Characterization of the flavin monooxygenase involved in biosynthesis of the antimalarial FR-900098

Kim Nguyen, Matthew A. DeSieno, Brian Bae, Tyler W. Johannes, Ryan E. Cobb, Huimin Zhao, Satish K Nair

Research output: Contribution to journalArticle

Abstract

The latter steps in this biosynthetic pathway for the antimalarial phosphonic acid FR-900098 include the installation of a hydroxamate onto 3-aminopropylphosphonate, which is catalyzed by the consecutive actions of an acetyltransferase and an amine hydroxylase. Here, we present the 1.6 Å resolution co-crystal structure and accompanying biochemical characterization of FrbG, which catalyzes the hydroxylation of aminopropylphosphonate. We show that FrbG is a flavin-dependent N-hydroxylating monooxygenase (NMO), which shares a similar overall structure with flavin-containing monooxygenases (FMOs). Notably, we also show that the cytidine-5′-monophosphate moiety of the substrate is a critical determinant of specificity, distinguishing FrbG from other FMOs in that the nucleotide cofactor-binding domain also serves in conferring substrate recognition. In the FrbG-FAD + -NADPH co-crystal structure, the C4 of the NADPH nicotinamide is situated near the N5 of the FAD isoalloxazine, and is oriented with a distance and stereochemistry to facilitate hydride transfer.

Original languageEnglish (US)
Pages (from-to)1506-1518
Number of pages13
JournalOrganic and Biomolecular Chemistry
Volume17
Issue number6
DOIs
StatePublished - Jan 1 2019

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dimethylaniline monooxygenase (N-oxide forming)
Flavin-Adenine Dinucleotide
biosynthesis
Biosynthesis
Antimalarials
Mixed Function Oxygenases
NADP
Crystal structure
Cytidine Monophosphate
nicotinamide
Cytidine
Hydroxylation
Stereochemistry
Acetyltransferases
crystal structure
Niacinamide
Biosynthetic Pathways
nucleotides
stereochemistry
Substrates

ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Characterization of the flavin monooxygenase involved in biosynthesis of the antimalarial FR-900098. / Nguyen, Kim; DeSieno, Matthew A.; Bae, Brian; Johannes, Tyler W.; Cobb, Ryan E.; Zhao, Huimin; Nair, Satish K.

In: Organic and Biomolecular Chemistry, Vol. 17, No. 6, 01.01.2019, p. 1506-1518.

Research output: Contribution to journalArticle

Nguyen, Kim ; DeSieno, Matthew A. ; Bae, Brian ; Johannes, Tyler W. ; Cobb, Ryan E. ; Zhao, Huimin ; Nair, Satish K. / Characterization of the flavin monooxygenase involved in biosynthesis of the antimalarial FR-900098. In: Organic and Biomolecular Chemistry. 2019 ; Vol. 17, No. 6. pp. 1506-1518.
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