Cys/Met metabolism PLP-dependent enzyme family explained
| Symbol: | Cys_Met_Meta_PP |
| Cys_Met_Meta_PP |
| Pfam: | PF01053 |
| Pfam Clan: | CL0061 |
| Interpro: | IPR000277 |
| Prosite: | PDOC00677 |
| Scop: | 1cs1 |
| Cdd: | cd00614 |
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.[1]
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.[2]
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.[3] [4] [5]
A number of pyridoxal-dependent enzymes involved in the metabolism of cysteine, homocysteine and methionine have been shown to be evolutionary related.[1] 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.[6]
Family members
There are five different structurally related types of PLP enzymes. Members of this family belong to the type I and are:[1]
- 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).[1]
Notes and References
- Ferla MP, Patrick WM . Bacterial methionine biosynthesis . Microbiology . 160 . Pt 8 . 1571–84 . 2014 . 24939187 . 10.1099/mic.0.077826-0 . free .
- Toney MD . Reaction specificity in pyridoxal phosphate enzymes . Arch. Biochem. Biophys. . 433 . 1 . 279–87 . January 2005 . 15581583 . 10.1016/j.abb.2004.09.037 .
- Hayashi H . Pyridoxal enzymes: mechanistic diversity and uniformity . J. Biochem. . 118 . 3 . 463–73 . September 1995 . 8690703 . 10.1093/oxfordjournals.jbchem.a124931. free .
- John RA . Pyridoxal phosphate-dependent enzymes . Biochim. Biophys. Acta . 1248 . 2 . 81–96 . April 1995 . 7748903 . 10.1016/0167-4838(95)00025-p .
- Eliot AC, Kirsch JF . Pyridoxal phosphate enzymes: mechanistic, structural, and evolutionary considerations . Annu. Rev. Biochem. . 73 . 383–415 . 2004 . 15189147 . 10.1146/annurev.biochem.73.011303.074021 .
- Aitken SM, Lodha PH, Morneau DJ . The enzymes of the transsulfuration pathways: Active-site characterizations . Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics . 1814 . 11 . 1511–7 . 2011 . 21435402. 10.1016/j.bbapap.2011.03.006 .
