Transsulfuration pathway

Short description: Metabolic pathway involving the transfer of a thiol group

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.[1]

The forward pathway is present in several bacteria, such as Escherichia coli[2] and Bacillus subtilis,[3] 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[4]). 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.[5] 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

Part of this section is transcluded from Cys/Met metabolism PLP-dependent enzyme family. (edit | history)

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). {{#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.[6] and the metZ or metY -encoded homocysteine synthase,[7]

## References

1. ↑ Weekley, C. M. and Harris, H. H. (2013). "Which form is that? The importance of selenium speciation and metabolism in the prevention and treatment of disease". Chem. Soc. Rev. 42 (23): 8870–8894. doi:10.1039/c3cs60272a. PMID 24030774.
2. ↑ Aitken, S. M.; Lodha, P. H.; Morneau, D. J. K. (2011). "The enzymes of the transsulfuration pathways: Active-site characterizations". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1814 (11): 1511–7. doi:10.1016/j.bbapap.2011.03.006. PMID 21435402.
3. ↑ Auger, S.; Yuen, W. H.; Danchin, A.; Martin-Verstraete, I. (2002). "The metIC operon involved in methionine biosynthesis in Bacillus subtilis is controlled by transcription antitermination". Microbiology 148 (Pt 2): 507–518. doi:10.1099/00221287-148-2-507. PMID 11832514.
4. ↑ Clausen, T.; Huber, R.; Laber, B.; Pohlenz, H. D.; Messerschmidt, A. (1996). "Crystal Structure of the Pyridoxal-5′-phosphate Dependent Cystathionine β-lyase fromEscherichia coliat 1.83 Å". Journal of Molecular Biology 262 (2): 202–224. doi:10.1006/jmbi.1996.0508. PMID 8831789.
5. ↑ Seiflein, T. A.; Lawrence, J. G. (2006). "Two Transsulfurylation Pathways in Klebsiella pneumoniae". Journal of Bacteriology 188 (16): 5762–5774. doi:10.1128/JB.00347-06. PMID 16885444.
6. ↑ Rabeh, W. M.; Cook, P. F. (2004). "Structure and Mechanism of O-Acetylserine Sulfhydrylase". Journal of Biological Chemistry 279 (26): 26803–26806. doi:10.1074/jbc.R400001200. PMID 15073190.
7. ↑ Hwang, B. J.; Yeom, H. J.; Kim, Y.; Lee, H. S. (2002). "Corynebacterium glutamicum utilizes both transsulfuration and direct sulfhydrylation pathways for methionine biosynthesis". Journal of Bacteriology 184 (5): 1277–1286. doi:10.1128/JB.184.5.1277-1286.2002. PMID 11844756.

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