=Kornberg>{{cite journal |author=Kornberg H, Krebs H |title=Synthesis of cell constituents from C2-units by a modified tricarboxylic acid cycle |journal=Nature |volume=179 |issue=4568 |pages=988–91 |year=1957 |pmid=13430766 |doi=10.1038/179988a0}}</ref><ref name=Ensign/>
Polysaccharides and [[glycans]] are made by the sequential addition of monosaccharides by [[glycosyltransferase]] from a reactive sugar-phosphate donor such as [[uridine diphosphate glucose]] (UDP-glucose) to an acceptor [[hydroxyl]] group on the growing polysaccharide. As any of the [[hydroxyl]] groups on the ring of the substrate can be acceptors, the polysaccharides produced can have straight or branched structures.<ref>{{cite journal |author=Rademacher T, Parekh R, Dwek R |title=Glycobiology |journal=Annu Rev Biochem |volume=57 |issue= |pages=785–838 |year=1988 |pmid=3052290 |doi=10.1146/annurev.bi.57.070188.004033}}</ref> The polysaccharides produced can have structural or metabolic functions themselves, or be transferred to lipids and proteins by enzymes called [[oligosaccharyltransferase]]s.<ref>{{cite journal |author=Opdenakker G, Rudd P, Ponting C, Dwek R |title=Concepts and principles of glycobiology |url=http://www.fasebj.org/cgi/reprint/7/14/1330 |journal=FASEB J |volume=7 |issue=14 |pages=1330–7 |year=1993 |pmid=8224606}}</ref><ref>{{cite journal |author=McConville M, Menon A |title=Recent developments in the cell biology and biochemistry of glycosylphosphatidylinositol lipids (review) |journal=Mol Membr Biol |volume=17 |issue=1 |pages=1–16 |year=2000 |pmid=10824734 |doi=10.1080/096876800294443}}</ref>
===Fatty acids, isoprenoids and steroids===
{{further|[[Fatty acid synthesis]], [[steroid metabolism]]}}
[[Image:Sterol synthesis.svg|thumb|right|350px|Simplified version of the [[steroid synthesis]] pathway with the intermediates [[isopentenyl pyrophosphate]] (IPP), [[dimethylallyl pyrophosphate]] (DMAPP), [[geranyl pyrophosphate]] (GPP) and [[squalene]] shown. Some intermediates are omitted for clarity.]]
Fatty acids are made by [[fatty acid synthase]]s that polymerize and then reduce acetyl-CoA units. The acyl chains in the fatty acids are extended by a cycle of reactions that add the actyl group, reduce it to an alcohol, [[dehydration reaction|dehydrate]] it to an [[alkene]] group and then reduce it again to an [[alkane]] group. The enzymes of fatty acid biosynthesis are divided into two groups, in animals and fungi all these fatty acid synthase reactions are carried out by a single multifunctional type I protein,<ref>{{cite journal |author=Chirala S, Wakil S |title=Structure and function of animal fatty acid synthase |journal=Lipids |volume=39 |issue=11 |pages=1045–53 |year=2004 |pmid=15726818 |doi=10.1007/s11745-004-1329-9}}</ref> while in plant [[plastid]]s and bacteria separate type II enzymes perform each step in the pathway.<ref>{{cite journal |author=White S, Zheng J, Zhang Y |title=The structural biology of type II fatty acid biosynthesis |journal=Annu Rev Biochem |volume=74 |issue= |pages=791–831 |year=2005 |pmid=15952903 |doi=10.1146/annurev.biochem.74.082803.133524}}</ref><ref>{{cite journal |author=Ohlrogge J, Jaworski J |title=Regulation of fatty acid synthesis |journal=Annu Rev Plant Physiol Plant Mol Biol |volume=48 |issue= |pages=109–136 |year=1997 |pmid=15012259 |doi=10.1146/annurev.arplant.48.1.109}}</ref>
[[Terpene]]s and [[terpenoid|isoprenoids]] are a large class of lipids that include the [[carotenoid]]s and form the largest class of plant [[natural product]]s.<ref>{{cite journal |author=Dubey V, Bhalla R, Luthra R |title=An overview of the non-mevalonate pathway for terpenoid biosynthesis in plants |url=http://www.ias.ac.in/jbiosci/sep2003/637.pdf |journal=J Biosci |volume=28 |issue=5 |pages=637–46 |year=2003 |pmid=14517367 |doi=10.1007/BF02703339}}</ref> These compounds are made by the assembly and modification of [[isoprene]] units donated from the reactive precursors [[isopentenyl pyrophosphate]] and [[dimethylallyl pyrophosphate]].<ref name=Kuzuyama>{{cite journal |author=Kuzuyama T, Seto H |title=Diversity of the biosynthesis of the isoprene units |journal=Nat Prod Rep |volume=20 |issue=2 |pages=171–83 |year=2003 |pmid=12735695 |doi=10.1039/b109860h}}</ref> These precursors can be made in different ways. In animals and archaea, the [[mevalonate pathway]] produces these compounds from acetyl-CoA,<ref>{{cite journal |author=Grochowski L, Xu H, White R |title=Methanocaldococcus jannaschii uses a modified mevalonate pathway for biosynthesis of isopentenyl diphosphate |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16621811 |journal=J Bacteriol |volume=188 |issue=9 |pages=3192–8 |year=2006 |pmid=16621811 |doi=10.1128/JB.188.9.3192-3198.2006}}</ref> while in plants and bacteria the [[non-mevalonate pathway]] uses pyruvate and [[glyceraldehyde 3-phosphate]] as substrates.<ref>{{cite journal |author=Lichtenthaler H |title=The 1-Ddeoxy-D-xylulose-5-phosphate pathway of isoprenoid biosynthesis in plants |journal=Annu Rev Plant Physiol Plant Mol Biol |volume=50 |issue= |pages=47–65 |year=1999 |pmid=15012203 |doi=10.1146/annurev.arplant.50.1.47}}</ref><ref name=Kuzuyama/> One important reaction that uses these activated isoprene donors is [[steroid biosynthesis]]. Here, the isoprene units are joined together to make [[squalene]] and then folded up and formed into a set of rings to make [[lanosterol]].<ref name=Schroepfer>{{cite journal |author=Schroepfer G |title=Sterol biosynthesis |journal=Annu Rev Biochem |volume=50 |issue= |pages=585–621 |year=1981 |pmid=7023367 |doi=10.1146/annurev.bi.50.070181.003101}}</ref> Lanosterol can then be converted into other steroids such as [[cholesterol]] and [[ergosterol]].<ref>{{cite journal |author=Lees N, Skaggs B, Kirsch D, Bard M |title=Cloning of the late genes in the ergosterol biosynthetic pathway of Saccharomyces cerevisiae—a review |journal=Lipids |volume=30 |issue=3 |pages=221–6 |year=1995 |pmid=7791529 |doi=10.1007/BF02537824}}</ref><ref name=Schroepfer/>
