Crossroads of L-Arginine/Arachidonate Metabolism

Abstract

Nitric oxide (NO) and prostacyclin (PGI, or prostaglandins (e.g., PGE) disclose a couple of biological similarities. The substrates for their biosynthesis [L-arginine (L-Arg) or arachidonate (AA)] abide structural peptides or phospholipids. Hydrolysis is required to present the zubstrates to corresponding diorygenases, i.e., NO synthase (NOS) or PGH synthase (PGHS) with its cyclooxygenase (COX) subunit. Both NOS and COX exist in their constinrtive (e.g., ecNOS, COX-I) or inducible (iNOS, COX-2) isoforms. Transcription of iNOS and COX-2 is triggered by cytokines or endotoxin (lipopolysaccharide from Escherichia coli, LPS). The endothelial constitutive enzymes release NO and PGI2 in a coupled manner (1,2). These endothelial mediators execute their cytoprotective firnctions through cyclic nucleotides, i.e., cyclic-GMP and cyclic-AMP, respectively. Some other eicosanoids, e.9., Coxderived thromboxane A2 (TXAz) or 5-lipoxygenasederived cysteinyl-letrkotrienes (e.9., LTCa) are cytotoxic just like NO might be (1 ,2). Free radicals are essential for the performance of NO and eicosanoids. For instance, superoxide anion (Ot) reveals its hidden cytotoxicity by making peroxynitrite (ONOO-) of NO. Peroxynitrite is the only generator of biogenic nitrotyrosine Q,4); it is an activator of polyadenosinediphosphateribose synthase (PARS) atrd, thereby, a depletor of cellular energy (5). It initiates membrane lipid peroxidation (6) and depletes intracellular glutathione (7). There is an ample evidence for differential biological activities of NO and ONOO-(8). NO seelns to be responsible for physiological cyclic-GMP-mediated responses while ONOO-covers pathology ascribed to NO unless thiols (e.9., cysteine or glutathione) will break peroxynitrite to a benignant S-nitrosothiol (9). Hydroxyl radical is essential for oxygenation of AA by COX, while various lipid peroxides intribit PGI, synthase (1 ,2). Among L-ArglAA crossroads the least known is an interaction at a level of NOS and COX. NO was claimed to inhibit COX (10); however, the real executor seeilN to be ONOO-, uls in the case of PGI2 synthase (11).