Methylmalonyl-CoA decarboxylase

 

Methylmalonyl-CoA decarboxylase (MMCD) is a member of the cronotase super family, a collection of enzymes characterised by the presence of oxy anion intermediates or transition states with a significant localisation of negative charge in their reactions. The breadth of catalytic action within this family is demonstrated by the spread of associated enzymes across all six of the Enzyme Commission classes.

 

Reference Protein and Structure

Sequence
P52045 UniProt (4.1.1.-) IPR001753 (Sequence Homologues) (PDB Homologues)
Biological species
Escherichia coli K-12 (Bacteria) Uniprot
PDB
1ef8 - CRYSTAL STRUCTURE OF METHYLMALONYL COA DECARBOXYLASE (1.85 Å) PDBe PDBsum 1ef8
Catalytic CATH Domains
3.90.226.10 CATHdb (see all for 1ef8)
Click To Show Structure

Enzyme Reaction (EC:7.2.4.3)

(S)-methylmalonyl-CoA(5-)
CHEBI:57327ChEBI
+
hydron
CHEBI:15378ChEBI
→
carbon dioxide
CHEBI:16526ChEBI
+
propionyl-CoA(4-)
CHEBI:57392ChEBI
Alternative enzyme names: (S)-2-methyl-3-oxopropanoyl-CoA carboxy-lyase, Methylmalonyl-coenzyme A decarboxylase, (S)-methylmalonyl-CoA carboxy-lyase,

Enzyme Mechanism

Introduction

MMCD catalyses the decarboxylation of (S)-methylmalonyl-CoA, forming propionyl-CoA and provides a pathway for the decarboxylation of succinate in E. Coli. The Tyr 140 residue binds to the anionic malonyl substrate through hydrogen bonding, and has been implicated in assisting decarboxylation. The sp2 anionic enolate oxygen points towards an oxyanion hole created by the backbone amide groups of His 66 and Gly110, introducing greater stability to the charged intermediate. The generally non polar nature of the binding pocket surrounding Tyr 140 destabilises the anionic carboxylate group, enhancing the rate of loss of CO2. An unspecified residue acts as a proton donor to the alpha carbon, forming the propionyl-CoA product.

Catalytic Residues Roles

UniProt PDB* (1ef8)
Gly110 (main-N), His66 (main-N) Gly110A (main-N), His66A (main-N) The residue backbone NH forms part of an oxyanion hole, stabilising the enolate anion intermediate. hydrogen bond donor, electrostatic stabiliser
Tyr140 Tyr140A The residue binds the carboxylate group of the substrate and facilitates decarboxylation by orientating the carboxylate group orthogonal to the plane of the thioester carbonyl group through hydrogen bonding. hydrogen bond donor, steric role
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

unimolecular elimination by the conjugate base, overall reactant used, overall product formed, decarboxylation, intermediate formation, proton transfer, assisted keto-enol tautomerisation, intermediate terminated, native state of enzyme is not regenerated

References

  1. Benning MM et al. (2000), Biochemistry, 39, 4630-4639. New Reactions in the Crotonase Superfamily:  Structure of Methylmalonyl CoA Decarboxylase fromEscherichia coli†,‡. DOI:10.1021/bi9928896. PMID:10769118.
  2. Hamed RB et al. (2008), Cell Mol Life Sci, 65, 2507-2527. Mechanisms and structures of crotonase superfamily enzymes – How nature controls enolate and oxyanion reactivity. DOI:10.1007/s00018-008-8082-6. PMID:18470480.
  3. Haller T et al. (2000), Biochemistry, 39, 4622-4629. Discovering new enzymes and metabolic pathways: conversion of succinate to propionate by Escherichia coli. PMID:10769117.

Step 1. Tyr140 draws carboxylate out of the plane. The substrate undergoes decarboxylation, with concomitant double bond rearrangement. The newly formed oxyanion is stabilised by the backbone amides of His66 and Gly110

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
His66A (main-N) hydrogen bond donor
Tyr140A hydrogen bond donor, steric role
Gly110A (main-N) hydrogen bond donor

Chemical Components

ingold: unimolecular elimination by the conjugate base, overall reactant used, overall product formed, decarboxylation, intermediate formation

Step 2. The oxyanion collapses, initiating double bond rearrangement. The substrate deprotonates an unidentified base (shown here as water) to form the final product.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
His66A (main-N) hydrogen bond donor, electrostatic stabiliser
Gly110A (main-N) hydrogen bond donor, electrostatic stabiliser

Chemical Components

proton transfer, assisted keto-enol tautomerisation, overall product formed, intermediate terminated, native state of enzyme is not regenerated
Download: Image, Marvin File

Step 1. Tyr140 draws carboxylate out of the plane. The substrate undergoes decarboxylation, with concomitant double bond rearrangement. The newly formed oxyanion is stabilised by the backbone amides of His66 and Gly110

Step 2. The oxyanion collapses, initiating double bond rearrangement. The substrate deprotonates an unidentified base (shown here as water) to form the final product.

Products.

Contributors

Gemma L. Holliday, Gail J. Bartlett, Daniel E. Almonacid, James W. Murray, Craig Porter