Insight into Structure-Function Relationships and Inhibition of the Fatty Acyl-AMP Ligase (FadD32) Orthologs from Mycobacteria

Autor: Lionel Mourey, Valérie Guillet, Simon Ladevèze, Hedia Marrakchi, Mamadou Daffé, Nathalie Eynard, Vincent Mariaule, Ségolène Galandrin, Cécile Bon, Laurent Maveyraud
Přispěvatelé: Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Rok vydání: 2016
Předmět:
Models
Molecular
0301 basic medicine
Protein Conformation
Molecular Sequence Data
Antitubercular Agents
Crystallography
X-Ray
Biochemistry
Mycobacterium
Ligases
03 medical and health sciences
Protein structure
Bacterial Proteins
Carbon-Sulfur Ligases
Tuberculosis
Amino Acid Sequence
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
Molecular Biology
Mycobacterium marinum
chemistry.chemical_classification
Mycobacterium Infections
DNA ligase
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Structural Biology [q-bio.BM]
030102 biochemistry & molecular biology
biology
Rational design
Active site
Mycobacterium tuberculosis
Cell Biology
biology.organism_classification
[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
3. Good health
030104 developmental biology
Enzyme
Mycolic Acids
chemistry
Drug Design
Protein Structure and Folding
biology.protein
Function (biology)
Zdroj: Journal of Biological Chemistry
Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2016, 291 (15), pp.7973-7989. ⟨10.1074/jbc.M115.712612⟩
ISSN: 0021-9258
1083-351X
Popis: International audience; 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 meromy-colic 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 homo-logous enzymes from Mycobacterium tuberculosis and Myco-bacterium 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.
Databáze: OpenAIRE
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