===Proteins===
{{further|[[Protein biosynthesis]], [[amino acid synthesis]]}}
Organisms vary in their ability to synthesize the 20 common amino acids. Most bacteria and plants can synthesize all twenty, but mammals can synthesize only the ten nonessential amino acids.<ref name=Nelson/> Thus, the [[essential amino acid]]s must be obtained from food. All amino acids are synthesized from intermediates in glycolysis, the citric acid cycle, or the pentose phosphate pathway. Nitrogen is provided by [[glutamate]] and [[glutamine]]. Amino acid synthesis depends on the formation of the appropriate alpha-keto acid, which is then [[Transaminase|transaminated]] to form an amino acid.<ref>{{cite book | last = Guyton | first = Arthur C. | coauthors = John E. Hall | title = Textbook of Medical Physiology | publisher = Elsevier | date = 2006 | location = Philadelphia | pages = 855-6 | isbn = 0-7216-0240-1}}</ref>
Amino acids are made into proteins by being joined together in a chain by [[peptide bond]]s. Each different protein has a unique sequence of amino acid residues: this is its [[primary structure]]. Just as the letters of the alphabet can be combined to form an almost endless variety of words, amino acids can be linked in varying sequences to form a huge variety of proteins. Proteins are made from amino acids that have been activated by attachment to a [[transfer RNA]] molecule through an [[ester]] bond. This aminoacyl-tRNA precursor is produced in an [[Adenosine triphosphate|ATP]]-dependent reaction carried out by an [[aminoacyl tRNA synthetase]].<ref>{{cite journal | author = Ibba M, Söll D | title = The renaissance of aminoacyl-tRNA synthesis | url=http://www.molcells.org/home/journal/include/downloadPdf.asp?articleuid={A158E3B4-2423-4806-9A30-4B93CDA76DA0} | journal = EMBO Rep | volume = 2 | issue = 5 | pages = 382-7 | year = 2001 | pmid = 11375928}}</ref> This aminoacyl-tRNA is then a substrate for the [[ribosome]], which joins the amino acid onto the elongating protein chain, using the sequence information in a [[messenger RNA]].<ref>{{cite journal | author = Lengyel P, Söll D | title = Mechanism of protein biosynthesis | url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=378322&blobtype=pdf | journal = Bacteriol Rev | volume = 33 | issue = 2 | pages = 264–301 | year = 1969 | pmid = 4896351}}</ref>
===Nucleotide synthesis and salvage===
{{further|[[Nucleotide salvage]], [[pyrimidine biosynthesis]], and [[Purine#Metabolism|purine metabolism]]}}
Nucleotides are made from amino acids, carbon dioxide and [[formic acid]] in pathways that require large amounts of metabolic energy.<ref name=Rudolph>{{cite journal |author=Rudolph F |title=The biochemistry and physiology of nucleotides |journal=J Nutr |volume=124 |issue=1 Suppl |pages=124S–127S |year=1994 |pmid=8283301}} {{cite journal |author=Zrenner R, Stitt M, Sonnewald U, Boldt R |title=Pyrimidine and purine biosynthesis and degradation in plants |journal=Annu Rev Plant Biol |volume=57 |issue= |pages=805–36 |year=2006 |pmid=16669783 |doi=10.1146/annurev.arplant.57.032905.105421}}</ref> Consequently, most organisms have efficient systems to salvage preformed nucleotides.<ref name=Rudolph/><ref>{{cite journal |author=Stasolla C, Katahira R, Thorpe T, Ashihara H |title=Purine and pyrimidine nucleotide metabolism in higher plants |journal=J Plant Physiol |volume=160 |issue=11 |pages=1271–95 |year=2003 |pmid=14658380 |doi=10.1078/0176-1617-01169}}</ref> [[Purine]]s are synthesized as [[nucleoside]]s (bases attached to [[ribose]]). Both [[adenine]] and [[guanine]] are made from the precursor nucleoside [[inosine]] monophosphate, which is synthesized using atoms from the amino acids [[glycine]], [[glutamine]], and [[aspartic acid]], as well as [[formate]] transferred from the [[coenzyme]] [[folic acid|tetrahydrofolate]]. [[Pyrimidine]]s, on the other hand, are synthesized from the base [[Pyrimidinecarboxylic acid|orotate]], which is formed from glutamine and aspartate.<ref>{{cite journal |author=Smith J |title=Enzymes of nucleotide synthesis |journal=Curr Opin Struct Biol |volume=5 |issue=6 |pages=752–7 |year=1995 |pmid=8749362 |doi=10.1016/0959-440X(95)80007-7}}</ref>
==Xenobiotics and redox metabolism==
{{further|[[Xenobiotic metabolism]], [[drug metabolism]] and [[antioxidant]]s}}
All organisms are constantly exposed to compounds that they cannot use as foods and would be harmful if they accumulated in cells, as they have no metabolic function. These potentially damaging compounds are called [[xenobiotic]]s.<ref>{{cite journal |author=Testa B, Krämer S |title=The biochemistry of drug metabolism—an introduction: part 1. Principles and overview |journal=Chem Biodivers |volume=3 |issue=10 |pages=1053–101 |year=2006 |pmid=17193224 |doi=10.1002/cbdv.200690111}}</ref> Xenobiotics such as [[drug|synthetic drugs]], [[poison|natural poisons]] and [[antibiotic]]s are detoxified by a set of xenobiotic-metabolizing enzymes. In humans, these include [[cytochrome P450|cytochrome P450 oxidases]],<ref>{{cite journal |author=Danielson P |title=The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans |journal=Curr Drug Metab |volume=3 |issue=6 |pages=561–97 |year=2002 |pmid=12369887 |doi=10.2174/1389200023337054}}</ref> [[Glucuronosyltransferase|UDP-glucuronosyltransferases]],<ref>{{cite journal |author=King C, Rios G, Green M, Tephly T |title=UDP-glucuronosyltransferases |journal=Curr Drug Metab |volume=1 |issue=2 |pages=143–61 |year=2000 |pmid=11465080 |doi=10.2174/1389200003339171}}</ref> and [[glutathione S-transferase|glutathione ''S''-transferases]].