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PDBsum entry 1hq5
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Hydrolase PDB id
1hq5

 

 

 

 

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Contents
Protein chains
308 a.a. *
Ligands
S2C ×2
Metals
_MN ×4
Waters ×54
* Residue conservation analysis
PDB id:
1hq5
Name: Hydrolase
Title: Crystal structure of the binuclear manganese metalloenzyme arginase complexed with s-(2-boronoethyl)-l-cysteine, an l-arginine analogue
Structure: Arginase 1. Chain: a, b. Engineered: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Trimer (from PDB file)
Resolution:
2.30Å     R-factor:   0.158     R-free:   0.194
Authors: N.N.Kim,J.D.Cox,R.F.Baggio,F.A.Emig,S.K.Mistry,S.L.Harper, D.W.Speicher,S.M.Morris Jr.,D.E.Ash,A.Traish,D.W.Christianson
Key ref:
N.N.Kim et al. (2001). Probing erectile function: S-(2-boronoethyl)-L-cysteine binds to arginase as a transition state analogue and enhances smooth muscle relaxation in human penile corpus cavernosum. Biochemistry, 40, 2678-2688. PubMed id: 11258879 DOI: 10.1021/bi002317h
Date:
14-Dec-00     Release date:   04-Apr-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P07824  (ARGI1_RAT) -  Arginase-1 from Rattus norvegicus
Seq:
Struc: 		323 a.a.
308 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.5.3.1  - arginase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway: 		Urea Cycle and Arginine Biosynthesis
      Reaction: L-arginine + H2O = urea + L-ornithine
L-arginine
 + H2O
 = urea
 + L-ornithine
      Cofactor: Mn(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1021/bi002317h Biochemistry 40:2678-2688 (2001)
PubMed id: 11258879  
 
 
Probing erectile function: S-(2-boronoethyl)-L-cysteine binds to arginase as a transition state analogue and enhances smooth muscle relaxation in human penile corpus cavernosum.
N.N.Kim, J.D.Cox, R.F.Baggio, F.A.Emig, S.K.Mistry, S.L.Harper, D.W.Speicher, S.M.Morris, D.E.Ash, A.Traish, D.W.Christianson.
 
