title: Insight into Structure-Function Relationships and Inhibition of the Fatty Acyl-AMP Ligase (FadD32) Orthologs from Mycobacteria.
abstract: Mycolic acids are essential components of the mycobacterial cell envelope, and their biosynthetic pathway is one of the targets of first-line antituberculous drugs. This pathway contains a number of potential targets, including some that have been identified only recently and have yet to be explored. One such target, FadD32, is required for activation of the long meromycolic chain and is essential for mycobacterial growth. We report here an in-depth biochemical, biophysical, and structural characterization of four FadD32 orthologs, including the very homologous enzymes fromMycobacterium tuberculosisandMycobacterium marinum Determination of the structures of two complexes with alkyl adenylate inhibitors has provided direct information, with unprecedented detail, about the active site of the enzyme and the associated hydrophobic tunnel, shedding new light on structure-function relationships and inhibition mechanisms by alkyl adenylates and diarylated coumarins. This work should pave the way for the rational design of inhibitors of FadD32, a highly promising drug target.
authors.affiliation: From the Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, 31077 Toulouse, France valerie.guillet@ipbs.fr.
authors.forename: Valérie
authors.initials: V
authors.lastname: Guillet
authors.affiliation: From the Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, 31077 Toulouse, France.
authors.forename: Ségolène
authors.initials: S
authors.lastname: Galandrin
authors.affiliation: From the Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, 31077 Toulouse, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Maveyraud
authors.affiliation: From the Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, 31077 Toulouse, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Ladevèze
authors.affiliation: From the Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, 31077 Toulouse, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mariaule
authors.affiliation: From the Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, 31077 Toulouse, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Bon
authors.affiliation: From the Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, 31077 Toulouse, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Eynard
authors.affiliation: From the Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, 31077 Toulouse, France.
authors.forename: Mamadou
authors.initials: M
authors.lastname: Daffé
authors.affiliation: From the Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, 31077 Toulouse, France hedia.marrakchi@ipbs.fr.
authors.forename: Hedia
authors.initials: H
authors.lastname: Marrakchi
authors.affiliation: From the Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, 31077 Toulouse, France lionel.mourey@ipbs.fr.
authors.forename: Lionel
authors.initials: L
authors.lastname: Mourey
mesh_terms: D000595:Amino Acid Sequence; D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D019730:Carbon-Sulfur Ligases; D018360:Crystallography, X-Ray; D015195:Drug Design; D008025:Ligases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009161:Mycobacterium / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D009164:Mycobacterium Infections / Q000188:drug therapy / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D009171:Mycolic Acids / Q000378:metabolism; D011487:Protein Conformation; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D009171:Mycolic Acids; D008025:Ligases; D019730:Carbon-Sulfur Ligases; C018749:long-chain-fatty-acid-(acyl-carrier-protein) ligase
keywords: crystal structure; drug design; enzyme inhibitor; fatty acyl ACP-synthase; fatty acyl-AMP ligase; mycobacteria; tuberculosis