<ref>{{cite journal |author=Sheehan D, Meade G, Foley V, Dowd C |title=Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=11695986 |journal=Biochem J |volume=360 |issue=Pt 1 |pages=1–16 |year=2001 |pmid=11695986 |doi=10.1042/0264-6021:3600001}}</ref> This system of enzymes acts in three stages to firstly oxidize the xenobiotic (phase I) and then conjugate water-soluble groups onto the molecule (phase II). The modified water-soluble xenobiotic can then be pumped out of cells and in multicellular organisms may be further metabolized before being excreted (phase III). In [[ecology]], these reactions are particularly important in microbial [[biodegradation]] of pollutants and the [[bioremediation]] of contaminated land and oil spills.<ref>{{cite journal |author=Galvão T, Mohn W, de Lorenzo V |title=Exploring the microbial biodegradation and biotransformation gene pool |journal=Trends Biotechnol |volume=23 |issue=10 |pages=497–506 |year=2005 |pmid=16125262 |doi=10.1016/j.tibtech.2005.08.002}}</ref> Many of these microbial reactions are shared with multicellular organisms, but due to the incredible diversity of types of microbes these organisms are able to deal with a far wider range of xenobiotics than multicellular organisms, and can degrade even [[persistent organic pollutant]]s such as [[organochloride]] compounds.<ref>{{cite journal |author=Janssen D, Dinkla I, Poelarends G, Terpstra P |title=Bacterial degradation of xenobiotic compounds: evolution and distribution of novel enzyme activities |journal=Environ Microbiol |volume=7 |issue=12 |pages=1868–82 |year=2005 |pmid=16309386 |doi=10.1111/j.1462-2920.2005.00966.x}}</ref>
A related problem for [[aerobic organism]]s is [[oxidative stress]].<ref name=Davies>{{cite journal |author=Davies K |title=Oxidative stress: the paradox of aerobic life |journal=Biochem Soc Symp |volume=61 |issue= |pages=1–31 |year=1995 |pmid=8660387}}</ref> Here, processes including [[oxidative phosphorylation]] and the formation of [[disulfide bond]]s during [[protein folding]] produce [[reactive oxygen species]] such as [[hydrogen peroxide]].<ref>{{cite journal |author=Tu B, Weissman J |title=Oxidative protein folding in eukaryotes: mechanisms and consequences |url=http://www.jcb.org/cgi/content/full/164/3/341 |journal=J Cell Biol |volume=164 |issue=3 |pages=341–6 |year=2004 |pmid=14757749 |doi=10.1083/jcb.200311055}}</ref> These damaging oxidants are removed by [[antioxidant]] metabolites such as [[glutathione]] and enzymes such as [[catalase]]s and [[peroxidase]]s.<ref name=Sies>{{cite journal |author=Sies H |title=Oxidative stress: oxidants and antioxidants |url=http://ep.physoc.org/cgi/reprint/82/2/291.pdf |journal=Exp Physiol |volume=82 |issue=2 |pages=291–5 |year=1997 |pmid=9129943}}</ref><ref name=Vertuani>{{cite journal |author=Vertuani S, Angusti A, Manfredini S |title=The antioxidants and pro-antioxidants network: an overview |journal=Curr Pharm Des |volume=10 |issue=14 |pages=1677–94 |year=2004 |pmid=15134565 |doi=10.2174/1381612043384655}}</ref>
==Thermodynamics of living organisms==
{{further|[[Biological thermodynamics]]}}
Living organisms must obey the [[laws of thermodynamics]], which describe the transfer of [[heat]] and [[work (thermodynamics)|work]]. The [[second law of thermodynamics]] states that in any [[closed system]], the amount of [[entropy]] (disorder) will tend to increase. Although living organisms' amazing complexity appears to contradict this law, life is possible as all organisms are [[open system (systems theory)|open systems]] that exchange matter and energy with their surroundings. Thus living systems are not in [[Thermodynamic equilibrium|equilibrium]], but instead are [[dissipative system]]s that maintain their state of high complexity by causing a larger increase in the entropy of their environments.<ref>{{cite journal |author=von Stockar U, Liu J |title=Does microbial life always feed on negative entropy? Thermodynamic analysis of microbial growth |journal=Biochim Biophys Acta |volume=1412 |issue=3 |pages=191–211 |year=1999 |pmid=10482783 |doi=10.1016/S0005-2728(99)00065-1}}</ref> The metabolism of a cell achieves this by coupling the [[spontaneous process]]es of catabolism to the non-spontaneous processes of anabolism. In [[non-equilibrium thermodynamics|thermodynamic]] terms, metabolism maintains order by creating disorder.<ref>{{cite journal |author=Demirel Y, Sandler S |title=Thermodynamics and bioenergetics |journal=Biophys Chem |volume=97 |issue=2–3 |pages=87–111 |year=2002 |pmid=12050002 |doi=10.1016/S0301-4622(02)00069-8}}</ref>
==Regulation and control==
{{further|[[Metabolic pathway]], [[metabolic control analysis]], [[hormone]], [[regulatory enzymes]], and [[cell signaling]]}}