  ABSTRACT  
 
The boronic acid-based arginine analogue S-(2-boronoethyl)-L-cysteine (BEC) has been synthesized and assayed as a slow-binding competitive inhibitor of the binuclear manganese metalloenzyme arginase. Kinetic measurements indicate a K(I) value of 0.4-0.6 microM, which is in reasonable agreement with the dissociation constant of 2.22 microM measured by isothermal titration calorimetry. The X-ray crystal structure of the arginase-BEC complex has been determined at 2.3 A resolution from crystals perfectly twinned by hemihedry. The structure of the complex reveals that the boronic acid moiety undergoes nucleophilic attack by metal-bridging hydroxide ion to yield a tetrahedral boronate anion that bridges the binuclear manganese cluster, thereby mimicking the tetrahedral intermediate (and its flanking transition states) in the arginine hydrolysis reaction. Accordingly, the binding mode of BEC is consistent with the structure-based mechanism proposed for arginase as outlined in Cox et al. [Cox, J. D., Cama, E., Colleluori D. M., Pethe, S., Boucher, J. S., Mansuy, D., Ash, D. E., and Christianson, D. W. (2001) Biochemistry 40, 2689-2701.]. Since BEC does not inhibit nitric oxide synthase, BEC serves as a valuable reagent to probe the physiological relationship between arginase and nitric oxide (NO) synthase in regulating the NO-dependent smooth muscle relaxation in human penile corpus cavernosum tissue that is required for erection. Consequently, we demonstrate that arginase is present in human penile corpus cavernosum tissue, and that the arginase inhibitor BEC causes significant enhancement of NO-dependent smooth muscle relaxation in this tissue. Therefore, human penile arginase is a potential target for the treatment of sexual dysfunction in the male.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20157303 A.Harraz, A.W.Shindel, and T.F.Lue (2010).
Emerging gene and stem cell therapies for the treatment of erectile dysfunction.
  Nat Rev Urol, 7, 143-152.  
20483789 D.R.Herbert, T.Orekov, A.Roloson, M.Ilies, C.Perkins, W.O'Brien, S.Cederbaum, D.W.Christianson, N.Zimmermann, M.E.Rothenberg, and F.D.Finkelman (2010).
Arginase I suppresses IL-12/IL-23p40-driven intestinal inflammation during acute schistosomiasis.
  J Immunol, 184, 6438-6446.  
20226211 D.Schade, J.Kotthaus, and B.Clement (2010).
Modulating the NO generating system from a medicinal chemistry perspective: current trends and therapeutic options in cardiovascular disease.
  Pharmacol Ther, 126, 279-300.  
20346044 E.A.Tronchini, M.H.de Miranda Neto, and J.N.Zanoni (2010).
Vitamin E (α-tocopherol) supplementation enhances nitric oxide production in penile tissue of diabetic rats.
  BJU Int, 106, 1788-1793.  
20563744 K.Krotova, J.M.Patel, E.R.Block, and S.Zharikov (2010).
Endothelial arginase II responds to pharmacological inhibition by elevation in protein level.
  Mol Cell Biochem, 343, 211-216.  
20153713 L.Di Costanzo, M.Ilies, K.J.Thorn, and D.W.Christianson (2010).
Inhibition of human arginase I by substrate and product analogues.
  Arch Biochem Biophys, 496, 101-108.
PDB codes: 3kv2 3lp4 3lp7
20107769 M.Warnken, S.Haag, S.Matthiesen, U.R.Juergens, and K.Racké (2010).
Species differences in expression pattern of arginase isoenzymes and differential effects of arginase inhibition on collagen synthesis in human and rat pulmonary fibroblasts.
  Naunyn Schmiedebergs Arch Pharmacol, 381, 297-304.  
20097867 N.D.Lewis, M.Asim, D.P.Barry, K.Singh, T.de Sablet, J.L.Boucher, A.P.Gobert, R.Chaturvedi, and K.T.Wilson (2010).
Arginase II restricts host defense to Helicobacter pylori by attenuating inducible nitric oxide synthase translation in macrophages.
  J Immunol, 184, 2572-2582.  
19093830 E.Y.Shishova, L.Di Costanzo, F.A.Emig, D.E.Ash, and D.W.Christianson (2009).
Probing the specificity determinants of amino acid recognition by arginase.
  Biochemistry, 48, 121-131.
PDB codes: 3e6k 3e6v 3e8q 3e8z 3e9b
19456858 G.A.Wells, I.B.Müller, C.Wrenger, and A.I.Louw (2009).
The activity of Plasmodium falciparum arginase is mediated by a novel inter-monomer salt-bridge between Glu295-Arg404.
  FEBS J, 276, 3517-3530.  
19133993 N.Huynh, E.Harris, J.Chin-Dusting, and K.Andrews (2009).
The vascular effects of different arginase inhibitors in rat isolated aorta and mesenteric arteries.
  Br J Pharmacol, 156, 84-93.  
18360740 D.P.Dowling, L.Di Costanzo, H.A.Gennadios, and D.W.Christianson (2008).
Evolution of the arginase fold and functional diversity.
  Cell Mol Life Sci, 65, 2039-2055.  
