alexa Mechanistic implications of the cysteine-nicotinamide adduct in aldehyde dehydrogenase based on quantum mechanical molecular mechanical simulations.
Pharmaceutical Sciences

Pharmaceutical Sciences

Journal of Bioequivalence & Bioavailability

Author(s): Wymore T, Deerfield DW nd, Hempel J

Abstract Share this page

Abstract Recent computer simulations of the cysteine nucleophilic attack on propanal in human mitochondrial aldehyde dehydrogenase (ALDH2) yielded an unexpected result: the chemically reasonable formation of a dead-end cysteine-cofactor adduct when NAD+ was in the "hydride transfer" position. More recently, this adduct found independent crystallographic support in work on formyltetrahydrofolate dehydrogenase, work which further found evidence of the same adduct on re-examination of deposited electron densities of ALDH2. Although the experimental data showed that this adduct was reversible, several mechanistic questions arise from the fact that it forms at all. Here, we present results from further quantum mechanical/molecular mechanical (QM/MM) simulations toward understanding the mechanistic implications of adduct formation. These simulations revealed formation of the oxyanion thiohemiacetal intermediate only when the nicotinamide ring of NAD+ is oriented away from the active site, contrary to prior arguments. In contrast, and in seeming paradox, when NAD is oriented to receive the hydride, disassociation of the oxyanion intermediate to form the dead-end adduct is more thermodynamically favored than maintaining the oxyanion intermediate necessary for catalysis to proceed. However, this disassociation to the adduct could be avoided through proton transfer from the enzyme to the intermediate. Our results continue to indicate that the unlikely source of this proton is the Cys302 main chain amide.
This article was published in Biochemistry and referenced in Journal of Bioequivalence & Bioavailability

Relevant Expert PPTs

Relevant Speaker PPTs

Recommended Conferences

Relevant Topics

Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

Agri, Food, Aqua and Veterinary Science Journals

Dr. Krish

[email protected]

1-702-714-7001 Extn: 9040

Clinical and Biochemistry Journals

Datta A

[email protected]

1-702-714-7001Extn: 9037

Business & Management Journals

Ronald

[email protected]

1-702-714-7001Extn: 9042

Chemical Engineering and Chemistry Journals

Gabriel Shaw

[email protected]

1-702-714-7001 Extn: 9040

Earth & Environmental Sciences

Katie Wilson

[email protected]

1-702-714-7001Extn: 9042

Engineering Journals

James Franklin

[email protected]

1-702-714-7001Extn: 9042

General Science and Health care Journals

Andrea Jason

[email protected]

1-702-714-7001Extn: 9043

Genetics and Molecular Biology Journals

Anna Melissa

[email protected]

1-702-714-7001 Extn: 9006

Immunology & Microbiology Journals

David Gorantl

[email protected]

1-702-714-7001Extn: 9014

Informatics Journals

Stephanie Skinner

[email protected]

1-702-714-7001Extn: 9039

Material Sciences Journals

Rachle Green

[email protected]

1-702-714-7001Extn: 9039

Mathematics and Physics Journals

Jim Willison

[email protected]

1-702-714-7001 Extn: 9042

Medical Journals

Nimmi Anna

[email protected]

1-702-714-7001 Extn: 9038

Neuroscience & Psychology Journals

Nathan T

[email protected]

1-702-714-7001Extn: 9041

Pharmaceutical Sciences Journals

John Behannon

[email protected]

1-702-714-7001Extn: 9007

Social & Political Science Journals

Steve Harry

[email protected]

1-702-714-7001 Extn: 9042

 
© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version
adwords