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Crystal Structure of GenD2, an NAD-Dependent Oxidoreductase Involved in the Biosynthesis of Gentamicin.
de Araújo, Natalia Cerrone; Bury, Priscila Dos Santos; Tavares, Maurício Temotheo; Huang, Fanglu; Parise-Filho, Roberto; Leadlay, Peter; Dias, Marcio Vinicius Bertacine.
Afiliação
  • de Araújo NC; Department of Microbiology, Institute of Biomedical Science , University of São Paulo , Avenida Prof. Lineu Prestes 1374 , 05508-900 São Paulo , Brazil.
  • Bury PDS; Department of Microbiology, Institute of Biomedical Science , University of São Paulo , Avenida Prof. Lineu Prestes 1374 , 05508-900 São Paulo , Brazil.
  • Tavares MT; Department of Pharmacy, Faculty of Pharmaceutical Sciences , University of São Paulo , Prof. Lineu Prestes Avenue 580 , 05508-900 São Paulo , Brazil.
  • Huang F; Department of Biochemistry , University of Cambridge , 80 Tennis Court Road , Cambridge CB2 1GA , U.K.
  • Parise-Filho R; Department of Pharmacy, Faculty of Pharmaceutical Sciences , University of São Paulo , Prof. Lineu Prestes Avenue 580 , 05508-900 São Paulo , Brazil.
  • Leadlay P; Department of Biochemistry , University of Cambridge , 80 Tennis Court Road , Cambridge CB2 1GA , U.K.
  • Dias MVB; Department of Microbiology, Institute of Biomedical Science , University of São Paulo , Avenida Prof. Lineu Prestes 1374 , 05508-900 São Paulo , Brazil.
ACS Chem Biol ; 14(5): 925-933, 2019 05 17.
Article em En | MEDLINE | ID: mdl-30995396
Gentamicins are clinically relevant aminoglycoside antibiotics produced by several Micromonospora species. Gentamicins are highly methylated and functionalized molecules, and their biosynthesis include glycosyltransferases, dehydratase/oxidoreductases, aminotransferases, and methyltransferases. The biosynthesis of gentamicin A from gentamicin A2 involves three enzymatic steps that modify the hydroxyl group at position 3″ of the unusual garosamine sugar to provide its substitution for an amino group, followed by an N-methylation. The first of these reactions is catalyzed by GenD2, an oxidoreductase from the Gfo/Idh/MocA protein family, which reduces the hydroxyl at the C3″ of gentamicin A to produce 3''-dehydro-3''-oxo-gentamicin A2 (DOA2). In this work, we solved the structure of GenD2 in complex with NAD+. Although the structure of GenD2 has a similar fold to other members of the Gfo/Idh/MocA family, this enzyme has several new features, including a 3D-domain swapping of two ß-strands that are involved in a novel oligomerization interface for this protein family. In addition, the active site of this enzyme also has several specialties which are possibly involved in the substrate specificity, including a number of aromatic residues and a negatively charged region, which is complementary to the polycationic aminoglycoside-substrate. Therefore, docking simulations provided insights into the recognition of gentamicin A2 and into the catalytic mechanism of GenD2. This is the first report describing the structure of an oxidoreductase involved in aminoglycoside biosynthesis and could open perspectives into producing new aminoglycoside derivatives by protein engineering.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxirredutases / Gentamicinas / NAD Idioma: En Revista: ACS Chem Biol Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxirredutases / Gentamicinas / NAD Idioma: En Revista: ACS Chem Biol Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos