Department of Biomolecular Chemistry, University of Wisconsin, Madison, Wisconsin 53715, USA.
J Biol Chem. 2012 Feb 3;287(6):3850-8. doi: 10.1074/jbc.M111.317404. Epub 2011 Dec 7.
Emerging proteomic evidence suggests that acetylation of metabolic enzymes is a prevalent post-translational modification. In a few recent reports, acetylation down-regulated activity of specific enzymes in fatty acid oxidation, urea cycle, electron transport, and anti-oxidant pathways. Here, we reveal that the glycolytic enzyme phosphoglycerate mutase-1 (PGAM1) is negatively regulated by Sirt1, a member of the NAD(+)-dependent protein deacetylases. Acetylated PGAM1 displays enhanced activity, although Sirt1-mediated deacetylation reduces activity. Acetylation sites mapped to the C-terminal "cap," a region previously known to affect catalytic efficiency. Overexpression of a constitutively active variant (acetylated mimic) of PGAM1 stimulated flux through glycolysis. Under glucose restriction, Sirt1 levels dramatically increased, leading to PGAM1 deacetylation and attenuated activity. Previously, Sirt1 has been implicated in the adaptation from glucose to fat burning. This study (i) demonstrates that protein acetylation can stimulate metabolic enzymes, (ii) provides biochemical evidence that glycolysis is modulated by reversible acetylation, and (iii) demonstrates that PGAM1 deacetylation and activity are directly controlled by Sirt1.
新兴的蛋白质组学证据表明，代谢酶的乙酰化是一种普遍的翻译后修饰。在最近的一些报告中，乙酰化下调了脂肪酸氧化、尿素循环、电子传递和抗氧化途径中特定酶的活性。在这里，我们揭示了糖酵解酶磷酸甘油酸变位酶-1（PGAM1）受 NAD(+)-依赖的蛋白去乙酰化酶 Sirt1 的负调控。乙酰化的 PGAM1 显示出增强的活性，尽管 Sirt1 介导的去乙酰化降低了活性。乙酰化位点映射到 C 末端“帽”，这是一个先前已知影响催化效率的区域。PGAM1 的组成活性变体（乙酰化模拟物）的过表达刺激了糖酵解途径的通量。在葡萄糖限制下，Sirt1 水平显著增加，导致 PGAM1 去乙酰化和活性降低。先前，Sirt1 已被牵连到从葡萄糖到脂肪燃烧的适应中。本研究（i）表明蛋白质乙酰化可以刺激代谢酶，（ii）提供了生化证据表明糖酵解可通过可逆乙酰化进行调节，以及（iii）表明 PGAM1 的去乙酰化和活性可直接受到 Sirt1 的控制。
