Characterization of the mycobacterial acyl-CoA carboxylase holo complexes reveals their functional expansion into amino acid catabolism.

Autor:	Ehebauer MT; European Molecular Biology Laboratory, Hamburg Unit, Hamburg, Germany., Zimmermann M; Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland., Jakobi AJ; European Molecular Biology Laboratory, Hamburg Unit, Hamburg, Germany; European Molecular Biology Laboratory, Structural Biology and Computational Biology Programme, Heidelberg, Germany., Noens EE; European Molecular Biology Laboratory, Hamburg Unit, Hamburg, Germany., Laubitz D; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland; Department of Genetics & Biotechnology, Warsaw University, Warsaw, Poland., Cichocki B; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland; Department of Genetics & Biotechnology, Warsaw University, Warsaw, Poland., Marrakchi H; Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Tuberculosis & Infection Biology Department, Toulouse, France; Université Paul Sabatier, Toulouse, France., Lanéelle MA; Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Tuberculosis & Infection Biology Department, Toulouse, France; Université Paul Sabatier, Toulouse, France., Daffé M; Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Tuberculosis & Infection Biology Department, Toulouse, France; Université Paul Sabatier, Toulouse, France., Sachse C; European Molecular Biology Laboratory, Structural Biology and Computational Biology Programme, Heidelberg, Germany., Dziembowski A; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland; Department of Genetics & Biotechnology, Warsaw University, Warsaw, Poland., Sauer U; Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland., Wilmanns M; European Molecular Biology Laboratory, Hamburg Unit, Hamburg, Germany; Center for Structural Systems Biology, Hamburg, Germany.
Jazyk:	angličtina
Zdroj:	PLoS pathogens [PLoS Pathog] 2015 Feb 19; Vol. 11 (2), pp. e1004623. Date of Electronic Publication: 2015 Feb 19 (Print Publication: 2015).
DOI:	10.1371/journal.ppat.1004623
Abstrakt:	Biotin-mediated carboxylation of short-chain fatty acid coenzyme A esters is a key step in lipid biosynthesis that is carried out by multienzyme complexes to extend fatty acids by one methylene group. Pathogenic mycobacteria have an unusually high redundancy of carboxyltransferase genes and biotin carboxylase genes, creating multiple combinations of protein/protein complexes of unknown overall composition and functional readout. By combining pull-down assays with mass spectrometry, we identified nine binary protein/protein interactions and four validated holo acyl-coenzyme A carboxylase complexes. We investigated one of these--the AccD1-AccA1 complex from Mycobacterium tuberculosis with hitherto unknown physiological function. Using genetics, metabolomics and biochemistry we found that this complex is involved in branched amino-acid catabolism with methylcrotonyl coenzyme A as the substrate. We then determined its overall architecture by electron microscopy and found it to be a four-layered dodecameric arrangement that matches the overall dimensions of a distantly related methylcrotonyl coenzyme A holo complex. Our data argue in favor of distinct structural requirements for biotin-mediated γ-carboxylation of α-β unsaturated acid esters and will advance the categorization of acyl-coenzyme A carboxylase complexes. Knowledge about the underlying structural/functional relationships will be crucial to make the target category amenable for future biomedical applications.
Databáze:	MEDLINE
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