Arginase–boronic acid complex highlights a physiological role in erectile function

  title={Arginase–boronic acid complex highlights a physiological role in erectile function},
  author={J. D. Cox and Noel N Kim and Abdulmaged M Traish and David W. Christianson},
  journal={Nature Structural Biology},
The crystal structure of the complex between the binuclear manganese metalloenzyme arginase and the boronic acid analog of L-arginine, 2(S)-amino-6-boronohexanoic acid (ABH), has been determined at 1.7 Å resolution from a crystal perfectly twinned by hemihedry. ABH binds as the tetrahedral boronate anion, with one hydroxyl oxygen symmetrically bridging the binuclear manganese cluster and a second hydroxyl oxygen coordinating to Mn2+A. This binding mode mimics the transition state of a metal… 
Inhibitor coordination interactions in the binuclear manganese cluster of arginase.
X-ray structures of a series of inhibitors bound to the active site of arginase are reported, and each inhibitor exploits a different mode of coordination with the Mn(2+)(2) cluster.
Structure and function of arginases.
  • D. Ash
  • Medicine, Chemistry
    The Journal of nutrition
  • 2004
These findings suggest that the enzyme may have other functions in addition to its role in nitrogen metabolism, as well as leading to a greater understanding of the role of arginase in nonhepatic tissues.
Probing the specificity determinants of amino acid recognition by arginase.
Structural comparisons of arginase with the related binuclear manganese metalloenzymes agmatinase and proclavaminic acid amidinohydrolase suggest that the evolution of substrate recognition in the arginases 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.
Inhibition of human arginase I by substrate and product analogues.
The crystal structure of the complex with L-lysine confirms the importance of hydrogen bond interactions with inhibitor alpha-carboxylate and alpha-amino groups as key specificity determinants of amino acid recognition in the arginase active site.
Binding of α,α-disubstituted amino acids to arginase suggests new avenues for inhibitor design.
This work highlights a new region of the protein surface that can be targeted for additional affinity interactions, as well as the first comparative structural insights on inhibitor discrimination between a human and a parasitic arginase.
Crystal structures of complexes with cobalt-reconstituted human arginase I.
It is suggested that a higher concentration of metal-bridging hydroxide ion at physiological pH for Co( 2+)(2)-HAI, a consequence of the lower pK(a) of a Co(2+)-bound water molecule compared with a Mn(2-)-boundWater molecule, strengthens electrostatic interactions with cationic amino acids and accounts for enhanced affinity as reflected in the lower K(M) value of L-Arg and the lower L-Orn.
Arginine Metabolism: Enzymology, Nutrition, and Clinical Significance
The arginases catalyze the divalent cation dependent hydrolysis of L-arginine to produce L-ornithine and urea. Although traditionally considered in terms of its role as the final enzyme of the urea
Formiminoglutamase from Trypanosoma cruzi is an arginase-like manganese metalloenzyme.
It is shown that reconstitution of this protein with Mn²⁺ confers maximal catalytic activity in the hydrolysis of formiminoglutamate to yield glutamate and formamide, thereby demonstrating that this protein is a metal-dependent formim inoglutamase.
Structural insights into human Arginase-1 pH dependence and its inhibition by the small molecule inhibitor CB-1158
Abstract Arginase-1 is a manganese-dependent metalloenzyme that catalyzes the hydrolysis of L-arginine into L-ornithine and urea. Arginase-1 is abundantly expressed by tumor-infiltrating myeloid
Probing the role of the hyper-reactive histidine residue of arginase.
Rat liver arginase (arginase I) is potently inactivated by diethyl pyrocarbonate, with a second-order rate constant of 113M(-1)s(-1) for the inactivation process at pH 7.0, 25 degrees C. Partial


Structure of a unique binuclear manganese cluster in arginase
Analysis of the structure of trimeric11 rat liver arginase reveals that this unique metal cluster resides at the bottom of an active-site cleft that is 15 Å deep, and indicates that arginine hydrolysis is achieved by a metal-activated solvent molecule which symmetrically bridges the two Mn2+ ions.
Crystal structures of Bacillus caldovelox arginase in complex with substrate and inhibitors reveal new insights into activation, inhibition and catalysis in the arginase superfamily.
BACKGROUND Arginase is a manganese-dependent enzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. In ureotelic animals arginase is the final enzyme of the urea cycle, but in
Rat liver arginase: kinetic mechanism, alternate substrates, and inhibitors.
Results suggest that the metal site is not readily accessible to solvent, and competitive inhibition by the products L-ornithine and urea indicates a rapid-equilibrium random mechanism for the enzyme.
alpha-Aminoboronic acid derivatives: effective inhibitors of aminopeptidases.
  • A. Shenvi
  • Chemistry, Medicine
  • 1986
Kinetic data suggest that the slow-binding step represents the formation of tetrahedral boronate species from trigonal boronic acid.
Mutagenesis of rat liver arginase expressed in Escherichia coli: role of conserved histidines.
The His141 Asn mutation produced an enzyme which, in contrast to the native, wild-type, His101 Asn, and His126 Asn arginases, was not inactivated by diethyl pyrocarbonate, suggesting a catalytic role for His141.
Inhibition of the serine proteases leukocyte elastase, pancreatic elastase, cathepsin G, and chymotrypsin by peptide boronic acids.
Three alpha-aminoboronic acid-containing analogs of good peptide substrates for serine proteases were synthesized and inhibition was not simply competitive, but showed kinetic properties corresponding to the mechanism for slow-binding inhibition.
Temporal expression of different pathways of 1-arginine metabolism in healing wounds.
The results indicate that the OAD pathway is expressed in this model predominantly during the early, polymorphonuclear leukocyte-predominant, phase of repair, and the reactive nitrogen intermediates resulting from the metabolism of arginine may mediate some of the events characteristic of early inflammation.
Nitric oxide in the penis: physiology and pathology.
Nitric oxide exerts a significant role in the physiology of the penis, operating chiefly as the principal mediator of erectile function, and may also directly contribute to or cause pathological consequences involving the penis.
Co-induction of arginase and nitric oxide synthase in murine macrophages activated by lipopolysaccharide.
Observations indicate that co-induction of iNOS and AII occurs by distinct transcriptional mechanisms, AII induction could diminish NO production by decreasing L-arginine availability, and IFN-gamma can prevent A II induction.
Nitric Oxide as a Mediator of Relaxation of the Corpus Cavernosum in Response to Nonadrenergic, Noncholinergic Neurotransmission
This work studied the smooth-muscle relaxant responses to stimulation by an electrical field and to nitric oxide to determine whether it is involved in the relaxation of the corpus cavernosum that allows penile erection.