Methylmalonyl-CoA epimerase

 

Methylmalonyl-CoA epimerase is essential for the breakdown of odd-numbered fatty acids and the amino acids valine, isoleucine and methionine. It is present in many species of bacteria and animals. Defective activity in humans can result in severe acidosis and damage to the central nervous system.

 

Reference Protein and Structure

Sequence
Q8VQN0 UniProt (5.1.99.1) IPR017515 (Sequence Homologues) (PDB Homologues)
Biological species
Propionibacterium freudenreichii subsp. shermanii (Bacteria) Uniprot
PDB
1jc5 - Crystal Structure of Native Methylmalonyl-CoA Epimerase (2.2 Å) PDBe PDBsum 1jc5
Catalytic CATH Domains
3.10.180.10 CATHdb (see all for 1jc5)
Cofactors
Cobalt(3+) (1), Cobalt(2+) (1) Metal MACiE
Click To Show Structure

Enzyme Reaction (EC:5.1.99.1)

(R)-methylmalonyl-CoA(5-)
CHEBI:57326ChEBI
→
(S)-methylmalonyl-CoA(5-)
CHEBI:57327ChEBI
Alternative enzyme names: 2-methyl-3-oxopropanoyl-CoA 2-epimerase, DL-methylmalonyl-CoA racemase, Methylmalonyl coenzyme A racemase, Methylmalonyl-CoA racemase,

Enzyme Mechanism

Introduction

Although there is no Co(II) present in the crystal structure, it has been determined that the ion is necessary and the most likely to bind well [PMID:11470438].

Glu48 deprotonates the chiral centre of methylmalonyl-CoA, forming an enol intermediate. Glu141 then deprotonates Glu48. The oxyanion intermediate collapses, reforming the ketone while the chiral centre is reformed by proton transfer from Glu141.

Catalytic Residues Roles

UniProt PDB* (1jc5)
Glu48, Glu141 Glu48A, Glu141A Acts as a general acid/base. hydrogen bond acceptor, hydrogen bond donor, proton acceptor, proton donor
Glu141, His12, Gln65, His91 Glu141A, His12A, Gln65A, His91A Binds the Co(II) ion. hydrogen bond acceptor, hydrogen bond donor, metal ligand, proton acceptor, proton donor
*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

proton transfer, assisted keto-enol tautomerisation, overall reactant used, intermediate formation, atom stereo change, decoordination from a metal ion, coordination to a metal ion, overall product formed, native state of enzyme regenerated, intermediate terminated

References

  1. McCarthy AA et al. (2001), Structure, 9, 637-646. Crystal structure of methylmalonyl-coenzyme A epimerase from P. shermanii: a novel enzymatic function on an ancient metal binding scaffold. PMID:11470438.
  2. Shi L et al. (2009), Proteins, 77, 994-999. Crystal structure of a putative methylmalonyl-coenzyme a epimerase fromThermoanaerobacter tengcongensisat 2.0 Å resolution. DOI:10.1002/prot.22528. PMID:19731367.
  3. Armstrong RN (2000), Biochemistry, 39, 13625-13632. Mechanistic Diversity in a Metalloenzyme Superfamily†. DOI:10.1021/bi001814v. PMID:11076500.
  4. Cameron AD et al. (1999), Biochemistry, 38, 13480-13490. Reaction Mechanism of Glyoxalase I Explored by an X-ray Crystallographic Analysis of the Human Enzyme in Complex with a Transition State Analogue†. DOI:10.1021/bi990696c. PMID:10521255.
  5. Stabler SP et al. (1985), Arch Biochem Biophys, 241, 252-264. Isolation and characterization of dl-methylmalonyl-coenzyme A racemase from rat liver. DOI:10.1016/0003-9861(85)90381-9.
  6. Leadlay PF (1981), Biochem J, 197, 413-419. Purification and characterization of methylmalonyl-CoA epimerase fromPropionibacterium shermanii. DOI:10.1042/bj1970413.

Step 1. Glu48 deprotonates the chiral centre of methylmalonyl-CoA, resulting in formation of an enol intermediate that is stabilised by the Co(II) centre.

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Catalytic Residues Roles

Residue Roles
Glu141A metal ligand
Glu48A hydrogen bond acceptor
His12A metal ligand
His91A metal ligand
Gln65A metal ligand
Glu48A proton acceptor

Chemical Components

proton transfer, assisted keto-enol tautomerisation, overall reactant used, intermediate formation, atom stereo change, decoordination from a metal ion, coordination to a metal ion

Step 2. Glu141 deprotonates Glu48.

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Catalytic Residues Roles

Residue Roles
Glu141A hydrogen bond acceptor, metal ligand
Glu48A hydrogen bond donor
His12A metal ligand
His91A metal ligand
Gln65A metal ligand
Glu48A proton donor
Glu141A proton acceptor

Chemical Components

proton transfer, decoordination from a metal ion, coordination to a metal ion

Step 3. The oxyanion collapses back to re-form the keto-form, the chiral centre is re-formed by proton transfer from Glu141.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Glu141A metal ligand, hydrogen bond donor
His12A metal ligand
Gln65A metal ligand
His91A metal ligand
Glu141A proton donor

Chemical Components

proton transfer, assisted keto-enol tautomerisation, atom stereo change, overall product formed, native state of enzyme regenerated, intermediate terminated, coordination to a metal ion, decoordination from a metal ion
Download: Image, Marvin File

Step 1. Glu48 deprotonates the chiral centre of methylmalonyl-CoA, resulting in formation of an enol intermediate that is stabilised by the Co(II) centre.

Step 2. Glu141 deprotonates Glu48.

Step 3. The oxyanion collapses back to re-form the keto-form, the chiral centre is re-formed by proton transfer from Glu141.

Products.

Contributors

Gemma L. Holliday, Gail J. Bartlett, Daniel E. Almonacid, Sophie T. Williams