PMID- 10542097
OWN - NLM
STAT- MEDLINE
DCOM- 20020618
LR  - 20141120
IS  - 1072-8368 (Print)
IS  - 1072-8368 (Linking)
VI  - 6
IP  - 11
DP  - 1999 Nov
TI  - Arginase-boronic acid complex highlights a physiological role in erectile
      function.
PG  - 1043-7
AB  - 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 A 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-activated hydroxide
      mechanism. This transition state structure differs from that occurring in NO
      biosynthesis, thereby explaining why ABH does not inhibit NO synthase. We also
      show that arginase activity is present in the penis. Accordingly, the tight
      binding and specificity of ABH allows us to probe the physiological role of
      arginase in modulating the NO-dependent smooth muscle relaxation required for
      erection. Strikingly, ABH causes significant enhancement of nonadrenergic,
      noncholinergic nerve-mediated relaxation of penile corpus cavernosum smooth
      muscle, suggesting that arginase inhibition sustains L-arginine concentrations
      for NO synthase activity. Therefore, human penile arginase is a potential target 
      for therapeutic intervention in the treatment of erectile dysfunction.
FAU - Cox, J D
AU  - Cox JD
AD  - Roy and Diana Vagelos Laboratories, Department of Chemistry, University of
      Pennsylvania, Philadelphia, Pennsylvania 19104-6323, USA.
FAU - Kim, N N
AU  - Kim NN
FAU - Traish, A M
AU  - Traish AM
FAU - Christianson, D W
AU  - Christianson DW
LA  - eng
SI  - PDB/1D3V
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Nat Struct Biol
JT  - Nature structural biology
JID - 9421566
RN  - 0 (2-amino-6-boronohexanoic acid)
RN  - 0 (Aminocaproates)
RN  - 0 (Boron Compounds)
RN  - 0 (Enzyme Inhibitors)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 94ZLA3W45F (Arginine)
RN  - EC 1.14.13.39 (NOS1 protein, human)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type I)
RN  - EC 1.14.13.39 (Nos1 protein, rat)
RN  - EC 3.5.3.1 (Arginase)
SB  - IM
MH  - Aminocaproates/chemistry/*metabolism/pharmacology
MH  - Animals
MH  - Arginase/antagonists & inhibitors/*chemistry/*metabolism
MH  - Arginine/chemistry/metabolism
MH  - Boron Compounds/chemistry/*metabolism/pharmacology
MH  - Crystallization
MH  - Crystallography, X-Ray
MH  - Enzyme Inhibitors/chemistry/*metabolism/pharmacology
MH  - Humans
MH  - In Vitro Techniques
MH  - Liver/enzymology
MH  - Male
MH  - Models, Molecular
MH  - Muscle Relaxation/drug effects
MH  - Muscle, Smooth/drug effects/physiology
MH  - Nitric Oxide/metabolism
MH  - Nitric Oxide Synthase/metabolism
MH  - Nitric Oxide Synthase Type I
MH  - Penile Erection/drug effects/*physiology
MH  - Penis/drug effects/*enzymology/innervation/*physiology
MH  - Protein Conformation
MH  - Rabbits
MH  - Rats
MH  - Structure-Activity Relationship
EDAT- 1999/12/14 09:00
MHDA- 2002/06/19 10:01
CRDT- 1999/12/14 09:00
PHST- 1999/12/14 09:00 [pubmed]
PHST- 2002/06/19 10:01 [medline]
PHST- 1999/12/14 09:00 [entrez]
AID - 10.1038/14929 [doi]
PST - ppublish
SO  - Nat Struct Biol. 1999 Nov;6(11):1043-7. doi: 10.1038/14929.