5ZJE

LDHA-mla

5ZJE の概要

• エントリーDOI: 10.2210/pdb5zje/pdb
• 分子名称: L-lactate dehydrogenase A chain, MALONATE ION (3 entities in total)
• 機能のキーワード: ldha wt, malonate, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 449800.54

構造登録者

Han, C.W.,Jang, S.B. (登録日: 2018-03-20, 公開日: 2019-07-24, 最終更新日: 2023-11-22)

主引用文献

Chung, T.-W.,Kim, E.-Y.,Han, C.W.,Park, S.Y.,Jeong, M.S.,Yoon, D.,Choi, H.-J.,Jin, L.,Park, M.-J.,Kwon, Y.J.,Lee, H.,Kim, K.-J.,Park, K.H.,Kim, S.,Jang, S.B.,Ha, K.-T.
Machilin A Inhibits Tumor Growth and Macrophage M2 Polarization Through the Reduction of Lactic Acid.
Cancers (Basel), 11:-, 2019

PubMed Abstract: Lactate dehydrogenase A (LDHA) is an important enzyme responsible for cancer growth and energy metabolism in various cancers via the aerobic glycolytic pathway. Here, we report that machilin A (MA), which acts as a competitive inhibitor by blocking the nicotinamide adenine dinucleotide (NAD) binding site of LDHA, suppresses growth of cancer cells and lactate production in various cancer cell types, including colon, breast, lung, and liver cancers. Furthermore, MA markedly decreased LDHA activity, lactate production, and intracellular adenosine triphosphate (ATP) levels induced by hypoxia-induced LDHA expression in cancer cells, and significantly inhibited colony formation, leading to reduced cancer cell survival. In mouse models inoculated with murine Lewis lung carcinoma, MA significantly suppressed tumor growth as observed by a reduction of tumor volume and weight; resulting from the inhibition of LDHA activity. Subsequently, the suppression of tumor-derived lactic acid in MA-treated cancer cells resulted in decrease of neovascularization through the regulation of alternatively activated macrophages (M2) polarization in macrophages. Taken together, we suggest that the reduction of lactate by MA in cancer cells directly results in a suppression of cancer cell growth. Furthermore, macrophage polarization and activation of endothelial cells for angiogenesis were indirectly regulated preventing lactate production in MA-treated cancer cells.

PubMed: 31324019
DOI: 10.3390/cancers11070963

実験手法

X-RAY DIFFRACTION (2.929 Å)