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Molecular Probes for the Mechanism of Action of the Enzyme Biotin Synthase

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Item Summary

Title:Molecular Probes for the Mechanism of Action of the Enzyme Biotin Synthase
Authors:Judd, Matthew
Date Issued:May 2015
Publisher:[Honolulu] : [University of Hawaii at Manoa], [May 2015]
Abstract:The enzyme biotin synthase uses two equivalents of the cofactor Sadenosylmethionine to generate in its active site a 5’-deoxyadenosyl carbon radical that can abstract a hydrogen atom from the substrate dethiobiotin. The resulting dethiobiotinyl carbon radicals can form carbon-sulfur bonds to close a tetrahydrothiophene ring that converts dethiobiotin into biotin. This transformation may be better understood by investigating the effect of exposing the enzyme to a series of rationally designed substrate analogs. These analogs could include either substrate homologs with selected modifications made at or near the reactive positions, or by isotopic substitutions to monitor a change in reaction kinetics. The initial efforts to refine a goal-oriented synthetic methodology to produce a library of dethiobiotin analogs was unsuccessful due to a series of reactions with low yields, which made it impractical for the generation of a library of compounds. A second approach involving defunctionalization of biotin itself was hampered by the high cost of the starting material and a lack of selectivity in the reaction pathway. A third approach involving the synthesis of a natural product precursor in the biotin biosynthetic pathway was limited by an unexpected incompatibility of substrate and catalysts. No effective route to produce the library of interest has yet been demonstrated.
Description:Ph.D. University of Hawaii at Manoa 2015.
Includes bibliographical references.
Appears in Collections: Ph.D. - Chemistry

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