From the Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109-0606
J Biol Chem. 2019 Feb 8;294(6):1779-1793. doi: 10.1074/jbc.X118.006184.
Omega-6 polyunsaturated fatty acids were identified as essential nutrients in 1930. Their essentiality is largely due to their function as prostaglandin (PG) precursors. I spent most of my career in biochemistry determining how PG biosynthesis is regulated. PGs are lipid mediators formed in response to certain circulating hormones and cytokines. PGs act near their sites of synthesis to signal neighboring cells to coordinate their responses ( when platelets interact with blood vessels). The committed step in PG synthesis is the conversion of a 20-carbon omega-6 fatty acid called arachidonic acid to prostaglandin endoperoxide H (PGH). Depending on the tissue and the hormone or cytokine stimulus, this reaction is catalyzed by either cyclooxygenase-1 or cyclooxygenase-2 (COX-1 or COX-2). Once formed, PGH is converted, again depending on the context, to one of several downstream PG subtypes that act via specific G protein-coupled receptors. Nonsteroidal anti-inflammatory drugs ( aspirin, ibuprofen, and naproxen) block PG synthesis by inhibiting COX-1 and COX-2. COX-2 is also inhibited by COX-2-selective inhibitors. Inhibition of COX-1 by low-dose aspirin prevents thrombosis. COX-2 inhibition reduces inflammation and pain. Investigating the mysteries of COXs anchored my scientific career. I attribute my successes to the great good fortune of having been surrounded by people who helped me make the most of my talents. I have written this reflection in a light-hearted fashion as a self-help essay, while highlighting the people and factors that most impacted me during my upbringing and then during my maturation and evolution as a biochemist.
ω-6 多不饱和脂肪酸于 1930 年被确定为必需营养素。它们的必需性主要是由于它们作为前列腺素 (PG) 前体的功能。我职业生涯的大部分时间都在从事生物化学研究,以确定 PG 生物合成是如何被调节的。PG 是对某些循环激素和细胞因子作出反应而形成的脂质介质。PG 作为在其合成部位附近的信号分子,作用于邻近细胞以协调它们的反应(当血小板与血管相互作用时)。PG 合成的关键步骤是将 20 碳 ω-6 脂肪酸花生四烯酸转化为前列腺素内过氧化物 H (PGH)。根据组织和激素或细胞因子的刺激,该反应由环加氧酶-1 或环加氧酶-2 (COX-1 或 COX-2) 催化。一旦形成,PGH 再次根据上下文转化为几种下游 PG 亚型之一,这些亚型通过特定的 G 蛋白偶联受体发挥作用。非甾体抗炎药(阿司匹林、布洛芬和萘普生)通过抑制 COX-1 和 COX-2 来阻断 PG 合成。COX-2 也被 COX-2 选择性抑制剂抑制。小剂量阿司匹林抑制 COX-1 可预防血栓形成。COX-2 抑制可减轻炎症和疼痛。研究 COX 的奥秘奠定了我的科学生涯。我将我的成功归因于我有幸被一群帮助我充分发挥才能的人所包围。我以轻松的方式撰写这篇反思,作为一篇自助文章,同时强调了在我成长过程中以及作为一名生物化学家的成熟和发展过程中对我影响最大的人和因素。