As the environments of most organisms are constantly changing, the reactions of metabolism must be finely [[Control theory|regulated]] to maintain a constant set of conditions within cells, a condition called [[homeostasis]].<ref>{{cite journal |author=Albert R |title=Scale-free networks in cell biology |url=http://jcs.biologists.org/cgi/content/full/118/21/4947 |journal=J Cell Sci |volume=118 |issue=Pt 21 |pages=4947–57 |year=2005 |pmid=16254242 |doi=10.1242/jcs.02714}}</ref><ref>{{cite journal |author=Brand M |title=Regulation analysis of energy metabolism |url=http://jeb.biologists.org/cgi/reprint/200/2/193 |journal=J Exp Biol |volume=200 |issue=Pt 2 |pages=193–202 |year=1997 |pmid=9050227}}</ref> Metabolic regulation also allows organisms to respond to signals and interact actively with their environments.<ref>{{cite journal |author=Soyer O, Salathé M, Bonhoeffer S |title=Signal transduction networks: topology, response and biochemical processes |journal=J Theor Biol |volume=238 |issue=2 |pages=416–25 |year=2006 |pmid=16045939}}</ref> Two closely-linked concepts are important for understanding how metabolic pathways are controlled. Firstly, the ''regulation'' of an enzyme in a pathway is how its activity is increased and decreased in response to signals. Secondly, the ''control'' exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway (the [[flux]] through the pathway).<ref name=Salter>{{cite journal |author=Salter M, Knowles R, Pogson C |title=Metabolic control |journal=Essays Biochem |volume=28 |issue= |pages=1–12 |year=1994 |pmid=7925313}}</ref> For example, an enzyme may show large changes in activity (''i.e.'' it is highly regulated) but if these changes have little effect on the flux of a metabolic pathway, then this enzyme is not involved in the control of the pathway.<ref>{{cite journal |author=Westerhoff H, Groen A, Wanders R |title=Modern theories of metabolic control and their applications (review) |journal=Biosci Rep |volume=4 |issue=1 |pages=1–22 |year=1984 |pmid=6365197 |doi=10.1007/BF01120819}}</ref>
[[Image:Insulin glucose metabolism ZP.svg|thumb|right|300px|'''Effect of insulin on glucose uptake and metabolism.''' Insulin binds to its receptor (1) which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the [[plasma membrane]] and influx of glucose (3), [[glycogen]] synthesis (4), [[glycolysis]] (5) and [[fatty acid]] synthesis (6).]]
There are multiple levels of metabolic regulation. In intrinsic regulation, the metabolic pathway self-regulates to respond to changes in the levels of substrates or products; for example, a decrease in the amount of product can increase the [[flux]] through the pathway to compensate.<ref name=Salter/> This type of regulation often involves [[allosteric regulation]] of the activities of multiple enzymes in the pathway.<ref>{{cite journal |author=Fell D, Thomas S |title=Physiological control of metabolic flux: the requirement for multisite modulation |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=7575476 |journal=Biochem J |volume=311 (Pt 1) |issue= |pages=35–9 |year=1995 |pmid=7575476}}</ref> Extrinsic control involves a cell in a multicellular organism changing its metabolism in response to signals from other cells. These signals are usually in the form of soluble messengers such as [[hormone]]s and [[growth factor]]s and are detected by specific [[receptor (biochemistry)|receptors]] on the cell surface.<ref>{{cite journal |author=Hendrickson W |title=Transduction of biochemical signals across cell membranes |journal=Q Rev Biophys |volume=38 |issue=4 |pages=321–30 |year=2005 |pmid=16600054 |doi=10.1017/S0033583506004136}}</ref> These signals are then transmitted inside the cell by [[second messenger system]]s that often involved the [[phosphorylation]] of proteins.<ref>{{cite journal |author=Cohen P |title=The regulation of protein function by multisite phosphorylation—a 25 year update |journal=Trends Biochem Sci |volume=25 |issue=12 |pages=596–601 |year=2000 |pmid=11116185 |doi=10.1016/S0968-0004(00)01712-6}}</ref>
A very well understood example of extrinsic control is the regulation of glucose metabolism by the hormone [[insulin]].<ref>{{cite journal |author=Lienhard G, Slot J, James D, Mueckler M |title=How cells absorb glucose |journal=Sci Am |volume=266 |issue=1 |pages=86–91 |year=1992 |pmid=1734513}}</ref> Insulin is produced in response to rises in [[blood sugar|blood glucose levels]]. Binding of the hormone to [[insulin receptor]]s on cells then activates a cascade of [[protein kinase]]s that cause the cells to take up glucose and convert it into storage molecules such as fatty acids and [[glycogen]].<ref>{{cite journal |author=Roach P |title=Glycogen and its metabolism |journal=Curr Mol Med |volume=2 |issue=2 |pages=101–20 |year=2002 |pmid=11949930 |doi=10.2174/1566524024605761}}</ref> The metabolism of glycogen is controlled by activity of [[phosphorylase]], the enzyme that breaks down glycogen, and [[glycogen synthase]], the enzyme that makes it. These enzymes are regulated in a reciprocal fashion, with phosphorylation inhibiting glycogen synthase, but activating phosphorylase. Insulin causes glycogen synthesis by activating [[phosphatase|protein phosphatases]] and producing a decrease in the phosphorylation of these enzymes.<ref>{{cite journal |author=Newgard C, Brady M, O'Doherty R, Saltiel A |title=Organizing glucose disposal: emerging roles of the glycogen targeting subunits of protein phosphatase-1 |url=http://diabetes.diabetesjournals.org/cgi/reprint/49/12/1967.pdf |journal=Diabetes |volume=49 |issue=12 |pages=1967–77 |year=2000 |pmid=11117996 |doi=10.2337/diabetes.49.12.1967}}</ref>
==Evolution==
{{further|[[Molecular evolution]] and [[phylogenetics]]}}
[[Image:Tree of life 1500px coloured.png|thumb|left|400px|[[Phylogenetic tree|Evolutionary tree]] showing the common ancestry of organisms from all three [[Domain (biology)|domains]] of life. [[Bacteria]] are colored blue, [[eukaryote]]s red, and [[archaea]] green. Relative positions of some of the [[phylum|phyla]] included are shown around the tree.]]
