Classical and slow-binding inhibitors of human type II arginase.
Arginases catalyze the hydrolysis of L-arginine to yield L-ornithine and urea. Recent studies indicate that arginases, both the type I and type II isozymes, participate in the regulation of nitric oxide production by modulating the availability of arginine for nitric oxide synthase. Due to the reciprocal regulation between arginase and nitric oxide synthase, arginase inhibitors have therapeutic potential in treating nitric oxide-dependent smooth muscle disorders, such as erectile dysfunction. We demonstrate the competitive inhibition of the mitochondrial human type II arginase by N(omega)-hydroxy-L-arginine, the intermediate in the reaction catalyzed by nitric oxide synthase, and its analogue N(omega)-hydroxy-nor-L-arginine, with K(i) values of 1.6 microM and 51 nM at pH 7.5, respectively. We also demonstrate the inhibition of human type II arginase by the boronic acid-based transition-state analogues 2(S)-amino-6-boronohexanoic acid (ABH) and S-(2-boronoethyl)-L-cysteine (BEC), which are known inhibitors of type I arginase. At pH 7.5, both ABH and BEC are classical, competitive inhibitors of human type II arginase with K(i) values of 0.25 and 0.31 microM, respectively. However, at pH 9.5, ABH and BEC are slow-binding inhibitors of the enzyme with K(i) values of 8.5 and 30 nM, respectively. The findings presented here indicate that the design of arginine analogues with uncharged, tetrahedral functional groups will lead to the development of more potent inhibitors of arginases at physiological pH.
Colleluori
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Department of Biochemistry, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, Pennsylvania 19140, USA.
Ash
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D000614:Aminocaproates / Q000378:metabolism; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D001667:Binding, Competitive; D001895:Boron; D001896:Boron Compounds / Q000378:metabolism; D001897:Boronic Acids / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000145:classification / Q000378:metabolism*; D006146:Guanidines / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D019906:Nuclear Magnetic Resonance, Biomolecular; D013379:Substrate Specificity; D013997:Time Factors
C425062:(2-boronoethyl)-cysteine; C121228:2-amino-6-boronohexanoic acid; D000614:Aminocaproates; D001896:Boron Compounds; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D006146:Guanidines; D007527:Isoenzymes; C404735:N(omega)-hydroxynorarginine; C068309:N(omega)-hydroxyarginine; D001120:Arginine; D001119:Arginase; D001895:Boron