Transsulfuration pathway

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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. Met pathway.svg
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]

Contents

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

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). There are five different structurally related types of PLP enzymes. Members of this family belong to the type I and are: [6]

Note: MetC, metB, metZ are closely related and have fuzzy boundaries so fall under the same NCBI orthologue cluster (COG0626). [6]

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. [7] and the metZ or metY -encoded homocysteine synthase, [8]

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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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 . hdl: 10722/42040 . 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. PMC   1540059 . PMID   16885444.
  6. 1 2 Ferla MP, Patrick WM (2014). "Bacterial methionine biosynthesis". Microbiology. 160 (Pt 8): 1571–84. doi: 10.1099/mic.0.077826-0 . PMID   24939187.
  7. ↑ 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.
  8. ↑ 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. PMC   134843 . PMID   11844756.
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