The central pathways of metabolism described above, such as glycolysis and the citric acid cycle, are present in all [[Three-domain system|three domains]] of living things and were present in the [[last universal ancestor]].<ref>{{cite journal |author=Romano A, Conway T |title=Evolution of carbohydrate metabolic pathways |journal=Res Microbiol |volume=147 |issue=6–7 |pages=448–55 |year=1996 |pmid=9084754 |doi=10.1016/0923-2508(96)83998-2}}</ref><ref name=SmithE/> This universal ancestral cell was [[prokaryote|prokaryotic]] and probably a [[methanogen]] that had extensive amino acid, nucleotide, carbohydrate and lipid metabolism.<ref>{{cite journal |author=Koch A |title=How did bacteria come to be? |journal=Adv Microb Physiol |volume=40 |pages=353–99 |year=1998 |pmid=9889982 |doi=10.1016/S0065-2911(08)60135-6}}</ref><ref>{{cite journal |author=Ouzounis C, Kyrpides N |title=The emergence of major cellular processes in evolution |journal=FEBS Lett |volume=390 |issue=2 |pages=119–23 |year=1996 |pmid=8706840 |doi=10.1016/0014-5793(96)00631-X}}</ref> The retention of these ancient pathways during later [[evolution]] may be the result of these reactions being an optimal solution to their particular metabolic problems, with pathways such as glycolysis and the citric acid cycle producing their end products highly efficiently and in a minimal number of steps.<ref name=Ebenhoh/><ref name=Cascante/>
The first pathways of enzyme-based metabolism may have been parts of [[purine]] nucleotide metabolism, with previous metabolic pathways being part of the ancient [[RNA world hypothesis|RNA world]].<ref>{{cite journal |author=Caetano-Anolles G, Kim HS, Mittenthal JE |title=The origin of modern metabolic networks inferred from phylogenomic analysis of protein architecture |journal=Proc Natl Acad Sci USA |volume=104 |issue=22 |pages=9358–63 |year=2007 |pmid=17517598 |doi=10.1073/pnas.0701214104}}</ref>
Many models have been proposed to describe the mechanisms by which novel metabolic pathways evolve. These include the sequential addition of novel enzymes to a short ancestral pathway, the duplication and then divergence of entire pathways as well as the recruitment of pre-existing enzymes and their assembly into a novel reaction pathway.<ref>{{cite journal |author=Schmidt S, Sunyaev S, Bork P, Dandekar T |title=Metabolites: a helping hand for pathway evolution? |journal=Trends Biochem Sci |volume=28 |issue=6 |pages=336–41 |year=2003 |pmid=12826406 |doi=10.1016/S0968-0004(03)00114-2}}</ref> The relative importance of these mechanisms is unclear, but genomic studies have shown that enzymes in a pathway are likely to have a shared ancestry, suggesting that many pathways have evolved in a step-by-step fashion with novel functions being created from pre-existing steps in the pathway.<ref>{{cite journal |author=Light S, Kraulis P |title=Network analysis of metabolic enzyme evolution in Escherichia coli |journal=BMC Bioinformatics |volume=5 |issue= |pages=15 |year=2004 |pmid=15113413 |doi=10.1186/1471-2105-5-15}} {{cite journal |author=Alves R, Chaleil R, Sternberg M |title=Evolution of enzymes in metabolism: a network perspective |journal=J Mol Biol |volume=320 |issue=4 |pages=751–70 |year=2002 |pmid=12095253 |doi=10.1016/S0022-2836(02)00546-6}}</ref> An alternative model comes from studies that trace the evolution of proteins' structures in metabolic networks, this has suggested that enzymes are pervasively recruited, borrowing enzymes to perform similar functions in different metabolic pathways (evident in the [[MANET database]])<ref>{{cite journal |author=Kim HS, Mittenthal JE, Caetano-Anolles G|title=MANET: tracing evolution of protein architecture in metabolic networks |journal=BMC Bioinformatics|volume=19 |issue=7 |pages=351 |year=2006 |pmid=16854231|doi=10.1186/1471-2105-7-351}}</ref> These recruitment processes result in an evolutionary enzymatic mosaic.<ref>{{cite journal |author=Teichmann SA, Rison SC, Thornton JM, Riley M, Gough J, Chothia C|title=Small-molecule metabolsim: an enzyme mosaic |journal=Trends Biotechnol|volume=19 |issue=12 |pages=482–6 |year=2001 |pmid=11711174|doi=10.1016/S0167-7799(01)01813-3}}</ref> A third possibility is that some parts of metabolism might exist as "modules" that can be reused in different pathways and perform similar functions on different molecules.<ref>{{cite journal |author=Spirin V, Gelfand M, Mironov A, Mirny L |title=A metabolic network in the evolutionary context: multiscale structure and modularity |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16731630 |journal=Proc Natl Acad Sci U S A |volume=103 |issue=23 |pages=8774–9 |year=2006 |pmid=16731630 |doi=10.1073/pnas.0510258103}}</ref>
As well as the evolution of new metabolic pathways, evolution can also cause the loss of metabolic functions. For example, in some [[parasite]]s metabolic processes that are not essential for survival are lost and preformed amino acids, nucleotides and carbohydrates may instead be scavenged from the [[host (biology)|host]].<ref>{{cite journal |author=Lawrence J |title=Common themes in the genome strategies of pathogens |journal=Curr Opin Genet Dev |volume=15 |issue=6 |pages=584–8 |year=2005 |pmid=16188434 |doi=10.1016/j.gde.2005.09.007}} {{cite journal |author=Wernegreen J |title=For better or worse: genomic consequences of intracellular mutualism and parasitism |journal=Curr Opin Genet Dev |volume=15 |issue=6 |pages=572–83 |year=2005 |pmid=16230003 |doi=10.1016/j.gde.2005.09.013}}</ref> Similar reduced metabolic capabilities are seen in [[endosymbiont|endosymbiotic]] organisms.<ref>{{cite journal |author=Pál C, Papp B, Lercher M, Csermely P, Oliver S, Hurst L |title=Chance and necessity in the evolution of minimal metabolic networks |journal=Nature |volume=440 |issue=7084 |pages=667–70 |year=2006 |pmid=16572170 |doi=10.1038/nature04568}}</ref>
==Investigation and manipulation==
{{further|[[Protein methods]], [[proteomics]], [[metabolomics]] and [[metabolic network modelling]]}}
[[Image:A thaliana metabolic network.png|thumb|300px|right|[[Metabolic network]] of the ''[[Arabidopsis thaliana]]'' [[citric acid cycle]]. [[Enzyme]]s and [[metabolomics|metabolites]] are shown as red squares and the interactions between them as black lines.]]
