title: Structure of the EssentialMtbFadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis.
abstract: Mycolic acids are indispensible lipids ofMycobacterium tuberculosis(Mtb), the causative agent of tuberculosis (TB), and contribute to the distinctive architecture and impermeability of the mycobacterial cell envelope. FadD32 plays a pivotal role in mycolic acid biosynthesis by functionally linking fatty acid synthase (FAS) and polyketide synthase (PKS) biosynthetic pathways. FadD32, a fatty acyl-AMP ligase (FAAL), represents one of the best genetically and chemically validated new TB drug targets. We have determined the three-dimensional crystal structure ofMtbFadD32 in complex with a ligand specifically designed to stabilize the catalytically active adenylate-conformation, which provides a foundation for structure-based drug design efforts against this essential protein. The structure also captures the unique interactions of a FAAL-specific insertion sequence and provides insight into the specificity and mechanism of fatty acid transfer.
authors.affiliation: Center for Structural Genomics of Infectious Diseases, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States; Center for Drug Design, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors.forename: Misty L
authors.initials: ML
authors.lastname: Kuhn
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors.forename: Evan
authors.initials: E
authors.lastname: Alexander
authors.affiliation: Center for Structural Genomics of Infectious Diseases, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
authors.forename: George
authors.initials: G
authors.lastname: Minasov
authors.affiliation: Center for Drug Design, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors.forename: Holland J
authors.initials: HJ
authors.lastname: Page
authors.affiliation: Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California 94132, United States.
authors.forename: Zdzislaw
authors.initials: Z
authors.lastname: Warwrzak
authors.affiliation: Center for Structural Genomics of Infectious Diseases, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
authors.forename: Ludmilla
authors.initials: L
authors.lastname: Shuvalova
authors.affiliation: Center for Structural Genomics of Infectious Diseases, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
authors.forename: Kristin J
authors.initials: KJ
authors.lastname: Flores
authors.affiliation: Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California 94132, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilson
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors.forename: Ce
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States; Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, California 94132, United States.
authors.forename: Courtney C
authors.initials: CC
authors.lastname: Aldrich
authors.affiliation: Center for Structural Genomics of Infectious Diseases, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
authors.forename: Wayne F
authors.initials: WF
authors.lastname: Anderson
keywords: FadD32; Mycobacterium tuberculosis; fatty acyl-AMP ligase; mycolic acid biosynthesis