Transcarboxylase 12S crystal structure: hexamer assembly and substrate binding to a multienzyme core

EMBO J. 2003 May 15;22(10):2334-47. doi: 10.1093/emboj/cdg244.


Transcarboxylase from Propionibacterium shermanii is a 1.2 MDa multienzyme complex that couples two carboxylation reactions, transferring CO(2)(-) from methylmalonyl-CoA to pyruvate, yielding propionyl-CoA and oxaloacetate. The 1.9 A resolution crystal structure of the central 12S hexameric core, which catalyzes the first carboxylation reaction, has been solved bound to its substrate methylmalonyl-CoA. Overall, the structure reveals two stacked trimers related by 2-fold symmetry, and a domain duplication in the monomer. In the active site, the labile carboxylate group of methylmalonyl-CoA is stabilized by interaction with the N-termini of two alpha-helices. The 12S domains are structurally similar to the crotonase/isomerase superfamily, although only domain 1 of each 12S monomer binds ligand. The 12S reaction is similar to that of human propionyl-CoA carboxylase, whose beta-subunit has 50% sequence identity with 12S. A homology model of the propionyl-CoA carboxylase beta-subunit, based on this 12S crystal structure, provides new insight into the propionyl-CoA carboxylase mechanism, its oligomeric structure and the molecular basis of mutations responsible for enzyme deficiency in propionic acidemia.

MeSH terms

  • Acyl Coenzyme A / metabolism
  • Amino Acid Sequence
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Cadmium / metabolism
  • Carboxyl and Carbamoyl Transferases / chemistry*
  • Carboxyl and Carbamoyl Transferases / genetics
  • Carboxyl and Carbamoyl Transferases / metabolism
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Multienzyme Complexes
  • Protein Binding
  • Protein Folding
  • Protein Structure, Quaternary*
  • Protein Structure, Secondary
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • Sequence Alignment


  • Acyl Coenzyme A
  • Bacterial Proteins
  • Multienzyme Complexes
  • Protein Subunits
  • Cadmium
  • methylmalonyl-coenzyme A
  • Carboxyl and Carbamoyl Transferases
  • Methylmalonyl-CoA carboxytransferase

Associated data

  • GENBANK/PS535715
  • PDB/1ON3
  • PDB/1ON9