Arginase : structure-based mechanism and role in erectile function / John David Cox.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Cox, John David.

Contributor:

Christianson, David, advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Local Subjects:

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Physical Description:

xi, 191 pages : illustrations (some color) ; 29 cm

Production:

2000.

Summary:

Arginase, a 105 kD homotrimer containing a binuclear manganese cluster in each protomer, catalyzes the hydrolysis of L-arginine to form L-ornithine and urea through a metal-activated hydroxide mechanism. X-ray crystal structures of arginase complexed to substrate analogues, transition state analogues, as well as the products complete a set of structural "snapshots" along the reaction coordinate of arginase catalysis. These structures highlight new details into the arginase catalysis and they render important insights on the structural determinants of tight binding inhibitors. Boronic acid analogs of L-arginine, (S)-2-amino-6-boronohexanoic acid (ABH) and S-(Boronoethyl)-L-Cysteine, are among the tightest-binding arginase inhibitors known to date. The X-ray crystal structures of the arginase-ABH and arginase-BEC complexes determined from perfectly twinned crystals reveal that ABH and BEC bind as the tetrahedral boronate anion, thereby mimicking the binding of the tetrahedral intermediate in the arginine hydrolysis reaction. Since ABH and BEC do not inhibit NO synthase, we can use these inhibitors to probe the physiological role of arginase in modulating NO-dependent smooth muscle relaxation required for penile erection. A collaborative study demonstrates that ABH and BEC cause 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.

Notes:

Supervisor: David Christianson.

Thesis (Ph.D. in Chemistry) -- University of Pennsylvania, 2000.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 9989582.

OCLC:

244972290