{{Short description|Metabolic pathway involving the transfer of a thiol group}} [[File:Met pathway.svg|thumb|400px|The reverse transsulfuration pathway depicting the conversion of homocysteine to cysteine in reactions 5 and 6. Reaction 5 is catalyzed by cystathionine beta-synthase while reaction 6 is catalyzed by cystathionine gamma-lyase. The required homocysteine is synthesized from methionine in reactions 1, 2, and 3.]]

The '''transsulfuration pathway''' is a metabolic pathway involving the interconversion of cysteine and homocysteine through the intermediate cystathionine. Two transsulfurylation pathways are known: the ''forward'' and the ''reverse''.<ref>{{cite journal|author=Weekley, C. M. and Harris, H. H.|year=2013|title=Which form is that? The importance of selenium speciation and metabolism in the prevention and treatment of disease|journal=Chem. Soc. Rev.|volume=42|issue=23|pages=8870–8894|doi= 10.1039/c3cs60272a|pmid=24030774}}</ref>

The ''forward pathway'' is present in several bacteria, such as ''Escherichia coli''<ref>{{Cite journal | last1 = Aitken | first1 = S. M. | last2 = Lodha | first2 = P. H. | last3 = Morneau | first3 = D. J. K. | doi = 10.1016/j.bbapap.2011.03.006 | title = The enzymes of the transsulfuration pathways: Active-site characterizations | journal = Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics | volume = 1814 | issue = 11 | pages = 1511–7 | year = 2011 | pmid = 21435402 }}</ref> and ''Bacillus subtilis'',<ref>{{Cite journal | last1 = Auger | first1 = S. | last2 = Yuen | first2 = W. H. | last3 = Danchin | first3 = A. | last4 = Martin-Verstraete | first4 = I. | title = The metIC operon involved in methionine biosynthesis in Bacillus subtilis is controlled by transcription antitermination | journal = Microbiology | volume = 148 | issue = Pt 2 | pages = 507–518 | year = 2002 | pmid = 11832514 | doi=10.1099/00221287-148-2-507 | doi-access = free | hdl = 10722/42040 | hdl-access = free }}</ref> and involves the transfer of the thiol group from cysteine to homocysteine (methionine precursor with the S-methyl group), thanks to the γ-replacement of the acetyl or succinyl group of a homoserine with cysteine via its thiol group to form cystathionine (catalysed by cystathionine γ-synthase, which is encoded by ''metB'' in ''E. coli'' and ''metI'' in ''B. subtilis''). Cystathionine is then cleaved by means of the β-elimination of the homocysteine portion of the molecule leaving behind an unstable imino acid, which is attacked by water to form pyruvate and ammonia (catalysed by the metC-encoded cystathionine β-lyase<ref>{{Cite journal | last1 = Clausen | first1 = T. | last2 = Huber | first2 = R. | last3 = Laber | first3 = B. | last4 = Pohlenz | first4 = H. D. | last5 = Messerschmidt | first5 = A. | title = Crystal Structure of the Pyridoxal-5′-phosphate Dependent Cystathionine β-lyase fromEscherichia coliat 1.83 Å | doi = 10.1006/jmbi.1996.0508 | journal = Journal of Molecular Biology | volume = 262 | issue = 2 | pages = 202–224 | year = 1996 | pmid = 8831789 }}</ref>). The production of homocysteine through transsulfuration allows the conversion of this intermediate to methionine, through a methylation reaction carried out by methionine synthase.

The ''reverse pathway'' is present in several organisms, including humans, and involves the transfer of the thiol group from homocysteine to cysteine via a similar mechanism. In ''Klebsiella pneumoniae'' the cystathionine β-synthase is encoded by ''mtcB'', while the γ-lyase is encoded by ''mtcC''.<ref>{{Cite journal | last1 = Seiflein | first1 = T. A. | last2 = Lawrence | first2 = J. G. | doi = 10.1128/JB.00347-06 | title = Two Transsulfurylation Pathways in Klebsiella pneumoniae | journal = Journal of Bacteriology | volume = 188 | issue = 16 | pages = 5762–5774 | year = 2006 | pmid = 16885444 | pmc =1540059 }}</ref> Humans are auxotrophic for methionine, therefore it's considered to be an essential amino acid. However humans are autotrophic for cysteine due to the reverse trans-sulfurylation pathway, meaning that cysteine is not considered to be an essential amino acid.

Mutations in the CBS pathway can cause a condition known as homocystinuria, an outcome of higher homocysteine levels (hyperhomocysteinemia).

==Role of pyridoxal phosphate== {{transcluded section|Cys/Met metabolism PLP-dependent enzyme family|part=true}} All four transsulfuration enzymes require vitamin B6 in its active form (pyridoxal phosphate or PLP). Three of these enzymes (cystathionine γ-synthase excluded) are part of the Cys/Met metabolism PLP-dependent enzyme family (type I PLP enzymes). {{trim|{{#section-h:Cys/Met metabolism PLP-dependent enzyme family|Family members}}}}

==Direct sulfurization== The direct sulfurylation pathways for the synthesis of cysteine or homocysteine proceeds via the replacement of the acetyl/succinyl group with free sulfide (via the ''cysK'' or ''cysM'' -encoded cysteine synthase.<ref>{{Cite journal | last1 = Rabeh | first1 = W. M. | last2 = Cook | first2 = P. F. | title = Structure and Mechanism of O-Acetylserine Sulfhydrylase | doi = 10.1074/jbc.R400001200 | journal = Journal of Biological Chemistry | volume = 279 | issue = 26 | pages = 26803–26806 | year = 2004 | pmid = 15073190| doi-access = free}}</ref> and the ''metZ'' or ''metY'' -encoded homocysteine synthase,<ref>{{Cite journal | last1 = Hwang | first1 = B. J. | last2 = Yeom | first2 = H. J. | last3 = Kim | first3 = Y. | last4 = Lee | first4 = H. S. | title = Corynebacterium glutamicum utilizes both transsulfuration and direct sulfhydrylation pathways for methionine biosynthesis | journal = Journal of Bacteriology | volume = 184 | issue = 5 | pages = 1277–1286 | year = 2002 | pmid = 11844756 | pmc = 134843 | doi = 10.1128/JB.184.5.1277-1286.2002 }}</ref> ==References== <references>

<ref name=review>{{cite journal | vauthors = Ferla MP, Patrick WM | title = Bacterial methionine biosynthesis | journal = Microbiology | volume = 160 | issue = Pt 8 | pages = 1571–84 | year = 2014 | pmid = 24939187 | doi = 10.1099/mic.0.077826-0 | doi-access = free }}</ref>

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Category:Nitrogen cycle Category:Sulfur metabolism Category:Metabolic pathways