Synthesis and evaluation of ω-borono-α-amino acids † as active-site probes of arginase and nitric oxide synthases

Collet, Syl­vain; Carreaux, François; Boucher, Jean‐Luc; Pèthe, Stéphanie; Lepoivre, Michel; Danion-Bougot, R.; Danion, D.

doi:10.1039/a908140b

Cited by 47 publications

(36 citation statements)

References 39 publications

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“…[5,6] The optical rotation (À2.78, see the Supporting Information) was the opposite sign to that of 2S-amino-5-hexynoic acid reported in the literature (+ 3.88). [7] This indicates that 2 has the 2R configuration (Scheme 1).…”

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confidence: 54%

Evidence for the Natural Toxins from the Mushroom Trogia venenata as a Cause of Sudden Unexpected Death in Yunnan Province, China

et al. 2012

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confidence: 54%

Evidence for the Natural Toxins from the Mushroom Trogia venenata as a Cause of Sudden Unexpected Death in Yunnan Province, China

et al. 2012

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“…The active site of arginase provides a well-coordinated balance of binding interactions that take place at each end of the substrate. Examination of a series of boronate analogs of L-arginine demonstrated the critical relationship between ␣ -amino to boron distance and IC 50 values (12). The substrate carboxyl group makes important interactions with active site serine and asparagine residues that contribute to substrate binding (10,23).…”

Section: Resultsmentioning

confidence: 99%

“…As a consequence of the reciprocal regulatory roles of arginase and nitric oxide synthase, arginase inhibition has therapeutic potential in treating nitric oxide-dependent smooth muscle disorders such as erectile dysfunction (10). A significant effort has been directed toward the evaluation of L-arginine analogs as possible arginase inhibitors (11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Alternative Substrates for Arginasease

Han

Moore

Viola

2002

Bioorganic Chemistry

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“…Thus, the direct hydrogen bond interaction makes a more pronounced contribution to affinity than the water-mediated hydrogen bond interaction. It is instructive to compare these parameters with those measured between wild-type rat arginase I and the alternative substrate agmatine (26) and its boronic acid analogue descarboxy-ABH (28), both of which lack the α-carboxylate moiety: here, substrate affinity is diminished 11-fold and inhibitor affinity is diminished 30,000-fold. Inhibitor affinity appears to be more sensitive than substrate affinity to the complete loss of all four hydrogen bond interactions with the α-carboxylate moiety of the amino acid.…”

Section: Discussionmentioning

confidence: 99%

Probing the Specificity Determinants of Amino Acid Recognition by Arginase

et al. 2008

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Arginase is a binuclear manganese metalloenzyme that serves as a therapeutic target for the treatment of asthma, erectile dysfunction, and atherosclerosis. In order to better understand the molecular basis of inhibitor affinity, we have employed site-directed mutagenesis, enzyme kinetics, and X-ray crystallography to probe the molecular recognition of the amino acid moiety (i.e., the α-amino and α-carboxylate groups) of substrate l-arginine and inhibitors in the active site of human arginase I. Specifically, we focus on: (1) a water-mediated hydrogen bond between the substrate α-carboxylate and T135, (2) a direct hydrogen bond between the substrate α-carboxylate and N130, and (3) a direct charged hydrogen bond between the substrate α-amino group and D183. Amino acid substitutions for T135, N130, and D183 generally compromise substrate affinity as reflected by increased KM values, but have less pronounced effects on catalytic function as reflected by minimal variations of kcat. As with substrate KM values, inhibitor Kd values increase for binding to enzyme mutants and suggest that the relative contribution of intermolecular interactions to amino acid affinity in the arginase active site is: water-mediated hydrogen bond < direct hydrogen bond < direct charged hydrogen bond. Structural comparisons of arginase with the related binuclear manganese metalloenzymes agmatinase and proclavaminic acid amidinohydrolase suggest that the evolution of substrate recognition in the arginase fold occurs by mutation of residues contained in specificity loops flanking the mouth of the active site (especially loops 4 and 5), thereby allowing diverse guanidinium substrates to be accommodated for catalysis.

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Synthesis and evaluation of ω-borono-α-amino acids † as active-site probes of arginase and nitric oxide synthases

Cited by 47 publications

References 39 publications

Evidence for the Natural Toxins from the Mushroom Trogia venenata as a Cause of Sudden Unexpected Death in Yunnan Province, China

Evidence for the Natural Toxins from the Mushroom Trogia venenata as a Cause of Sudden Unexpected Death in Yunnan Province, China

Synthesis and Evaluation of Alternative Substrates for Arginasease

Probing the Specificity Determinants of Amino Acid Recognition by Arginase

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