Classically, metabolism is studied by a [[reductionism|reductionist]] approach that focuses on a single metabolic pathway. Particularly valuable is the use of [[radioactive tracer]]s at the whole-organism, tissue and cellular levels, which define the paths from precursors to final products by identifying radioactively-labelled intermediates and products.<ref>{{cite journal |author=Rennie M |title=An introduction to the use of tracers in nutrition and metabolism |journal=Proc Nutr Soc |volume=58 |issue=4 |pages=935–44 |year=1999 |pmid=10817161 |doi=10.1017/S002966519900124X}}</ref> The enzymes that catalyze these chemical reactions can then be [[protein purification|purified]] and their [[enzyme kinetics|kinetics]] and responses to [[enzyme inhibitor|inhibitors]] investigated. A parallel approach is to identify the small molecules in a cell or tissue; the complete set of these molecules is called the [[metabolome]]. Overall, these studies give a good view of the structure and function of simple metabolic pathways, but are inadequate when applied to more complex systems such as the metabolism of a complete cell.<ref>{{cite journal |author=Phair R |title=Development of kinetic models in the nonlinear world of molecular cell biology |journal=Metabolism |volume=46 |issue=12 |pages=1489–95 |year=1997 |pmid=9439549 |doi=10.1016/S0026-0495(97)90154-2}}</ref>
An idea of the complexity of the [[metabolic network]]s in cells that contain thousands of different enzymes is given by the figure showing the interactions between just 43 proteins and 40 metabolites to the right: the sequences of genomes provide lists containing anything up to 45,000 genes.<ref>{{cite journal |author=Sterck L, Rombauts S, Vandepoele K, Rouzé P, Van de Peer Y |title=How many genes are there in plants (... and why are they there)? |journal=Curr Opin Plant Biol |volume=10 |issue=2 |pages=199–203 |year=2007 |pmid=17289424 |doi=10.1016/j.pbi.2007.01.004}}</ref> However, it is now possible to use this genomic data to reconstruct complete networks of biochemical reactions and produce more [[Holism|holistic]] mathematical models that may explain and predict their behavior.<ref>{{cite journal |author=Borodina I, Nielsen J |title=From genomes to in silico cells via metabolic networks |journal=Curr Opin Biotechnol |volume=16 |issue=3 |pages=350–5 |year=2005 |pmid=15961036 |doi=10.1016/j.copbio.2005.04.008}}</ref> These models are especially powerful when used to integrate the pathway and metabolite data obtained through classical methods with data on [[gene expression]] from [[proteomics|proteomic]] and [[DNA microarray]] studies.<ref>{{cite journal |author=Gianchandani E, Brautigan D, Papin J |title=Systems analyses characterize integrated functions of biochemical networks |journal=Trends Biochem Sci |volume=31 |issue=5 |pages=284–91 |year=2006 |pmid=16616498 |doi=10.1016/j.tibs.2006.03.007}}</ref> Using these techniques, a model of human metabolism has now been produced, which will guide future drug discovery and biochemical research.<ref>{{cite journal |author=Duarte NC, Becker SA, Jamshidi N, ''et al'' |title=Global reconstruction of the human metabolic network based on genomic and bibliomic data |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=104 |issue=6 |pages=1777–82 |year=2007 |month=February |pmid=17267599 |doi=10.1073/pnas.0610772104 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=17267599}}</ref>
A major technological application of this information is [[metabolic engineering]]. Here, organisms such as [[yeast]], [[plant]]s or [[bacteria]] are genetically-modified to make them more useful in [[biotechnology]] and aid the production of [[drug]]s such as [[antibiotic]]s or industrial chemicals such as [[1,3-Propanediol|1,3-propanediol]] and [[shikimic acid]].<ref>{{cite journal |author=Thykaer J, Nielsen J |title=Metabolic engineering of beta-lactam production |journal=Metab Eng |volume=5 |issue=1 |pages=56–69 |year=2003 |pmid=12749845 |doi=10.1016/S1096-7176(03)00003-X}}
{{cite journal |author=González-Pajuelo M, Meynial-Salles I, Mendes F, Andrade J, Vasconcelos I, Soucaille P |title=Metabolic engineering of Clostridium acetobutylicum for the industrial production of 1,3-propanediol from glycerol |journal=Metab Eng |volume=7 |issue=5–6 |pages=329–36 |year=2005 |pmid=16095939 |doi=10.1016/j.ymben.2005.06.001}}
{{cite journal |author=Krämer M, Bongaerts J, Bovenberg R, Kremer S, Müller U, Orf S, Wubbolts M, Raeven L |title=Metabolic engineering for microbial production of shikimic acid |journal=Metab Eng |volume=5 |issue=4 |pages=277–83 |year=2003 |pmid=14642355 |doi=10.1016/j.ymben.2003.09.001}}</ref> These genetic modifications usually aim to reduce the amount of energy used to produce the product, increase yields and reduce the production of wastes.<ref>{{cite journal |author=Koffas M, Roberge C, Lee K, Stephanopoulos G |title=Metabolic engineering |journal=Annu Rev Biomed Eng |volume=1 |issue= |pages=535–57 |year=1999 |pmid=11701499 |doi=10.1146/annurev.bioeng.1.1.535}}</ref>
==History==
{{further|[[History of biochemistry]] and [[history of molecular biology]]}}
[[Image:SantoriosMeal.jpg|thumb|right|150px|[[Santorio Santorio]] in his steelyard balance, from ''Ars de statica medecina'', first published 1614.]]
