Homocysteine 105223 225893046 2008-07-15T22:04:14Z 41.208.227.122 /* Bone weakness and breaks */ {{NatOrganicBox | image=[[Image:Homocysteine.png]] | name=(2S)-2-amino-4-sulfanyl-butanoic acid | abbreviations=Hcy | C=4 | H=9 | N=1 | O=2 | S=1 | charge= | mass=135.186 | melt_point= | density= | isoelectric_point= | dissoc_constant= | CAS= 454-29-5 | EINECS= | PubChem=91552 | SMILES=C(CS)C(C(=O)O)N }} '''Homocysteine''' is a [[chemical compound]] with the formula HSCH<sub>2</sub>CH<sub>2</sub>CH(NH<sub>2</sub>)CO<sub>2</sub>H. It is a [[homologous series|homologue]] of the naturally-occurring [[amino acid]] [[cysteine]], differing in that its [[side-chain]] contains an additional [[methylene]] (-CH<sub>2</sub>-) group before the [[thiol]] (-SH) group. Alternatively, homocysteine can be derived from [[methionine]] by removing the latter's terminal C<sup>ε</sup> methyl group. ==Organic chemical properties== The "extra" (relative to cysteine) one carbon methylene group allows this molecule to form a five-membered ring, homocysteine thio[[lactone]]. The facility of this reaction precludes the formation of stable [[peptide bond]]s. In other words, a protein containing homocysteine would tend to cleave itself. The 4 carbon homocysteine is (only) made from the 5 carbon [[methionine]], an essential [[amino acid]], in a multi step reaction via [[S-adenosyl methionine]]. Homocysteine can be recycled back into [[methionine]] or it can be permanently converted to [[cysteine]] via the [[transsulfuration pathway]]. Homocysteine is not obtained from the diet; it is a normal temporary and chemically reactive reaction product that can be measured in blood.<ref name="AnRvNutrition1999-Selhub">{{cite journal | author=Selhub, J. | title=Homocysteine metabolism. | journal=Annual Review of Nutrition | year=1999 | volume=19 | pages=217&ndash;246 | pmid=10448523 | doi=10.1146/annurev.nutr.19.1.217}}</ref> Due to its high reactivity to proteins, it is almost always bound to proteins, 'thiolating' (and thus degrading) most notably the [[lysine]] and [[cysteine]] components thereof. This can permanently affect protein function. In blood, it is found bound to [[albumin]] and to [[hemoglobin]]. It affects enzymes with cysteine-containing active sites; for example, it inhibits [[lysyl oxidase]] a key enzyme in the production of [[collagen]] and [[elastin]], two main structural proteins in artery, bone and skin. ==Elevated homocysteine== As a consequence of the biochemical reactions in which homocysteine is involved, deficiencies of the vitamins [[folic acid]] (B<sub><small>9</small></sub>), [[Vitamin B6|pyridoxine]] (B<sub><small>6</small></sub>), or [[cyanocobalamin|B<sub><small>12</small></sub>]] ([[cyanocobalamin]]) can lead to high homocysteine levels.<!-- --><ref name="AmJClinNutrition1994-Miller">{{cite journal | author=Miller JW, Nadeau MR, Smith D and Selhub J | title=Vitamin B-6 deficiency vs folate deficiency: comparison of responses to methionine loading in rats | journal=American Journal of Clinical Nutrition | year=1994 | volume=59 | pages= 1033&ndash;1039 | pmid=8172087}}</ref> Supplementation with pyridoxine, folic acid, B<sub><small>12</small></sub> or [[trimethylglycine]] (betaine) reduces the concentration of homocysteine in the bloodstream.<!-- --><ref name="ExpertOpPharm2001-Coen">{{cite journal | author=Coen DA Stehouwer, Coen van Guldener | title=Homocysteine-lowering treatment: an overview | journal=Expert Opinion on Pharmacotherapy | year=2001 | volume=2 | issue=9 | pages= 1449&ndash;1460 | pmid=11585023 | doi=10.1517/14656566.2.9.1449}}</ref> <!