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

@article{Cox1999ArginaseboronicAC,
  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},
  year={1999},
  volume={6},
  pages={1043-1047}
}
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… Expand
Inhibitor coordination interactions in the binuclear manganese cluster of arginase.
TLDR
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. Expand
Structure and function of arginases.
  • D. Ash
  • Medicine, Chemistry
  • The Journal of nutrition
  • 2004
TLDR
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. Expand
Probing the specificity determinants of amino acid recognition by arginase.
TLDR
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. Expand
Inhibition of human arginase I by substrate and product analogues.
TLDR
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. Expand
Binding of α,α-disubstituted amino acids to arginase suggests new avenues for inhibitor design.
TLDR
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. Expand
Crystal structures of complexes with cobalt-reconstituted human arginase I.
TLDR
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. Expand
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 ureaExpand
Formiminoglutamase from Trypanosoma cruzi is an arginase-like manganese metalloenzyme.
TLDR
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. Expand
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 myeloidExpand
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. PartialExpand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 29 REFERENCES
Structure of a unique binuclear manganese cluster in arginase
TLDR
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. Expand
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 inExpand
Rat liver arginase: kinetic mechanism, alternate substrates, and inhibitors.
TLDR
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. Expand
alpha-Aminoboronic acid derivatives: effective inhibitors of aminopeptidases.
TLDR
Kinetic data suggest that the slow-binding step represents the formation of tetrahedral boronate species from trigonal boronic acid. Expand
Mutagenesis of rat liver arginase expressed in Escherichia coli: role of conserved histidines.
TLDR
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. Expand
Inhibition of the serine proteases leukocyte elastase, pancreatic elastase, cathepsin G, and chymotrypsin by peptide boronic acids.
TLDR
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. Expand
Temporal expression of different pathways of 1-arginine metabolism in healing wounds.
TLDR
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. Expand
Nitric oxide in the penis: physiology and pathology.
TLDR
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. Expand
Co-induction of arginase and nitric oxide synthase in murine macrophages activated by lipopolysaccharide.
TLDR
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. Expand
Nitric Oxide as a Mediator of Relaxation of the Corpus Cavernosum in Response to Nonadrenergic, Noncholinergic Neurotransmission
TLDR
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. Expand
...
1
2
3
...