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

DOI: 10.1016/j.str.2013.05.001
PMID: 23791943

Authors: Sean Froese (Structural Genomics Consortium, University of Oxford) , Farhad Forouhar (Northeast Structural Genomics Consortium, Columbia University) , Timothy h. Tran (Northeast Structural Genomics Consortium, Columbia University) , Melanie Vollmar (Structural Genomics Consortium, University of Oxford) , Yi seul Kim (Northeast Structural Genomics Consortium, Columbia University) , Scott Lew (Northeast Structural Genomics Consortium, Columbia University) , Helen Neely (Northeast Structural Genomics Consortium, Columbia University) , Jayaraman Seetharaman (Northeast Structural Genomics Consortium, Columbia University) , Yang Shen (Northeast Structural Genomics Consortium, Columbia University) , Rong Xiao (Rutgers University; Structural Genomics Consortium, Robert Wood Johnson Medical School) , Thomas b. Acton (Rutgers University; Structural Genomics Consortium, Robert Wood Johnson Medical School) , John k. Everett (Rutgers University; Structural Genomics Consortium, Robert Wood Johnson Medical School) , Giuseppe Cannone (University of Edinburgh) , Sriharsha Puranik (Structural Genomics Consortium, University of Oxford) , Pavel Savitsky (Structural Genomics Consortium, University of Oxford) , Tobias Krojer (Structural Genomics Consortium, University of Oxford) , Ewa Pilka (Structural Genomics Consortium, University of Oxford) , Wasim Kiyani (Structural Genomics Consortium, University of Oxford) , Wen hwa Lee (Structural Genomics Consortium, University of Oxford) , Brian d. Marsden (Structural Genomics Consortium, University of Oxford) , Frank Von Delft (Structural Genomics Consortium, University of Oxford) , Charles K. Allerston (Structural Genomics Consortium, University of Oxford) , Laura Spagnolo (Structural Genomics Consortium, University of Oxford) , Opher Gileadi (Structural Genomics Consortium, University of Oxford) , Gaetano T. Montelione (Rutgers University; Northeast Structural Genomics Consortium, Robert Wood Johnson Medical School) , Udo Oppermann (Structural Genomics Consortium, University of Oxford; NIHR Oxford Biomedical Research Unit, Botnar Research Centre) , Wyatt Yue (NIHR Oxford Biomedical Research Unit, Botnar Research Centre) , Liang Tong (Northeast Structural Genomics Consortium, Columbia University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure

State: Published (Approved)
Published: June 2013

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.

Journal Keywords: Bacterial; Carboxy-Lyases; Catalytic; Crystallography; X-Ray; Deficiency; Enzyme; Humans; Hydrogen; Kinetics; Models; Molecular; Mutation; Missense; Protein; Quaternary; Protein; Secondary; Structural; Protein

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography