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PDBsum entry 1hq5
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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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.
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Authors
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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.
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Ref.
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Biochemistry, 2001,
40,
2678-2688.
[DOI no: ]
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PubMed id
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Abstract
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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.
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