癌症中的乙酰辅酶A代谢

SCI

28 January 2022

Acetyl-CoA metabolism in cancer

(Nature Reviews Cancer, IF: 69.800)

David A. Guertin 1 & Kathryn E. Wellen

CORRESPONDENCE TO; david.guertin@umassmed.edu; wellenk@upenn.edu

Few metabolites can claim a more central and versatile role in cell metabolism than acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is produced during nutrient catabolism to fuel the tricarboxylic acid cycle and is the essential building block for fatty acid and isoprenoid biosynthesis. It also functions as a signalling metabolite as the substrate for lysine acetylation reactions, enabling the modulation of protein functions in response to acetyl-CoA availability. Recent years have seen exciting advances in our understanding of acetyl-CoA metabolism in normal physiology and in cancer, buoyed by new mouse models, in vivo stable-isotope tracing approaches and improved methods for measuring acetyl-CoA, including in specific subcellular compartments. Efforts to target acetyl-CoA metabolic enzymes are also advancing, with one therapeutic agent targeting acetyl-CoA synthesis receiving approval from the US Food and Drug Administration. In this Review, we give an overview of the regulation and cancer relevance of major metabolic pathways in which acetyl-CoA participates. We further discuss recent advances in understanding acetyl-CoA metabolism in normal tissues and tumours and the potential for targeting these pathways therapeutically. We conclude with a commentary on emerging nodes of acetyl-CoA metabolism that may impact cancer biology.

很少有代谢产物能比乙酰辅酶A（acetyl-CoA）在细胞代谢中发挥更重要和更广泛的作用。乙酰辅酶A是在营养分解代谢过程中产生的，为三羧酸循环提供燃料，是脂肪酸和类异戊二烯生物合成的重要组成部分。它还作为赖氨酸乙酰化反应的底物起信号代谢产物的作用，能够响应乙酰辅酶a的可用性调节蛋白质功能。近年来，在我们对正常生理学和癌症中乙酰辅酶A代谢机制的研究取得了令人兴奋的进展，这得益于新的小鼠模型、体内稳定同位素示踪方法和在特定亚细胞隔室中改进的测量乙酰辅酶a的方法。针对乙酰辅酶A代谢酶的努力也在推进，一种针对乙酰辅酶A合成的治疗剂获得了美国食品和药物管理局的批准。在这篇综述中，我们概述了乙酰辅酶A参与的主要代谢途径的调控和癌症相关性。我们进一步讨论了正常组织和肿瘤中乙酰辅酶A代谢的最新进展，以及治疗靶向这些途径的潜力。最后，我们对可能影响癌症生物学的乙酰辅酶A代谢新出现的节点进行了评论。