Structural Study of Monomethyl Fumarate-Bound Human GAPDH

Molecules and Cells
Jun Bae ParkHyun-Soo Cho

Abstract

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.

Methods Mentioned

BETA
gel filtration
density gradient centrifugation

Software Mentioned

COOT
MOLREP
REFMAC5
DALI
GraphPad
HKL2000
FlowJo
Prism

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