Transsulfuration pathway

Source: Wikipedia, the free encyclopedia.
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

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 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. PMID 24030774.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  2. PMID 21435402
    .
  3. PMID 11832514
    .
  4. PMID 8831789
    .
  5. PMID 16885444
    .
  6. ^
    PMID 24939187
    .
  7. PMID 15073190
    .
  8. PMID 11844756
    .
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