Structural Study of Monomethyl Fumarate-Bound Human GAPDH
Jun Bae Park1, Hayeong Park1, Jimin Son2, Sang-Jun Ha2, and Hyun-Soo Cho1,*
1Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea, 2Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
Received May 29, 2019; Revised July 19, 2019; Accepted July 19, 2019.; Published online August 6, 2019.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is acore enzyme of the aerobic glycolytic pathway with versatilefunctions and is associated with cancer development.Recently, Kornberg et al. published the detailed correlationbetween GAPDH and di- or monomethyl fumarate (DMFor MMF), which are well-known GAPDH antagonists inthe immune system. As an extension, herein, we report thecrystal structure of MMF-bound human GAPDH at 2.29Å. The MMF molecule is covalently linked to the catalyticCys152 of human GAPDH, and inhibits the catalytic activityof the residue and dramatically reduces the enzymaticactivity of GAPDH. Structural comparisons between NAD+-bound GAPDH and MMF-bound GAPDH revealed that thecovalently linked MMF can block the binding of the NAD+ cosubstrate due to steric hindrance of the nicotinamide portionof the NAD+ molecule, illuminating the specific mechanismby which MMF inhibits GAPDH. Our data provide insightsinto GAPDH antagonist development for GAPDH-mediateddisease treatment.
Keywords: crystallography, glyceraldehyde-3-phosphate dehydrogenase, inhibitor, monomethyl fumarate
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31 July 2019 Volume 42,
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