Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a core enzyme of the aerobic glycolytic pathway with versatile functions and is associated with cancer development. Recently, Kornberg et al. published the detailed correlation between GAPDH and di-or monomethyl fumarate (DMF or MMF), which are well-known GAPDH antagonists in the immune system. As an extension, herein, we report the crystal structure of MMF-bound human GAPDH at 2.29 Å. The MMF molecule is covalently linked to the catalytic Cys152 of human GAPDH, and inhibits the catalytic activity of the residue and dramatically reduces the enzymatic activity of GAPDH. Structural comparisons between NAD+-bound GAPDH and MMF-bound GAPDH revealed that the covalently linked MMF can block the binding of the NAD+ co-substrate due to steric hindrance of the nicotinamide portion of the NAD+ molecule, illuminating the specific mechanism by which MMF inhibits GAPDH. Our data provide insights into GAPDH antagonist development for GAPDH-mediated disease treatment.
Bibliographical noteFunding Information:
We thank the staff scientists at the beamline 5A and 1A of the Photon Factory and the beamline 11C of Pohang Light Source for their assistance. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (NRF-2016R1A2B2013305, 2016R1A5A1010764, and 2017M3A9F6029755) and by the Strategic Initiative for Microbiomes in Agriculture and Food funded by the Ministry of Agriculture, Food and Rural Affairs (918012-4).
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology