Cys/Met metabolism PLP-dependent enzyme family

Mechanism of action

PLP is employed as it binds to amino groups and stabilises carbanion intermediates. PLP enzymes exist in their resting state as a Schiff base, the aldehyde group of PLP forming a linkage with the epsilon-amino group of an active site lysine residue on the enzyme. The alpha-amino group of the substrate displaces the lysine epsilon-amino group, in the process forming a new aldimine with the substrate. This aldimine is the common central intermediate for all PLP-catalysed reactions, enzymatic and non-enzymatic.

Function

PLP is the active form of vitamin B6 (pyridoxine or pyridoxal). PLP is a versatile catalyst, acting as a coenzyme in a multitude of reactions, including decarboxylation, deamination and transamination.

A number of pyridoxal-dependent enzymes involved in the metabolism of cysteine, homocysteine and methionine have been shown to be evolutionary related.

Family members

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

• 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).

References

References

1. (2014). "Bacterial methionine biosynthesis". Microbiology.
2. (January 2005). "Reaction specificity in pyridoxal phosphate enzymes". Arch. Biochem. Biophys..
3. (September 1995). "Pyridoxal enzymes: mechanistic diversity and uniformity". J. Biochem..
4. (April 1995). "Pyridoxal phosphate-dependent enzymes". Biochim. Biophys. Acta.
5. (2004). "Pyridoxal phosphate enzymes: mechanistic, structural, and evolutionary considerations". Annu. Rev. Biochem..
6. (2011). "The enzymes of the transsulfuration pathways: Active-site characterizations". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics.