Date of Award:

12-2008

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Chemistry and Biochemistry

Committee Chair(s)

Lisa M. Berreau

Committee

Lisa M. Berreau

Committee

John L. Hubbard

Committee

Alvan Hengge

Committee

Marie K. Walsh

Committee

Lance C. Seefeldt

Abstract

The work outlined herein presents an investigation of synthetic model complexes of relevance to the active sites of Ni(II)-containing enzymes, particularly urease, glyoxalase I, and acireductone dioxygenase. The research focuses on studying the structural and reactivity features of nickel complexes with biologically relevant substrates. The anion of acetohydroxamic acid is a well-known inhibitor of urease enzymes, including those isolated from Klebsiella aerogenes and Bacillus pasteurii. A precursor to the acetohydroxamate coordination in ureases is proposed to be an interaction between Ni(II) and acetohydroxamic acid. By using a novel supporting chelate ligand capable of secondary hydrogen bonding interactions a novel pseudo-octahedral, Ni(II) acetohydroxamic acid complex has been isolated and characterized. Detailed analysis of the structural features and acetohydroxamic displacement reactivity of this complex has provided fundamental chemical insight toward understanding of the inhibition mechanism in urease enzymes. Glyoxalase I (Glx I) catalyzes one step of the cellular detoxification pathway for α-ketoaldehydes (e.g. methylglyoxal) in humans and bacteria. The GlxI enzyme from E. coli is a Ni(II)-containing enzyme that catalyzes the isomerization of a hemithioacetal to produce a thioester. Of relevance to this enzyme, the first example of a Ni(II) complex that promotes a hemithioacetal isomerization is reported herein. In order to monitor this type of reaction a new approach involving a a deuterium-labeled hemithioacetal (PhC(O)CH(OH)SCD3) and 2H NMR was employed. Acireductone dioxygenases (ARDs) catalyze aliphatic oxidative C-C bond cleavage of an acireductone (1,2-dihydroxy-3-oxo-5-(methylthio)pent-1-ene) intermediate in the methionine salvage pathway. A unique aspect of these enzymes is that the regioselectivity of the dioxygenase reaction depends on the metal ion bound in the active site. Outlined herein are descriptions of the synthesis, characterization, and O2 reactivity of a novel trinuclear Ni(II) enediolate complex of relevance to the proposed enzyme/substrate adduct in Ni(II)-ARD. Efforts have also been made toward the preparation of C(1)-H acireductone compounds using a combined synthetic/enzymatic approach. A phenyl appended-C(1)-H acireductone was isolated and introduced to a Ni(II) precursor complex. This reaction produced spectroscopic changes consistent with the formation of a new Ni(II) acireductone complex. Preliminary studies of the O2 reactivity of this complex are reported.

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