Structural insights into the mechanism and inhibition of prostaglandin H2 synthase-1 / Kushol Gupta.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Gupta, Kushol.

Contributor:

Loll, Patrick J. (Patrick John), 1958- advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Pharmacological sciences.

Pharmacological sciences--Penn dissertations.

Pharmacological Sciences.

Academic Dissertations as Topic.

Medical Subjects:

Pharmacological Sciences.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Pharmacological sciences.

Pharmacological sciences--Penn dissertations.

Physical Description:

xvii, 254 pages : illustrations (some color) ; 29 cm

Production:

2003.

Summary:

Prostanoids are fatty acid autocoids that are involved in platelet aggregation, inflammation, and the pathophysiology of cardiovascular disease. Prostaglandin H2 synthase (PGHS; EC 1.14.99.1) is an important drug target essential to their formation. This bifunctional heme-dependent enzyme functions as a homodimer, where each monomer contains both a cyclooxygenase and a peroxidase active site. These active sites work in concert to transform arachidonic acid into PGH2, the precursor to the prostanoids. There are two known isoforms of this enzyme, which differ mainly in their expression patterns: PGHS-1 is a constitutively expressed isoform involved in "housekeeping" functions, while PGHS-2 expression is induced in response to inflammatory stimuli. Both isoforms are susceptible to inhibition by the class of drugs known as nonsteroidal antiinflammatory drugs (NSAIDs), which act by blocking the cyclooxygenase active site.

The goal of this dissertation was to use x-ray crystallography to expand the current understanding of the structure of PGHS. In doing so, key issues, including the structural consequences of peroxidase impairment by protoporphyrin substitution and the structural basis of NSAID binding were investigated. As a result of this study, six unique x-ray crystal structures of PGHS were determined. Among these structures, the first high-resolution (2.0 A) structures of PGHS-1 were solved, and together these structures yield insights into the architecture of the two active sites of PGHS, the nature of inhibitor binding in the cyclooxygenase active site, and the structural consequences of protoporphyrin substitution.

Notes:

Supervisor: Patrick J. Loll.

Thesis (Ph.D. in Pharmacological Sciences) -- University of Pennsylvania, 2003.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 3095886.

OCLC:

244973654