The term ''metabolism'' is derived from the [[Greek language|Greek]] Μεταβολισμός – "Metabolismos" for "change", or "overthrow".<ref>{{cite web | title=Metabolism |publisher=The Online Etymology Dictionary | url=http://www.etymonline.com/index.php?term=metabolism |accessdate=2007-02-20}}</ref> The history of the scientific study of metabolism spans several centuries and has moved from examining whole animals in early studies, to examining individual metabolic reactions in modern biochemistry. The concept of metabolism dates back to [[Ibn al-Nafis]] (1213-1288), who stated that "the body and its parts are in a continuous state of dissolution and [[Nutrition|nourishment]], so they are inevitably undergoing permanent change."<ref name=Roubi>Dr. Abu Shadi Al-Roubi (1982), "Ibn Al-Nafis as a philosopher", ''Symposium on Ibn al Nafis'', Second International Conference on Islamic Medicine: Islamic Medical Organization, Kuwait ([[cf.]] [http://www.islamset.com/isc/nafis/drroubi.html Ibnul-Nafees As a Philosopher], ''Encyclopedia of Islamic World'').</ref> The first controlled [[experiment]]s in human metabolism were published by [[Santorio Santorio]] in 1614 in his book ''Ars de statica medecina''.<ref>{{cite journal |author=Eknoyan G |title=Santorio Sanctorius (1561–1636) - founding father of metabolic balance studies |journal=Am J Nephrol |volume=19 |issue=2 |pages=226–33 |year=1999 |pmid=10213823 |doi=10.1159/000013455}}</ref> He described how he weighed himself before and after eating, sleeping, working, sex, fasting, drinking, and excreting. He found that most of the food he took in was lost through what he called "insensible perspiration".
In these early studies, the mechanisms of these metabolic processes had not been identified and a [[vitalism|vital force]] was thought to animate living tissue.<ref>Williams, H. S. (1904) [http://etext.lib.virginia.edu/toc/modeng/public/Wil4Sci.html A History of Science: in Five Volumes. Volume IV: Modern Development of the Chemical and Biological Sciences] Harper and Brothers (New York) Retrieved on 2007-03-26</ref> In the 19th century, when studying the [[fermentation (food)|fermentation]] of sugar to [[alcohol]] by [[yeast]], [[Louis Pasteur]] concluded that fermentation was catalyzed by substances within the yeast cells he called "ferments". He wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells."<ref>{{cite journal |author=Dubos J.|year=1951 |title= Louis Pasteur: Free Lance of Science, Gollancz. Quoted in Manchester K. L. (1995) Louis Pasteur (1822 – 1895)—chance and the prepared mind|journal= Trends Biotechnol| volume=13 |issue=12 |pages=511–515 |pmid= 8595136 |doi=10.1016/S0167-7799(00)89014-9}}</ref> This discovery, along with the publication by [[Friedrich Woehler|Friedrich Wöhler]] in 1828 of the chemical synthesis of [[urea]],<ref>{{cite journal |author=Kinne-Saffran E, Kinne R |title=Vitalism and synthesis of urea. From Friedrich Wöhler to Hans A. Krebs |journal=Am J Nephrol |volume=19 |issue=2 |pages=290–4 |year=1999 |pmid=10213830 |doi=10.1159/000013463}}</ref> proved that the organic compounds and chemical reactions found in cells were no different in principle than any other part of chemistry.
It was the discovery of [[enzyme]]s at the beginning of the 20th century by [[Eduard Buchner]] that separated the study of the chemical reactions of metabolism from the biological study of cells, and marked the beginnings of [[biochemistry]].<ref>Eduard Buchner's 1907 [http://nobelprize.org/nobel_prizes/chemistry/laureates/1907/buchner-lecture.html Nobel lecture] at http://nobelprize.org Accessed 2007-03-20</ref> The mass of biochemical knowledge grew rapidly throughout the early 20th century. One of the most prolific of these modern biochemists was [[Hans Adolf Krebs|Hans Krebs]] who made huge contributions to the study of metabolism.<ref>{{cite journal |author=Kornberg H |title=Krebs and his trinity of cycles |journal=Nat Rev Mol Cell Biol |volume=1 |issue=3 |pages=225–8 |year=2000 |pmid=11252898 |doi=10.1038/35043073}}</ref> He discovered the urea cycle and later, working with [[Hans Kornberg]], the citric acid cycle and the glyoxylate cycle.<ref>Krebs H A, Henseleit K (1932) "Untersuchungen über die Harnstoffbildung im tierkorper." ''Z. Physiol. Chem.'' 210, 33 – 66. {{cite journal |author=Krebs H, Johnson W |title=Metabolism of ketonic acids in animal tissues |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16746382 |journal=Biochem J |volume=31 |issue=4 |pages=645–60 |year=1937 |pmid=16746382}}</ref><ref name=Kornberg/> Modern biochemical research has been greatly aided by the development of new techniques such as [[chromatography]], [[X-ray diffraction]], [[protein nuclear magnetic resonance spectroscopy|NMR spectroscopy]], [[radioisotopic labelling]], [[electron microscope|electron microscopy]] and [[molecular dynamics]] simulations. These techniques have allowed the discovery and detailed analysis of the many molecules and metabolic pathways in cells.
