SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion.
SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion.
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DOI：
10.1016/j.cmet.2017.03.003
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发表时间：
2017-04-04
期刊：
影响因子：
29
通讯作者：
Hirschey MD
中科院分区：
文献类型：
--
作者：
Anderson KA;Huynh FK;Fisher-Wellman K;Stuart JD;Peterson BS;Douros JD;Wagner GR;Thompson JW;Madsen AS;Green MF;Sivley RM;Ilkayeva OR;Stevens RD;Backos DS;Capra JA;Olsen CA;Campbell JE;Muoio DM;Grimsrud PA;Hirschey MD
Sirtuins是一种依赖NAD+的蛋白脱酰酶，调节新陈代谢和衰老的几个方面。与其他哺乳动物sirtuin相比，线粒体sirtuin 4(SIRT4)的主要酶活性及其在代谢控制中的整体作用仍然是个谜。结合系统发育学、结构生物学和酶学，我们证明SIRT4从赖氨酸残基中去除了三个酰基-甲基戊二酰基(MG)、羟甲基戊二酰基(HMG)和3-甲基谷氨酰基(MGC)-赖氨酸。导致这些翻译后修饰的代谢产物是亮氨酸氧化的中间产物，我们发现SIRT4在小鼠体内控制这一途径的主要作用。此外，我们发现SIRT4KO小鼠的亮氨酸代谢异常导致基础和刺激的胰岛素分泌增加，这逐渐发展为葡萄糖耐量异常和胰岛素抵抗。这些发现确定了SIRT4具有很强的酶活性，揭示了控制支链氨基酸流量的机制，并将SIRT4定位为在衰老过程中维持胰岛素分泌和葡萄糖动态平衡的关键角色。
Sirtuins are NAD+-dependent protein deacylases that regulate several aspects of metabolism and aging. In contrast to the other mammalian sirtuins, the primary enzymatic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control has remained enigmatic. Using a combination of phylogenetics, structural biology, and enzymology, we show that SIRT4 removes three acyl moieties from lysine residues – methylglutaryl(MG)-, hydroxymethylglutaryl(HMG)-, and 3-methylglutaconyl(MGc)-lysine. The metabolites leading to these post-translational modifications are intermediates in leucine oxidation, and we show a primary role for SIRT4 in controlling this pathway in mice. Furthermore, we find that dysregulated leucine metabolism in SIRT4KO mice leads to elevated basal and stimulated insulin secretion, which progressively develops into glucose intolerance and insulin resistance. These findings identify a robust enzymatic activity for SIRT4, uncover a mechanism controlling branched-chain amino acid flux, and position SIRT4 as a crucial player maintaining insulin secretion and glucose homeostasis during aging.