The biosynthetic pathway of the benzoxazole in nataxazole proceeds via an unstable ester and has synthetic utility

DOI: 10.1002/anie.201915685

Authors: Haigang Song (University of Oxford) , Cong Rao (Wuhan University) , Zixin Deng (Wuhan University) , Yu Yi (Wuhan University) , James H. Naismith (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Angewandte Chemie International Edition

State: Published (Approved)
Published: January 2020

Abstract: Heterocycles, a class of molecules that includes oxazoles, constitute one of the most common building blocks in current pharmaceuticals and are common in medicinally important natural products. The antitumor natural product nataxazole is a model for a large class of benzoxazole containing molecules that are made by a pathway that is not characterized. We report structural, biochemical and chemical evidence that benzoxazole biosynthesis proceeds through an ester generated by an ATP dependent adenylating enzyme. The ester re‐arranges via a tetrahedral hemiorthoamide to yield an amide which is a shunt product and not, as previously thought, an intermediate in the pathway. A second zinc dependent enzyme catalyses formation of hemiorthoamide from the ester but, by shuttling protons, the enzyme eliminates water, a reverse hydrolysis reaction, to yield the benzoxazole and avoids the amide. These insights have allowed us to harness the pathway to synthesize a series of novel halogenated benzoxazoles.

Journal Keywords: heterocycle; benzoxazole; amidohydrolase; unstable ester; hemiorthoamide intermediate

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Documents:
Song_et_al-2020.pdf

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)