College of Pharmacy, Dongguk University-Seoul, Goyang, Gyeonggi 10326, Korea.
Biomolecules. 2022 Aug 25;12(9):1175. doi: 10.3390/biom12091175.
Malate dehydrogenase (MDH), which catalyzes a reversible conversion of -malate to oxaloacetate, plays essential roles in common metabolic processes, such as the tricarboxylic acid cycle, the oxaloacetate-malate shuttle, and the glyoxylate cycle. MDH2 has lately been recognized as a promising anticancer target; however, the structural information for the human homologue with natural ligands is very limited. In this study, various complex structures of hMDH2, with its substrates and/or cofactors, were solved by X-ray crystallography, which could offer knowledge about the molecular and enzymatic mechanism of this enzyme and be utilized to design novel inhibitors. The structural comparison suggests that phosphate binds to the substrate binding site and brings the conformational change of the active loop to a closed state, which can secure the substate and cofactor to facilitate enzymatic activity.
苹果酸脱氢酶（MDH）可催化 - 苹果酸可逆转化为草酰乙酸，在三羧酸循环、草酰乙酸-苹果酸穿梭和乙醛酸循环等常见代谢过程中发挥重要作用。MDH2 最近被认为是一种很有前途的抗癌靶点；然而，具有天然配体的人同源物的结构信息非常有限。在这项研究中，通过 X 射线晶体学解决了各种具有其底物和/或辅因子的 hMDH2 复合物结构，这为该酶的分子和酶学机制提供了知识，并可用于设计新型抑制剂。结构比较表明，磷酸盐结合到底物结合位点，并使活性环的构象发生变化，使其处于封闭状态，从而固定底物和辅因子，促进酶的活性。
