Issue 6, 2019

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

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.

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

Supplementary files

Article information

Article type
Paper
Submitted
14 Nov. 2018
Accepted
21 Janv. 2019
First published
21 Janv. 2019

Org. Biomol. Chem., 2019,17, 1506-1518

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

K. Nguyen, M. A. DeSieno, B. Bae, T. W. Johannes, R. E. Cobb, H. Zhao and S. K. Nair, Org. Biomol. Chem., 2019, 17, 1506 DOI: 10.1039/C8OB02840K

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