We propose to continue our studies of the likely reactants and products of biotin mediated carboxylation reactions. Biotin is a vitamin that serves as an obligatory cofactor for a host of carboxylase and decarboxylase enzymes. Our studies will center around the details of half reaction mechanisms currently being proposed for the uptake and transfer of biological carbon dioxide catalyzed by these enzymes. Our principal tools will be high resolution X-ray diffraction and quantum chemical techniques, and these will be employed to study the electronic, vibronic and geometrical properties of reactants and products as well as the most probable reaction pathways that interconnect them. Our goal is to perfect these techniques further and apply them to the biotin questions at large. As a by-product we expect the new approaches to be more robust, simpler to use, and suitable for wider application to biologically interesting problems. The biotin enzymes play pivotal roles in metabolism. Pyruvate carboxylase catalyzes the critical step in gluconeogenesis. Acetylcoenzyme A carboxylase plays that role in fatty acid synthesis. Other biotin dependent enzymes are involved in amino acid and purine metabolism. The preponderance of evidence is that all the biotin enzymes work with a common mechanism. These enzymes show a remarkable degree of genetic conservation, over species and substrates. Therefore, the knowledge we gain from our studies is applicable to a vide body of biochemical processes. Our ultimate goal is to understand the chemistry of the vitamin in detail.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK019856-16
Application #
3226567
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Project Start
1977-08-01
Project End
1994-07-31
Budget Start
1992-08-01
Budget End
1994-07-31
Support Year
16
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Hauptman-Woodward Medical Research Institute
Department
Type
DUNS #
074025479
City
Buffalo
State
NY
Country
United States
Zip Code
14203
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Souhassou, M; Espinosa, E; Lecomte, C et al. (1995) Experimental electron density in crystalline H3PO4. Acta Crystallogr B 51 ( Pt 5):661-8
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Weeks, C M; DeTitta, G T; Hauptman, H A et al. (1994) Structure solution by minimal-function phase refinement and Fourier filtering. II. Implementation and applications. Acta Crystallogr A 50 ( Pt 2):210-20
Miller, R; DeTitta, G T; Jones, R et al. (1993) On the application of the minimal principle to solve unknown structures. Science 259:1430-3
Langs, D A; Blessing, R H; Duax, W L (1992) Crystal structure of valinomycin-monohydrate cage complexes crystallized from dioxane. Int J Pept Protein Res 39:291-9
Souhassou, M; Lecomte, C; Blessing, R H et al. (1991) Electron distributions in peptides and related molecules. 1. An experimental and theoretical study of N-acetyl-L-tryptophan methylamide. Acta Crystallogr B 47 ( Pt 2):253-66
Guo, D Y; Blessing, R H; Hauptman, H A (1991) On integrating the techniques of direct methods with anomalous dispersion. II. Statistical properties of the two-phase structure invariants. Acta Crystallogr A 47 ( Pt 4):340-5

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