Structures of Iridoid Synthase from Cantharanthus roseus with Bound NAD(+) , NADPH, or NAD(+) /10-Oxogeranial: Reaction Mechanisms

Angewandte Chemie
Yumei HuRey-Ting Guo

Abstract

Structures of the iridoid synthase nepetalactol synthase in the presence of NAD(+) , NADPH or NAD(+) /10-oxogeranial were solved. The 10-oxogeranial substrate binds in a transoid-O1-C3 conformation and can be reduced by hydride addition to form the byproduct S-10-oxo-citronellal. Tyr178 Oζ is positioned 2.5 Å from the substrate O1 and provides the second proton required for reaction. Nepetalactol product formation requires rotation about C1-C2 to form the cisoid isomer, leading to formation of the cis-enolate, together with rotation about C4-C5, which enables cyclization and lactol production. The structure is similar to that of progesterone-5β-reductase, with almost identical positioning of NADP, Lys146(147), Tyr178(179), and F342(343), but only Tyr178 and Phe342 appear to be essential for activity. The transoid 10-oxogeranial structure also serves as a model for β-face hydride attack in progesterone 5β-reductases and is of general interest in the context of asymmetric synthesis.

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Citations

Jan 22, 2019·Chemistry : a European Journal·Benjamin R LichmanHajo Kries
Oct 28, 2019·Natural Product Reports·Jeffrey D Rudolf, Chin-Yuan Chang
Dec 12, 2018·Nature Chemical Biology·Benjamin R LichmanSarah E O'Connor
Oct 6, 2020·Chemistry, an Asian Journal·Ryuji Kouda, Fumika Yakushiji
Apr 15, 2021·Chemistry : a European Journal·Suzanne J PartridgeMichael A Birkett
Aug 26, 2017·Chemical Reviews·David W Christianson
Nov 24, 2021·Journal of the American Chemical Society·Sei-Hyun ChoiHung-Wen Liu

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