Antihypertensive drug valsartan as a novel BDK inhibitor.
Antihypertensive drug valsartan as a novel BDK inhibitor.
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DOI：
10.1016/j.phrs.2021.105518
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发表时间：
2021-02
影响因子：
9.3
通讯作者：
Y. Kitaura;Daichi Shindo;T. Ogawa;Ayato Sato;Y. Shimomura
中科院分区：
文献类型：
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作者：
Y. Kitaura;Daichi Shindo;T. Ogawa;Ayato Sato;Y. Shimomura
支链氨基酸（BCAAs）的代谢受多种生理条件的影响，其异常与糖代谢、心脏病和神经功能障碍有关。BCAA代谢途径的前两步是三种BCAA（亮氨酸，异亮氨酸和缬氨酸）共同的。第二步是由支链α-酮酸脱氢酶（BCKDH）催化的不可逆限速反应，该酶与特定激酶BCKDH激酶（BDK）结合，并通过磷酸化失活。在这里，我们研究了潜在的新的BDK抑制剂，并发现缬沙坦，血管紧张素II 1型受体（AT 1 R）阻滞剂，作为一种新的BDK抑制剂。体外缬沙坦可抑制BCKDH磷酸化和BCKDH-BDK相互作用。大鼠给予缬沙坦可通过降低BCKDH复合物的去磷酸化水平、BCKDH复合物中BDK的结合形式以及降低血浆BCAA浓度来增加BCKDH活性。缬沙坦是一种新型的BDK抑制剂，通过与别构抑制剂不同的机制与ATP竞争。BDK抑制剂已被证明可以保护压力超负荷诱导的心力衰竭小鼠的心脏功能，并减轻肥胖小鼠的胰岛素抵抗。我们的研究结果表明，缬沙坦是一种有效的种子化合物，用于开发一种强大的BDK抑制剂和治疗心力衰竭和代谢性疾病与抑制BCAA催化剂的有用药物。
Catabolism of branched-chain amino acids (BCAAs) is affected by various physiological conditions and its abnormality is associated with glucose metabolism, heart disease, and neurological dysfunction. The first two steps of the BCAA metabolic pathway are common to the three BCAAs (leucine, isoleucine, and valine). The second step is an irreversible rate-limited reaction catalyzed by branched-chain α-keto acid dehydrogenase (BCKDH), which is bound to a specific kinase, BCKDH kinase (BDK), and inactivated by phosphorylation. Here, we investigated potential new BDK inhibitors and discovered valsartan, an angiotensin II type 1 receptor (AT1R) blocker, as a new BDK inhibitor. BCKDH phosphorylation and the BCKDH-BDK interaction were inhibited by valsartanin vitro. Valsartan administration in rats resulted in increased BCKDH activity by decreasing the dephosphorylated level of BCKDH complex, bound forms of BDK from BCKDH complex as well as decreased plasma BCAA concentrations. Valsartan is a novel BDK inhibitor that competes with ATP,viaa different mechanism from allosteric inhibitors. The BDK inhibitor has been shown to preserve cardiac function in pressure overload-induced heart failure mice and to attenuate insulin resistance in obese mice. Our findings suggest that valsartan is a potent seed compound for developing a powerful BDK inhibitor and useful medication for treating heart failure and metabolic diseases with suppressed BCAA catabolism.