, Volume 1, Issue 1, pp 73-82

Nω-Hydroxyamino-α-amino acids as a new class of very strong inhibitors of arginases

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Abstract

 The effects of various compounds bearing an N-OH group such as N-hydroxy-guanidines, amidoximes, and hydroxylamines, on bovine and rat liver arginases was studied. Some of these compounds with an l-α-amino acid function at an appropriate distance from the N-OH group acted as strong competitive liver arginase inhibitors, displaying Ki values between 4 and 150 μM. Two compounds, N ε-hydroxy-l-lysine and N ω-hydroxy-d,l-indospicine, which exhibited Ki values of 4 and 20 μM (at pH 7.4), were the most potent inhibitors of arginase described to date. The distance between the α-amino acid and N-OH functions appeared to be crucial for potent inhibition of arginase, as N δ-hydroxy-l-ornithine, which has one -CH2 group less than N ε-hydroxy-l-lysine, exhibited a 37-fold higher Ki value than N ε-hydroxy-l-lysine. Based on these results, a model for the interaction of N ω-hydroxyamino-l-α-amino acids with the arginase active site is proposed. This model involves the binding of the N-OH group of the inhibitors to the arginase Mn(II) center and suggests that N ε-hydroxy-l-lysine is a good transition state analog of arginase.