==See also==
{{wikibooks}}
{{Wikiversity|Topic:Biochemistry}}
{{portalpar|Metabolism}}
* [[Anthropogenic metabolism]]
* [[Basal metabolic rate]]
* [[Calorimetry]]
* [[Inborn error of metabolism]]
* [[Individual growth]]
* [[Iron-sulfur world theory]], a "metabolism first" theory of the [[origin of life]].
* [[Respirometry]]
* [[Thermic effect of food]]
* [[Water metabolism]]
==References==
{{reflist|2}}
==Further reading==
'''Introductory'''
* {{aut|Rose, S.}} and {{aut|Mileusnic, R.}}, ''The Chemistry of Life.'' (Penguin Press Science, 1999), ISBN 0-14027-273-9
* {{aut|Schneider, E. D.}} and {{aut|Sagan, D.}}, ''Into the Cool: Energy Flow, Thermodynamics, and Life.'' (University Of Chicago Press, 2005), ISBN 0-22673-936-8
* {{aut|Lane, N.}}, ''Oxygen: The Molecule that Made the World.'' (Oxford University Press, USA, 2004), ISBN 0-19860-783-0
'''Advanced'''
* {{aut|Price, N.}} and {{aut|Stevens, L.}}, ''Fundamentals of Enzymology: Cell and Molecular Biology of Catalytic Proteins.'' (Oxford University Press, 1999), ISBN 0-19850-229-X
* {{aut|Berg, J.}} {{aut|Tymoczko, J.}} and {{aut|Stryer, L.}}, ''Biochemistry.'' (W. H. Freeman and Company, 2002), ISBN 0-71674-955-6
* {{aut|Cox, M.}} and {{aut|Nelson, D. L.}}, ''Lehninger Principles of Biochemistry.'' (Palgrave Macmillan, 2004), ISBN 0-71674-339-6
* {{aut|Brock, T. D.}} {{aut|Madigan, M. T.}} {{aut|Martinko, J.}} and {{aut|Parker J.}}, ''Brock's Biology of Microorganisms.'' (Benjamin Cummings, 2002), ISBN 0-13066-271-2
* {{aut|Da Silva, J.J.R.F.}} and {{aut|Williams, R. J. P.}}, ''The Biological Chemistry of the Elements: The Inorganic Chemistry of Life.'' (Clarendon Press, 1991), ISBN 0-19855-598-9
* {{aut|Nicholls, D. G.}} and {{aut|Ferguson, S. J.}}, ''Bioenergetics.'' (Academic Press Inc., 2002), ISBN 0-12518-121-3
==<font color=#FFFFFF>External links</font>==
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<div style="background: #ccddcc; text-align: center; border: 1px solid #667766" class="NavHead">'''External links'''
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'''General information'''
* [http://www.biochemweb.org/metabolism.shtml Metabolism, Cellular Respiration and Photosynthesis] The Virtual Library of Biochemistry and Cell Biology at biochemweb.org
* [http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb1/MB1index.html The Biochemistry of Metabolism]
* [http://www.stthomas.edu/biol/ecophys/homepage/homepage.html Advanced Animal Metabolism Calculators/ Interactive Learning Tools]
* [http://www.slic2.wsu.edu:82/hurlbert/micro101/pages/Chap7.html Microbial metabolism] Simple overview. School level.
* [http://www.gwu.edu/~mpb/ Metabolic Pathways of Biochemistry] Graphical representations of major metabolic pathways.
* [http://www.chemsoc.org/networks/LearnNet/cfb/contents.htm Chemistry for biologists] Introduction to the chemistry of metabolism. School level.
* [http://www.sparknotes.com/testprep/books/sat2/biology/ Sparknotes SAT biochemistry] Overview of biochemistry. School level.
* [http://www.sciencegateway.org/resources/biologytext/index.html MIT Biology Hypertextbook] Undergraduate-level guide to molecular biology.
* [http://www.britannica.com/eb/article-9109831/metabolism Article on metabolism at The Encyclopœdia Britannica] Concentrates on human metabolism (Free access).
'''Glossaries and dictionaries'''
* [http://biology.clc.uc.edu/scripts/glossary.pl Glossary of biochemical terms]
* [http://www.portlandpress.com/pp/books/online/glick/default.htm Glossary of biochemical terms]
* [http://www.biology-online.org/dictionary.asp On-line biology dictionary]
'''Human metabolism'''
* [http://library.med.utah.edu/NetBiochem/titles.htm Topics in Medical Biochemistry] Guide to human metabolic pathways. School level.
* [http://www.indstate.edu/thcme/mwking/ THE Medical Biochemistry Page] Comprehensive resource on human metabolism.
'''Databases'''
* [http://BioCyc.org/ The BioCyc Collection of Pathway/Genome Databases]
* [http://www.expasy.org/cgi-bin/show_thumbnails.pl Flow Chart of Metabolic Pathways] at [[ExPASy]]
* [http://www.genome.ad.jp/kegg/ The KEGG PATHWAY Database]
* [http://www.sigmaaldrich.com/img/assets/4202/MetabolicPathways_6_17_04_.pdf IUBMB-Nicholson Metabolic Pathways Chart]
* [http://www.reactome.org/ Reactome - a knowledgebase of biological processes]
'''Metabolic pathways'''
* [http://www2.ufp.pt/~pedros/bq/integration.htm Interactive Flow Chart of the Major Metabolic Pathways]
* [http://biotech.icmb.utexas.edu/glycolysis/glycohome.html Guide to Glycolysis] School level.
* {{wayback|helios.bto.ed.ac.uk/bto/microbes/nitrogen.htm|The Nitrogen cycle and Nitrogen fixation}}
* [http://www.oxygraphics.co.uk/cds.htm Downloadable guide to photosynthesis] School level.
* [http://photoscience.la.asu.edu/photosyn/education/learn.html What is Photosynthesis?] Collection of photosynthesis articles and resources.
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{{Biochemical families}}
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{{Glycolipid/sphingolipid metabolism enzymes}}
{{Eicosanoid metabolism enzymes}}
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