Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
Mol Cells. 2019 Aug 31;42(8):597-603. doi: 10.14348/molcells.2019.0114.
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 NADbound 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.
甘油醛-3-磷酸脱氢酶（GAPDH）是有氧糖酵解途径的核心酶，具有多种功能，与癌症的发展有关。最近，Kornberg 等人发表了 GAPDH 与二甲基富马酸（DMF 或 MMF）之间的详细相关性，DMF 或 MMF 是免疫系统中众所周知的 GAPDH 拮抗剂。在此基础上，我们报告了在 2.29Å分辨率下结合 MMF 的人 GAPDH 的晶体结构。MMF 分子与 GAPDH 的催化半胱氨酸 152 共价结合，抑制该残基的催化活性，并显著降低 GAPDH 的酶活性。NAD 结合 GAPDH 与 MMF 结合 GAPDH 的结构比较表明，由于 NAD 分子的烟酰胺部分的空间位阻，共价结合的 MMF 可以阻止 NAD 辅助底物的结合，阐明了 MMF 抑制 GAPDH 的具体机制。我们的数据为 GAPDH 介导的疾病治疗中 GAPDH 拮抗剂的开发提供了深入了解。
