Global view of cognate kinase activation by the human pyruvate dehydrogenase complex.
Global view of cognate kinase activation by the human pyruvate dehydrogenase complex.
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DOI：
10.1038/srep42760
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发表时间：
2017-02-23
影响因子：
4.6
通讯作者：
Jordan F
中科院分区：
文献类型：
--
作者：
Guevara EL;Yang L;Birkaya B;Zhou J;Nemeria NS;Patel MS;Jordan F
人丙酮酸脱氢酶复合物（PDC）由E1、E3、E2和一个E3结合蛋白（E3BP）组成，后两者构成E2·E3BP亚复合物的核心。丙酮酸通过PDC的通量通过四种PDC激酶（PDKs）在E1上的磷酸化（失活）和两种PDC磷酸酶的再激活来调节。PDK异构体基因表达上调在多种癌症中都有报道，而PDK可能通过与E2·E3BP核心结合而进一步被PDC激活。因此，PDK: E2·E3BP相互作用提供了新的治疗靶点。我们进行了功能动力学和热力学研究，以证明PDK同工异构体通过与E2·E3BP核心结合而激活的显著差异：(i) PDK2不需要E2·E3BP激活即可有效发挥功能，而PDK4是四个同工异构体中最不有效的，不能被E2·E3BP激活。因此，抑制PDK2和PDK4与E2·E3BP相互作用的抑制剂的开发前景并不乐观；（ii）设计干扰E2·E3BP与PDK1和PDK3相互作用的抑制剂是有希望的。PDK3需要E2·E3BP核心进行活化，E2衍生的催化结构域和三元结构域的协同组合是实现活化的最佳途径。
The human pyruvate dehydrogenase complex (PDC) comprises four multidomain components, E1, E3, E2 and an E3-binding protein (E3BP), the latter two forming the core as E2·E3BP sub-complex. Pyruvate flux through PDC is regulated via phosphorylation (inactivation) at E1 by four PDC kinases (PDKs), and reactivation by two PDC phosphatases. Up-regulation of PDK isoform gene expression is reported in several forms of cancer, while PDKs may be further activated by PDC by binding to the E2·E3BP core. Hence, the PDK: E2·E3BP interaction provides new therapeutic targets. We carried out both functional kinetic and thermodynamic studies to demonstrate significant differences in the activation of PDK isoforms by binding to the E2·E3BP core: (i) PDK2 needs no activation by E2·E3BP for efficient functioning, while PDK4 was the least effective of the four isoforms, and could not be activated by E2·E3BP. Hence, development of inhibitors to the interaction of PDK2 and PDK4 with E2·E3BP is not promising; (ii) Design of inhibitors to interfere with interaction of E2·E3BP with PDK1 and PDK3 is promising. PDK3 needs E2·E3BP core for activation, an activation best achieved by synergistic combination of E2-derived catalytic domain and tridomain.