A secondary kinetic isotope effect study of the 1-deoxy-D-xylulose-5-phosphate reductoisomerase-catalyzed reaction: evidence for a retroaldol-aldol rearrangement

Journal of the American Chemical Society
Jeffrey W MunosHung-Wen Liu

Abstract

1-Deoxy-d-xylulose 5-phosphate (DXP) reductoisomerase (DXR, also known as methyl-d-erythritol 4-phosphate (MEP) synthase) is a NADPH-dependent enzyme, which catalyzes the conversion of DXP to MEP in the nonmevalonate pathway of isoprene biosynthesis. Two mechanisms have been proposed for the DXR-catalyzed reaction. In the alpha-ketol rearrangement mechanism, the reaction begins with deprotonation of the C-3 hydroxyl group followed by a 1,2-migration to give methylerythrose phosphate, which is then reduced to MEP by NADPH. In the retroaldol/aldol rearrangement mechanism, DXR first cleaves the C3-C4 bond of DXP in a retroaldol manner to generate a three-carbon and a two-carbon phosphate bimolecular intermediate. These two species are then reunited by an aldol reaction to form a new C-C bond, yielding an aldehyde intermediate. Subsequent reduction by NADPH affords MEP. To differentiate these mechanisms, we have prepared [3-(2)H]- and [4-(2)H]-DXP and carried out a competitive secondary kinetic isotope effect (KIE) study of the DXR reaction. The normal 2 degrees KIEs observed for [3-(2)H]- and [4-(2)H]-DXP provide compelling evidence supporting a retroaldol/aldol mechanism for the rearrangement catalyzed by DXR, with the rate-limit...Continue Reading

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Citations

Nov 2, 2013·Chemical Reviews·Alexander R MoiseEleanore T Wurtzel
Aug 10, 2011·Chemical Communications : Chem Comm·Sei-hyun ChoiHung-Wen Liu
Jun 12, 2013·Annual Review of Biochemistry·Lishan ZhaoPinghua Liu
May 1, 2013·Journal of the American Chemical Society·Bradley M HoverKenichi Yokoyama
Jul 12, 2011·Cellular and Molecular Life Sciences : CMLS·Tobias GräwertWolfgang Eisenreich
Dec 27, 2011·Progress in Lipid Research·Andréa HemmerlinThomas J Bach
Dec 21, 2016·Chemical Reviews·Annika Frank, Michael Groll
Jan 27, 2016·MedChemComm·Jonathan R ChekanSatish K Nair
Oct 8, 2011·Natural Product Reports·Jeroen S Dickschat
Apr 26, 2013·The Biochemical Journal·Jordi Pérez-Gil, Manuel Rodríguez-Concepción
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Jul 13, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ge YanWen-Yun Gao
Aug 13, 2010·Journal of the American Chemical Society·Charles L Perrin, Phaneendrasai Karri

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