title: Crystal structures of malonyl-coenzyme A decarboxylase provide insights into its catalytic mechanism and disease-causing mutations.
abstract: 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.
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: D Sean
authors.initials: DS
authors.lastname: Froese
authors.forename: Farhad
authors.initials: F
authors.lastname: Forouhar
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Tran
authors.forename: Melanie
authors.initials: M
authors.lastname: Vollmar
authors.forename: Yi Seul
authors.initials: YS
authors.lastname: Kim
authors.forename: Scott
authors.initials: S
authors.lastname: Lew
authors.forename: Helen
authors.initials: H
authors.lastname: Neely
authors.forename: Jayaraman
authors.initials: J
authors.lastname: Seetharaman
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.forename: Rong
authors.initials: R
authors.lastname: Xiao
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Acton
authors.forename: John K
authors.initials: JK
authors.lastname: Everett
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cannone
authors.forename: Sriharsha
authors.initials: S
authors.lastname: Puranik
authors.forename: Pavel
authors.initials: P
authors.lastname: Savitsky
authors.forename: Tobias
authors.initials: T
authors.lastname: Krojer
authors.forename: Ewa S
authors.initials: ES
authors.lastname: Pilka
authors.forename: Wasim
authors.initials: W
authors.lastname: Kiyani
authors.forename: Wen Hwa
authors.initials: WH
authors.lastname: Lee
authors.forename: Brian D
authors.initials: BD
authors.lastname: Marsden
authors.forename: Frank
authors.initials: F
authors.lastname: von Delft
authors.forename: Charles K
authors.initials: CK
authors.lastname: Allerston
authors.forename: Laura
authors.initials: L
authors.lastname: Spagnolo
authors.forename: Opher
authors.initials: O
authors.lastname: Gileadi
authors.forename: Gaetano T
authors.initials: GT
authors.lastname: Montelione
authors.forename: Udo
authors.initials: U
authors.lastname: Oppermann
authors.forename: Wyatt W
authors.initials: WW
authors.lastname: Yue
authors.forename: Liang
authors.initials: L
authors.lastname: Tong
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry*; D002262:Carboxy-Lyases / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003677:Deficiency Diseases / Q000235:genetics; D004795:Enzyme Stability; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D040681:Structural Homology, Protein
chemical_list: D001426:Bacterial Proteins; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase