Editing Homocysteine (section)

==Biosynthesis and biochemical roles==

[[Image:Met pathway.svg|thumb|left|Two of homocysteine's main biochemical roles (homocysteine is seen in the left middle of the image). It can be synthesized from methionine and then converted back to methionine via the SAM cycle or used to create cysteine and alpha-ketobutyrate.]]

Homocysteine is biosynthesized naturally via a multi-step process.<ref name="AnRvNutrition1999-Selhub">{{cite journal | author=Selhub, J. | title=Homocysteine metabolism | journal=Annual Review of Nutrition | year=1999 | volume=19 | pages=217–246 | pmid=10448523 | doi=10.1146/annurev.nutr.19.1.217| s2cid=2335090 }}</ref> First, methionine receives an adenosine group from [[Adenosine triphosphate|ATP]], a reaction catalyzed by [[S-adenosyl-methionine synthetase]], to give [[S-adenosyl methionine|''S''-adenosyl methionine]] (SAM). SAM is widely used source of methyl radicals as a cofactor for [[radical SAM enzymes]].  Transfer of the methyl group to an acceptor molecule gives S-adenosyl-homocysteine. [[Hydrolysis]] of this thioether gives <small>L</small>-homocysteine. <small>L</small>-Homocysteine reacts with [[tetrahydrofolate]] (THF) to give [[methionine|<small>L</small>-methionine]].{{huh?|date=April 2025}}<ref>Champe, PC and Harvey, RA. "Biochemistry.  Lippincott's Illustrated Reviews" 4th ed. Lippincott Williams and Wilkins, 2008</ref>

===Biosynthesis of cysteine===
Mammals biosynthesize the amino acid cysteine via homocysteine. [[Cystathionine-beta-synthase|Cystathionine β-synthase]] catalyses the condensation of homocysteine and [[serine]] to give [[cystathionine]]. This reaction uses [[pyridoxine]] (vitamin B<sub>6</sub>) as a cofactor. [[Cystathionine gamma-lyase|Cystathionine γ-lyase]] then converts this double amino acid to cysteine, ammonia, and α-ketobutyrate. Bacteria and plants rely on a different pathway to produce cysteine, relying on ''O''-acetylserine.<ref>Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. {{ISBN|1-57259-153-6}}.</ref>

[[Image:MTHFR metabolism.svg|right|thumb|600px|MTHFR metabolism: folate cycle, methionine cycle, trans-sulfuration and [[hyperhomocysteinemia]] - [[5-MTHF]]: 5-methyltetrahydrofolate; 5,10-methyltetrahydrofolate; [[Bcl-2-associated X protein|BAX]]: Bcl-2-associated X protein; [[BHMT]]: betaine-homocysteine S-methyltransferase; [[cystathionine beta synthase|CBS]]: cystathionine beta synthase; [[cystathionine gamma-lyase|CGL]]: cystathionine gamma-lyase; [[dihydrofolate|DHF]]: dihydrofolate (vitamin B9); [[dimethylglycine|DMG]]: dimethylglycine; [[dTMP]]: thymidine monophosphate; [[dUMP]]: deoxyuridine monophosphate; [[Flavin adenine dinucleotide|FAD<sup>+</sup>]] flavine adenine dicucleotide; [[10-formyltetrahydrofolate|FTHF]]: 10-formyltetrahydrofolate; [[methionine synthase|MS]]: methionine synthase; [[MTHFR]]: mehtylenetetrahydrofolate reductase; [[S-adenosyl-L-homocysteine|SAH]]: S-adenosyl-L-homocysteine; [[S-adenosyl-L-methionine|SAME]]: S-adenosyl-L-methionine; [[tetrahydrofolate|THF]]: tetrahydrofolate]]

===Methionine salvage===
Homocysteine can be recycled into [[methionine]]. This process uses N5-methyl tetrahydrofolate as the methyl donor and [[cobalamin]] (vitamin B<sub>12</sub>)-related enzymes. More detail on these enzymes can be found in the article for [[methionine synthase]].

===Other reactions of biochemical significance===
Homocysteine can cyclize to give [[homocysteine thiolactone]], a five-membered [[heterocycle]].  Because of this "self-looping" reaction, homocysteine-containing [[peptide]]s tend to cleave themselves by reactions generating [[oxidative stress]].<ref>{{cite journal | pmid=20080717 | doi=10.1073/pnas.0909737107 | volume=107 | issue=2 | title=Homocystamides promote free-radical and oxidative damage to proteins | pmc=2818928 | date=January 2010 | vauthors=Sibrian-Vazquez M, Escobedo JO, Lim S, Samoei GK, Strongin RM | journal=Proc. Natl. Acad. Sci. U.S.A. | pages=551–4 | bibcode=2010PNAS..107..551S | doi-access=free }}</ref>

Homocysteine also acts as an [[allosteric modulator|allosteric antagonist]] at Dopamine D<sub>2</sub> receptors.<ref>{{cite journal|last=Agnati|first=LF|author2=Ferré, S|author3=Genedani, S|author4=Leo, G|author5=Guidolin, D|author6=Filaferro, M|author7=Carriba, P|author8=Casadó, V|author9=Lluis, C|author10=Franco, R|author11=Woods, AS|author12=Fuxe, K|title=Allosteric modulation of dopamine D2 receptors by homocysteine|journal=Journal of Proteome Research|date=Nov 2006|volume=5|issue=11|pages=3077–83|pmid=17081059|doi=10.1021/pr0601382|url=http://www.cigs.unimo.it/cigsdownloads/labs/cnf_sp2/pubblicazioni/19-agnati%20allosteric%20modulation.pdf|url-status=live|archive-url=https://web.archive.org/web/20170809142808/http://www.cigs.unimo.it/CigsDownloads/labs/cnf_sp2/pubblicazioni/19-Agnati%20allosteric%20modulation.pdf|archive-date=2017-08-09|citeseerx=10.1.1.625.26}}</ref>

It has been proposed that both homocysteine and its thiolactone may have played a significant role in the [[Abiogenesis|appearance of life]] on the early Earth.<ref>{{Cite journal|last1=Vallee|first1=Yannick|last2=Shalayel|first2=Ibrahim|last3=Ly|first3=Kieu-Dung|last4=Rao|first4=K. V. Raghavendra|last5=Paëpe|first5=Gael De|last6=Märker|first6=Katharina|last7=Milet|first7=Anne|date=2017-11-08|title=At the very beginning of life on Earth: the thiol-rich peptide (TRP) world hypothesis|url=http://www.ijdb.ehu.es/web/paper/170028yv/at-the-very-beginning-of-life-on-earth-the-thiol-rich-peptide-trp-world-hypothesis|journal=International Journal of Developmental Biology|volume=61|issue=8–9|pages=471–478|doi=10.1387/ijdb.170028yv|pmid=29139533|issn=0214-6282|doi-access=free}}</ref>