-- --><ref name="NYT2006-Crichton">Legal note: Metabolite Laboratories is defending a patent as of March 2006 that may cover the mere mention or consideration of the relationship of vitamin B12 and homocysteine levels. See {{cite news | first=Michael | last=Crichton | url= http://www.nytimes.com/2006/03/19/opinion/19crichton.html?ei=5088&en=9addb806498d2739&ex=1300424400 | title=This Essay Breaks the Law | work= The New York Times | publisher= The New York Times Company | date=March 19, 2006 | accessdate=2006-03-20}}</ref> Increased levels of homocysteine are linked to high concentrations of [[endothelial]] [[asymmetric dimethylarginine]]. Elevations of homocysteine also occur in the rare [[genetics|hereditary]] disease [[homocystinuria]] and in the [[MTHFR|methylene-tetrahydrofolate-reductase]] [[polymorphism]] genetic traits. The latter is quite common (about 10% of the world population) and it is linked to an increased incidence of [[thrombosis]] and [[cardiovascular disease]] and that occurs more often in people with above minimal levels of homocysteine (about 6 μmol/L). Common levels in Western populations are 10 to 12 and levels of 20 μmol/L are found in populations with low B-vitamin intakes (New Delhi) or in the older elderly (Rotterdam, Framingham). Women have 10-15% less homocysteine during their reproductive decades than men which may help explain the fact they suffer [[myocardial infarction]] (heart attacks) on average 10 to 15 years later than men. ==Cardiovascular risks== A high level of [[blood]] [[blood plasma|serum]] homocysteine is a powerful risk factor for cardiovascular disease. Unfortunately, one study which attempted to decrease the risk by lowering homocysteine was not fruitful.<!-- --><ref name="BBC2005-NewsBvit">{{cite news | url=http://news.bbc.co.uk/1/hi/health/4218186.stm | title= B vitamins do not protect hearts | work=BBC News | publisher=BBC | date=September 6, 2005 | accessdate=2006-03-20}}</ref> This study was conducted on nearly 5000 Norwegian heart attack survivors who already had severe, late-stage heart disease. No study has yet been conducted in a preventive capacity on subjects who are in a relatively good state of health. Studies reported in 2006 have shown that giving vitamins [folic acid, B6 and B12] to reduce homocysteine levels may not quickly offer benefit, however a significant 25% reduction in stroke was found in the HOPE-2 study <ref name="NEJM2006a">{{cite journal | author= | title=Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease | journal=N Engl J Med | year=2006 | pages= | volume= | pmid=16531613 [http://content.nejm.org/cgi/reprint/NEJMoa060900v1.pdf Full text PDF]}}</ref> even in patients mostly with existing serious arterial decline although the overall death rate was not significantly changed by the intervention in the trial. Clearly, reducing homocysteine does not quickly repair existing structural damage of the artery architecture. However, the science is strongly supporting the biochemistry that homocysteine degrades and inhibits the formation of the three main structural components of the artery, [[collagen]], [[elastin]] and the [[proteoglycans]]. Homocysteine permanently degrades cysteine [disulfide bridges] and lysine amino acid residues in proteins, gradually affecting function and structure. Simply put, homocysteine is a 'corrosive' of long-living [collagen, elastin] or life-long proteins [fibrillin]. These long-term effects are difficult to establish in clinical trials focusing on groups with existing artery decline. The main role of reducing homocysteine is likely in 'prevention' but with a slow but probable role in 'cure'. <!-- --><ref name="NEJM2006a"/><!-- --><ref name="JAmCollCardiol2006-Zoungas">{{cite journal | author=Zoungas S, McGrath BP, Branley P, Kerr PG, Muske C, Wolfe R, Atkins RC, Nicholls K, Fraenkel M, Hutchison BG, Walker R, McNeil JJ | title=Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial | journal=J Am Coll Cardiol | year=2006 | pages=1108–16 | volume=47 | issue=6 | pmid=16545638 | doi=10.1016/j.jacc.2005.10.064}}</ref><!