Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC, USA.
Department of Pharmacology & Cancer Biology, Durham, NC, USA.
Nat Commun. 2022 May 10;13(1):2542. doi: 10.1038/s41467-022-30060-w.
Statins are a class of drug widely prescribed for the prevention of cardiovascular disease, with pleiotropic cellular effects. Statins inhibit HMG-CoA reductase (HMGCR), which converts the metabolite HMG-CoA into mevalonate. Recent discoveries have shown HMG-CoA is a reactive metabolite that can non-enzymatically modify proteins and impact their activity. Therefore, we predicted that inhibition of HMGCR by statins might increase HMG-CoA levels and protein modifications. Upon statin treatment, we observe a strong increase in HMG-CoA levels and modification of only a single protein. Mass spectrometry identifies this protein as fatty acid synthase (FAS), which is modified on active site residues and, importantly, on non-lysine side-chains. The dynamic modifications occur only on a sub-pool of FAS that is located near HMGCR and alters cellular signaling around the ER and Golgi. These results uncover communication between cholesterol and lipid biosynthesis by the substrate of one pathway inhibiting another in a rapid and reversible manner.
他汀类药物是一类广泛用于预防心血管疾病的药物，具有多种细胞作用。他汀类药物抑制 HMG-CoA 还原酶（HMGCR），该酶将代谢物 HMG-CoA 转化为甲羟戊酸。最近的发现表明，HMG-CoA 是一种反应性代谢物，可以非酶促修饰蛋白质并影响其活性。因此，我们预测他汀类药物抑制 HMGCR 可能会增加 HMG-CoA 水平和蛋白质修饰。在他汀类药物治疗后，我们观察到 HMG-CoA 水平显著升高，并且仅修饰了一种蛋白质。质谱鉴定出这种蛋白质是脂肪酸合酶（FAS），它在活性位点残基和重要的非赖氨酸侧链上被修饰。动态修饰仅发生在靠近 HMGCR 的 FAS 的亚池上，并且改变了 ER 和高尔基体周围的细胞信号。这些结果揭示了胆固醇和脂质生物合成之间的通讯，即一条途径的底物以快速和可逆的方式抑制另一条途径。
