Goodwin D C, Landino L M, Marnett L J
Department of Biochemistry, A. B. Hancock Jr. Memorial Laboratory for Cancer Research, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
FASEB J. 1999 Jul;13(10):1121-36. doi: 10.1096/fasebj.13.10.1121.
Prostaglandins and NO. are important mediators of inflammation and other physiological and pathophysiological processes. Continuous production of these molecules in chronic inflammatory conditions has been linked to development of autoimmune disorders, coronary artery disease, and cancer. There is mounting evidence for a biological relationship between prostanoid biosynthesis and NO. biosynthesis. Upon stimulation, many cells express high levels of nitric oxide synthase (NOS) and prostaglandin endoperoxide synthase (PGHS). There are reports of stimulation of prostaglandin biosynthesis in these cells by direct interaction between NO. and PGHS, but this is not universally observed. Clarification of the role of NO. in PGHS catalysis has been attempted by examining NO. interactions with purified PGHS, including binding to its heme prosthetic group, cysteines, and tyrosyl radicals. However, a clear picture of the mechanism of PGHS stimulation by NO. has not yet emerged. Available studies suggest that NO. may only be a precursor to the molecule that interacts with PGHS. Peroxynitrite (from O2.-+NO.) reacts directly with PGHS to activate prostaglandin synthesis. Furthermore, removal of O2.- from RAW 267.4 cells that produce NO. and PGHS inhibits prostaglandin biosynthesis to the same extent as NOS inhibitors. This interaction between reactive nitrogen species and PGHS may provide new approaches to the control of inflammation in acute and chronic settings.
前列腺素和一氧化氮是炎症以及其他生理和病理生理过程的重要介质。在慢性炎症状态下，这些分子的持续产生与自身免疫性疾病、冠状动脉疾病和癌症的发展有关。越来越多的证据表明类前列腺素生物合成与一氧化氮生物合成之间存在生物学关系。受到刺激后，许多细胞会大量表达一氧化氮合酶（NOS）和前列腺素内过氧化物合酶（PGHS）。有报道称，一氧化氮与PGHS之间的直接相互作用可刺激这些细胞中的前列腺素生物合成，但并非普遍观察到这种现象。通过研究一氧化氮与纯化的PGHS的相互作用，包括与其血红素辅基、半胱氨酸和酪氨酸自由基的结合，试图阐明一氧化氮在PGHS催化中的作用。然而，一氧化氮刺激PGHS的机制仍未完全明确。现有研究表明，一氧化氮可能只是与PGHS相互作用的分子的前体。过氧亚硝酸盐（由超氧阴离子O₂⁻与一氧化氮反应生成）可直接与PGHS反应以激活前列腺素合成。此外，在产生一氧化氮和PGHS的RAW 267.4细胞中去除超氧阴离子，对前列腺素生物合成的抑制程度与NOS抑制剂相同。活性氮物种与PGHS之间的这种相互作用可能为急性和慢性炎症的控制提供新方法。
