SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells.
SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells.
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DOI：
10.1016/j.freeradbiomed.2014.08.001
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发表时间：
2014-11
影响因子：
7.4
通讯作者：
Gius, David
中科院分区：
文献类型：
--
作者：
Ozden, Ozkan;Park, Seong-Hoon;Wagner, Brett A.;Song, Ha Yong;Zhu, Yueming;Vassilopoulos, Athanassios;Jung, Barbara;Buettner, Garry R.;Gius, David
丙酮酸脱氢酶E1 α（PDHE 1 α或PDHA 1）是丙酮酸脱氢酶（PDH）复合物（PDC）的第一个组分酶，通过丙酮酸脱羧将丙酮酸转化为乙酰辅酶A，随后被柠檬酸循环和氧化磷酸化用于生成ATP。因此，PDH连接正常细胞和癌细胞中的糖酵解和氧化磷酸化。在本文中，我们报告SIRT 3与PDHA 1相互作用，并通过蛋白质乙酰化的变化指导其酶活性。SIRT 3使PDHA 1赖氨酸321（K321）和PDHA 1突变体脱乙酰，模拟与K321乙酰化模拟物（PDHA 1 K321 Q）或野生型PDHA 1相比，脱乙酰赖氨酸（PDHA 1 K321 R）增加PDH活性。最后，与PDHA 1 K321 R相比，PDHA 1 K321 Q表现出更多的体外细胞表型转化。这些结果表明，PDHA 1的乙酰化提供了另一层酶的调节，除了磷酸化，涉及可逆的乙酰基-赖氨酸，表明乙酰基组，以及激酶组，链接糖酵解呼吸。
Pyruvate dehydrogenase E1 alpha (PDHE1α or PDHA1) is the first component enzyme of the pyruvate dehydrogenase (PDH) complex (PDC) that transforms pyruvate, via pyruvate decarboxylation, into acetyl-CoA that is subsequently used by both the citric acid cycle and oxidative phosphorylation to generate ATP. As such, PDH links glycolysis and oxidative phosphorylation in normal as well as cancer cells. Herein we report that SIRT3 interacts with PDHA1 and directs its enzymatic activity via changes in protein acetylation. SIRT3 deacetylates PDHA1 lysine 321 (K321) and a PDHA1 mutant, mimicking a deacetylated lysine (PDHA1K321R) increases in PDH activity, as compared to the K321 acetylation mimic (PDHA1K321Q) or wild-type PDHA1. Finally, PDHA1K321Q exhibited a more transformed in vitro cellular phenotype as compared to PDHA1K321R. These results suggest that the acetylation of PDHA1 provides another layer of enzymatic regulation, in addition to phosphorylation, involving a reversible acetyl-lysine suggesting that the acetylome, as well as the kinome, links glycolysis to respiration.
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影响因子：
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影响因子：
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