18269446 H.Masuda (2008).
Significance of nitric oxide and its modulation mechanisms by endogenous nitric oxide synthase inhibitors and arginase in the micturition disorders and erectile dysfunction.
  Int J Urol, 15, 128-134.  
  18768883 K.Ckless, A.Lampert, J.Reiss, D.Kasahara, M.E.Poynter, C.G.Irvin, L.K.Lundblad, R.Norton, A.van der Vliet, and Y.M.Janssen-Heininger (2008).
Inhibition of arginase activity enhances inflammation in mice with allergic airway disease, in association with increases in protein S-nitrosylation and tyrosine nitration.
  J Immunol, 181, 4255-4264.  
18358516 K.Sasatomi, S.Hiragata, M.Miyazato, M.B.Chancellor, S.M.Morris, and N.Yoshimura (2008).
Nitric oxide-mediated suppression of detrusor overactivity by arginase inhibitor in rats with chronic spinal cord injury.
  Urology, 72, 696-700.  
  18719233 L.Santhanam, D.W.Christianson, D.Nyhan, and D.E.Berkowitz (2008).
Arginase and vascular aging.
  J Appl Physiol, 105, 1632-1642.  
16775612 B.Musicki, and A.L.Burnett (2007).
Endothelial dysfunction in diabetic erectile dysfunction.
  Int J Impot Res, 19, 129-138.  
17469833 L.Di Costanzo, M.E.Pique, and D.W.Christianson (2007).
Crystal structure of human arginase I complexed with thiosemicarbazide reveals an unusual thiocarbonyl mu-sulfide ligand in the binuclear manganese cluster.
  J Am Chem Soc, 129, 6388-6389.
PDB codes: 2pha 2pho 2zav
17562323 L.Di Costanzo, M.Moulin, M.Haertlein, F.Meilleur, and D.W.Christianson (2007).
Expression, purification, assay, and crystal structure of perdeuterated human arginase I.
  Arch Biochem Biophys, 465, 82-89.
PDB code: 2pll
17850365 M.Ghasemi, H.Sadeghipour, and A.R.Dehpour (2007).
Anandamide improves the impaired nitric oxide-mediated neurogenic relaxation of the corpus cavernosum in diabetic rats: involvement of cannabinoid CB1 and vanilloid VR1 receptors.
  BJU Int, 100, 1385-1390.  
17428245 N.Numao, H.Masuda, Y.Sakai, Y.Okada, K.Kihara, and H.Azuma (2007).
Roles of attenuated neuronal nitric-oxide synthase protein expression and accelerated arginase activity in impairing neurogenic relaxation of corpus cavernosum in aged rabbits.
  BJU Int, 99, 1495-1499.  
16445692 N.N.Huynh, and J.Chin-Dusting (2006).
Amino acids, arginase and nitric oxide in vascular health.
  Clin Exp Pharmacol Physiol, 33, 1-8.  
16970814 N.N.Kim, M.Stankovic, A.Armagan, T.T.Cushman, I.Goldstein, and A.M.Traish (2006).
Effects of tamoxifen on vaginal blood flow and epithelial morphology in the rat.
  BMC Womens Health, 6, 14.  
17212779 R.Alarcón, M.S.Orellana, B.Neira, E.Uribe, J.R.García, and N.Carvajal (2006).
Mutational analysis of substrate recognition by human arginase type I--agmatinase activity of the N130D variant.
  FEBS J, 273, 5625-5631.  
16185164 F.L.Ricciardolo, J.Zaagsma, and H.Meurs (2005).
The therapeutic potential of drugs targeting the arginase pathway in asthma.
  Expert Opin Investig Drugs, 14, 1221-1231.  
15748286 H.Maarsingh, M.A.Tio, J.Zaagsma, and H.Meurs (2005).
Arginase attenuates inhibitory nonadrenergic noncholinergic nerve-induced nitric oxide generation and airway smooth muscle relaxation.
  Respir Res, 6, 23.  
16141327 L.Di Costanzo, G.Sabio, A.Mora, P.C.Rodriguez, A.C.Ochoa, F.Centeno, and D.W.Christianson (2005).
Crystal structure of human arginase I at 1.29-A resolution and exploration of inhibition in the immune response.
  Proc Natl Acad Sci U S A, 102, 13058-13063.
PDB codes: 1wva 2aeb
16128822 V.López, R.Alarcón, M.S.Orellana, P.Enríquez, E.Uribe, J.Martínez, and N.Carvajal (2005).
Insights into the interaction of human arginase II with substrate and manganese ions by site-directed mutagenesis and kinetic studies. Alteration of substrate specificity by replacement of Asn149 with Asp.
  FEBS J, 272, 4540-4548.  
15355972 H.J.Ahn, K.H.Kim, J.Lee, J.Y.Ha, H.H.Lee, D.Kim, H.J.Yoon, A.R.Kwon, and S.W.Suh (2004).
Crystal structure of agmatinase reveals structural conservation and inhibition mechanism of the ureohydrolase superfamily.
  J Biol Chem, 279, 50505-50513.
PDB codes: 1wog 1woh 1woi
15090903 S.M.Morris (2004).
Recent advances in arginine metabolism.
  Curr Opin Clin Nutr Metab Care, 7, 45-51.  
12647314 W.Yang, X.Gao, and B.Wang (2003).
Boronic acid compounds as potential pharmaceutical agents.
  Med Res Rev, 23, 346-368.  
12055339 S.M.Morris (2002).
Regulation of enzymes of the urea cycle and arginine metabolism.
  Annu Rev Nutr, 22, 87.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

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