Crystal Structures of Malonyl-Coenzyme A Decarboxylase Provide Insights into Its Catalytic Mechanism and Disease-Causing Mutations

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. •Structures of human and bacterial MCDs were determined at up to 2.3 Å resolution•Distinct tetrameric and dimeric MCD oligomerizations were observed•Unexpected homology to the GNAT superfamily gives insights into catalytic mechanism•The structures provide the molecular basis for the disease-causing mutations in MCD Malonyl-CoA decarboxylase (MCD) is important in fatty acid metabolism. Froese et al. report structures of several MCDs and show that the MCD catalytic domain shares structural homology with GNAT superfamily. The structures further our understanding of catalysis, pathogenic mutations, and drug design.