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Structural Study of Monomethyl Fumarate-Bound Human GAPDH
Jun Bae Park1, Hayeong Park1, Jimin Son2
1Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
Monomethyl fumarate (MMF) covalently binds to human Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), inhibiting its enzymatic activity. This structural study reveals MMF blocks NAD+ binding, offering insights for developing new GAPDH-targeting therapies.
Area of Science:
- Biochemistry
- Structural Biology
- Enzymology
Background:
- Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme implicated in cancer.
- Monomethyl fumarate (MMF) is a known antagonist of GAPDH in the immune system.
Purpose of the Study:
- To elucidate the crystal structure of MMF-bound human GAPDH.
- To understand the molecular mechanism of MMF-induced GAPDH inhibition.
Main Methods:
- X-ray crystallography to determine the 2.29 Å structure of MMF-bound human GAPDH.
- Structural comparison with NAD+-bound GAPDH.
Main Results:
- MMF forms a covalent bond with the catalytic Cys152 residue of human GAPDH.
- MMF binding sterically hinders the nicotinamide portion of NAD+, preventing cosubstrate binding.
- Enzymatic activity of GAPDH is significantly reduced by MMF covalent linkage.
Conclusions:
- The crystal structure reveals the precise mechanism of MMF inhibition of GAPDH.
- Understanding this interaction provides a basis for designing novel GAPDH antagonists for therapeutic applications in diseases involving GAPDH.
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