Structural studies of carbonic anhydrase isozymes / Paula Ann Boriack-Sjodin.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Boriack-Sjodin, Paula Ann.

Contributor:

Christianson, David W., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Local Subjects:

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Physical Description:

xiv, 222 pages : illustrations ; 29 cm

Production:

1996.

Summary:

The studies contained in this thesis provide insights into structure/function relationships of the carbonic anhydrase isozymes. The X-ray crystallographic structure of wild-type CAV has complemented the kinetic studies investigating the unique proton transfer pathway in this mitochondrial isozyme. The crystal structures of CA-inhibitor complexes have allowed visualization of the binding modes of these inhibitors in the CAII and CAV active sites and have provided a foundation for understanding their high affinity binding. Additionally, these studies provide a starting point for the design of isozyme-specific inhibitors.

The major conclusions drawn from this thesis are as follows: (1) The tetrahedrally-coordinated zinc ion of CAV and its immediate environment is similar to that of the other CA isozymes. Differences in the mechanism of CAV are probably due to differences 6 to 8 A distant from the zinc ion. (2) The bulky side chain of Phe 65 compromises the proton transfer abilities of the residue at position 64. (3) Tyr 64 is not the native proton shuttle, however, a His residue at position 64 is a proton transfer group. Proton transfer at this position is greatly increased by replacing Phe 65 with Ala. (4) Inhibitor tails have preferred binding interactions. Nonaromatic pendant groups bind to the Leu 198/Pro 202 hydrophobic wall; aromatic pendant groups interact with Phe 131. (5) The thienothiazine ring system of the inhibitors has a preferred mode of interaction. Deviations from this binding mode increase the dissociation constant of the inhibitor. In addition, this ring system confers much of the binding affinity of these inhibitors.

Notes:

Adviser: David W. Christianson.

Thesis (Ph.D. in Chemistry) -- University of Pennsylvania, 1996.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 97-12891.

OCLC:

187469523