5ZJF

LDHA-MA

Summary for 5ZJF

• Entry DOI: 10.2210/pdb5zjf/pdb
• Descriptor: L-lactate dehydrogenase A chain, 5,5'-[(2R,3S)-2,3-dimethylbutane-1,4-diyl]bis(2H-1,3-benzodioxole) (3 entities in total)
• Functional Keywords: ldha, inhibitor, machilin a, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 12
• Total formula weight: 449514.65

Authors

Han, C.W.,Jang, S.B. (deposition date: 2018-03-20, release date: 2019-07-24, Last modification date: 2023-11-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.602 Å)