Transsulfuration pathway

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, hence it is called an "essential amino acid" by nutritionists, but are not for cysteine due to the reverse trans-sulfurylation pathway. Mutations in this pathway lead to a disease known as homocystinuria, due to homocysteine accumulation.

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

  • in the transsulfurylation route for methionine biosynthesis:
    • Cystathionine γ-synthase (metB) which joins an activated homoserine ester (acetyl or succinyl) with cysteine to form cystathionine
    • Cystathionine β-lyase (metC) which splits cystathionine into homocysteine and a deaminated alanine (pyruvate and ammonia)
  • in the direct sulfurylation pathway for methionine biosynthesis:
    • O-acetyl homoserine sulfhydrylase (metY) which adds a thiol group to an activated homoserine ester
    • O-succinylhomoserine sulfhydrylase (metZ) which adds a thiol group to an activated homoserine ester
  • in the reverse transsulfurylation pathway for cysteine biosynthesis:
    • Cystathionine γ-lyase (no common gene name) which joins an activated serine ester (acetyl or succinyl) with homocysteine to form cystathionine
    • Not Cystathionine β-synthase which is a PLP enzyme type II
  • cysteine biosynthesis from serine:
    • O-acetyl serine sulfhydrylase (cysK or cysM) which adds a thiol group to an activated serine ester
  • methionine degradation:
  • Methionine gamma-lyase (mdeA) which breaks down methionine at the thioether and amine bounds

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. ^ a b 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.