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Malonyl-coenzyme A decarboxylase (MCD) is found from bacteria to humans, has important roles in regulating fatty acid metabolism and food intake, and is an attractive target for drug discovery. We report here four crystal structures of MCD from human, Rhodopseudomonas palustris, Agrobacterium vitis, and Cupriavidus metallidurans at up to 2.3 Å resolution. The MCD monomer contains an N-terminal helical domain involved in oligomerization and a C-terminal catalytic domain. The four structures exhibit substantial differences in the organization of the helical domains and, consequently, the oligomeric states and intersubunit interfaces. Unexpectedly, the MCD catalytic domain is structurally homologous to those of the GCN5-related N-acetyltransferase superfamily, especially the curacin A polyketide synthase catalytic module, with a conserved His-Ser/Thr dyad important for catalysis. Our structures, along with mutagenesis and kinetic studies, provide a molecular basis for understanding pathogenic mutations and catalysis, as well as a template for structure-based drug design.

Original publication

DOI

10.1016/j.str.2013.05.001

Type

Journal article

Journal

Structure (London, England : 1993)

Publication Date

07/2013

Volume

21

Pages

1182 - 1192

Addresses

Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.

Keywords

Humans, Deficiency Diseases, Carboxy-Lyases, Bacterial Proteins, Crystallography, X-Ray, Enzyme Stability, Amino Acid Sequence, Catalytic Domain, Protein Structure, Quaternary, Protein Structure, Secondary, Structural Homology, Protein, Kinetics, Mutation, Missense, Hydrogen Bonding, Models, Molecular, Molecular Sequence Data