Department of Molecular Biology, College of Natural Sciences, Pusan National University, 2, Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan, 46241, Republic of Korea.
Institute of Systems Biology, Pusan National University, Jangjeon-dong, Geumjeong-gu, Busan, 46241, Republic of Korea.
Biochem Biophys Res Commun. 2024 Nov 12;733:150721. doi: 10.1016/j.bbrc.2024.150721. Epub 2024 Sep 19.
Lactate dehydrogenase A (LDHA) is a key enzyme in Warburg's effect, a characteristic of cancer cells. LDHA is a target of anticancer agents that inhibit the metabolism of cancer cells. Gossypol is a known cancer therapeutic agent that inhibits LDHA by competitive inhibition. However, the mechanisms of inhibition of LDHA by gossypol is unknown. Here, we elucidate the binding of gossypol and LDHA using biochemical and biophysical methods. The crystal structure of the complex between LDHA and gossypol is presented. The binding of gossypol affects LDHA activity by a conformational change in the active-site loop. Our research contributes to the structural insight into LDHA with gossypol and approaches gossypol as a novel therapeutic candidate targeting the metabolic pathways for cancer cells.
乳酸脱氢酶 A（LDHA）是沃伯格效应的关键酶，也是癌细胞的特征。LDHA 是抗癌药物的靶点，这些药物可以抑制癌细胞的代谢。棉酚是一种已知的癌症治疗药物，通过竞争性抑制来抑制 LDHA。然而，棉酚抑制 LDHA 的机制尚不清楚。在这里，我们使用生化和生物物理方法阐明了棉酚与 LDHA 的结合。提出了 LDHA 与棉酚复合物的晶体结构。棉酚的结合通过活性位点环的构象变化影响 LDHA 的活性。我们的研究为 LDHA 与棉酚的结构提供了深入的了解，并将棉酚作为一种针对癌细胞代谢途径的新型治疗候选药物进行研究。
