Cys/Met metabolism PLP-dependent enzyme family
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cystathionine beta-lyase (cbl) from escherichia coli in complex with n-hydrazinocarbonylmethyl-2-trifluoromethyl-benzamide
In molecular biology, the Cys/Met metabolism PLP-dependent enzyme family is a family of proteins including enzymes involved in cysteine and methionine metabolism which use PLP (pyridoxal-5'-phosphate) as a cofactor.
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.
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. These enzymes are tetrameric proteins of about 400 amino-acid residues. Each monomer has an active site, which however requires the N-terminal of another monomer to be completed (salt bridges to phosphate and entrance way). The phosphopyridoxyl group is attached to a lysine residue located in the central section of these enzymes and is stabilised by π-stacking interactions with a tyrosine residue above it.
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 ether (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 ether
- O-succinylhomoserine sulfhydrylase (metZ) which adds a thiol group to an activated homoserine ether
- in the reverse transsulfurylation pathway for cysteine biosynthesis:
- Cystathionine γ-lyase (no common gene name) which joins an activated serine ether (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 ether
- 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).
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