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Mol Cells. 2019 Aug 31;42(8):597-603. doi: 10.14348/molcells.2019.0114.

Structural Study of Monomethyl Fumarate-Bound Human GAPDH.

Author information

1
Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
2
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.

Abstract

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+ cosubstrate 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.

KEYWORDS:

crystallography; glyceraldehyde-3-phosphate dehydrogenase; inhibitor; monomethyl fumarate

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