-- --><ref name="NEJM2006-Bonna">{{cite journal | author=Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Arnesen E, Rasmussen K | title=Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction | journal=N Engl J Med | year=2006 | pages=1578| volume= 354| pmid=16531614 [http://content.nejm.org/cgi/reprint/NEJMoa055227v1.pdf Full text PDF] | doi=10.1056/NEJMoa055227}}</ref> Hypotheses have been offered to address the failure of homocysteine-lowering therapies to reduce cardiovascular event frequency<ref name="NEJM2006-Loscalzo">{{cite journal | author=Loscalzo J | title=Homocysteine Trials — Clear Outcomes for Complex Reasons | journal=N Engl J Med | year=2006 | pages=1629–1632 | volume=354 | issue=15 | pmid=17224870 | doi=10.1056/NEJMe068060}}</ref>. One suggestion is that folic acid may directly cause an increased build-up of arterial plaque, independent of its homocysteine-lowering effects. Alternatively, folic acid and vitamin B12 may cause an overall change in gene methlyation levels in vascular cells, which may also promote plaque growth. Finally, altering methlyation activity in cells might increases methylation of l-arginine to asymmetric dimethylarginine which can increase the risk of vascular disease. Thus alternative homocysteine-lowering therapies may yet be developed which show greater effects on development and progression of cardiovascular disease. ==Bone weakness and breaks== Elevated levels of homocysteine have been linked to increased [[Fracture (bone)|fractures]] in elderly persons. Elevated levels may be due to renal or liver disease, deficiency of folic acid, vitamin B6 or vitamin B12. The high level of homocysteine will auto-oxidise and react with reactive oxyten intermediates and damage endothelial cells and has a higher risk to form a thrombus. <!-- --><ref name="NEJM2004-McLean">{{cite journal | author=McLean RR ''et al''| title=Homocysteine as a predictive factor for hip fracture in older persons. | journal=New England Journal of Medicine | year=2004 | volume=350 | pages= 2042&ndash;2049 | pmid=15141042 | doi=10.1056/NEJMoa032739}} [http://content.nejm.org/cgi/content/full/350/20/2042 Free text after free registration]</ref><!-- --><ref name="NEJM2004-vanMeurs">{{cite journal | author=van Meurs JB ''et al'' | title=Homocysteine levels and the risk of osteoporotic fracture. | journal=New England Journal of Medicine | year=2004 | volume=350 | pages= 2033&ndash;2041 | pmid=15141041 | doi=10.1056/NEJMoa032546}} [http://content.nejm.org/cgi/content/full/350/20/2033 Free text after free registration]</ref> Homocysteine does not affect bone density. Instead, it appears that homocysteine affects [[collagen]] by interfering with the cross-linking between the collagen fibers and the tissues they reinforce. While the HOPE-2 trial [6] showed a reduction in stroke incidence, in those with stroke there is a high rate of hip fractures in the affected side. A trial with 2 homocysteine lowering vitamins (folate and B<sub><small>12</small></sub>) in people with prior stroke, there was an 80% reduction in fractures, mainly hip, after 2 years. Interestingly, also here, bone density (and the number of falls) were identical in the vitamin and the placebo groups. [http://jama.ama-assn.org/cgi/content/full/293/9/1082] [[Vitamin]] supplements counter the deleterious effects of homocysteine on collagen. As B<sub><small>12</small></sub> is inefficiently absorbed from food by elderly persons, they may benefit from taking higher doses orally such as 100 mcg/day (found in some multivitamins) or by [[intramuscular injection]]. ==References== {{reflist|2}} ==External links== {{Amino acid metabolism intermediates}} [[Category:Sulfur amino acids]] [[de:Homocystein]] [[fr:Homocystéine]] [[it:Omocisteina]] [[he:הומוציסטאין]] [[nl:Homocysteïne]] [[ja:ホモシステイン]] [[pl:Homocysteina]] [[fi:Homokysteiini]] [[zh:高半胱氨酸]]