The objectives of this research continue to encompass elucidation of the basic chemistry of coenzyme B12 and related organocobalt compounds, notably those aspects of the chemistry that are relevant to the biochemical roles of coenzyme B12. Research during the next project period will focus particularly on the following themes: (i) further elucidation of the factors that influence cobalt-alkyl bond dissociation energies and that, accordingly, may contribute to enzyme-induced coenzyme B12 cobalt-carbon bond weakening and dissociation, (ii) elucidation of the chemistry of B12-substrate radicals and of the (direct and indirect) mechanisms of their rearrangements. Pursuit of the first of these objectives will utilize methods for determining cobalt-carbon and dissociation energies previously developed in our laboratories. Pursuit of the second objective will involve extension of the method previously employed by us to measure the rate of a methylmalonyl-CoA model radical and will explore suggestions that B12-dependent rearrangements of the omega- amino mutase and glutamate mutase substrates proceed through imine migrations in the corresponding Schiff base radicals. Structures of selected organocobalt complexes, notably of cobalt porphyrins, will be elucidated by X-ray crystallography, with a view to identifying steric and electronic influences on cobalt- carbon bond dissociation energies and rates. The binding of 02 and of organic free radicals to iron and cobalt will be compared by synthesizing selected organoiron prophyrin complexes and determining their iron-alkyl bond dissociation energies. The proposed research encompasses several bioinorganic, organometallic and biochemical themes. The anticipated results should contribute to a better understanding of important aspects of the mechanisms of coenzyme B12-dependent, and possibly of cytochrome P450-dependent, processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK013339-22
Application #
3483021
Study Section
Metallobiochemistry Study Section (BMT)
Project Start
1978-04-01
Project End
1993-08-31
Budget Start
1990-09-01
Budget End
1991-08-31
Support Year
22
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Arts and Sciences
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637