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Title: Analysis of the peroxidase-catalysed oxidation of hydroxamic acids
Author: Preis, Martina
ISNI:       0000 0004 2686 1159
Awarding Body: University of Greenwich
Current Institution: University of Greenwich
Date of Award: 2010
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A combination of kinetic methods (primarily stopped-flow spectrometry) and computational modelling of the binding of hydroxamic acids to the active site of a model peroxidase (horseradish, LPO; myeloperoxidase, MPO) was used to provide insight into structure-function relationships of peroxidases. Hydroxamic acids acted as inhibitors of the native state (E), by formation of an E-hydroxamic acid complex that prevents H2O2 from binding. Hydroxamic acids donate one proton and one electron to peroxidase intermediates (CI and CII) and are oxidised to a radical themselves. It is likely that the proton of the hydroxamic acid group is transferred to the His residue via a H-bond network involving Pro139, His42, Arg38 in HRP and His109, Gln105, Asp108, Arg255 and Glu258 in LPO as the hydroxamic acid group of all substrates investigated was bound in the vicinity of these active site residues. However, ambiguity remains as to the precise mechanism of proton transfer. Two mechanisms were proposed for electron-transfer. Mechanism one involves the transfer of an electron to the solvent-exposed haem edge (i.e. δ-haem edge in HRP; D-haem edge in LPO). Mechanism two involves the transfer of an electron to an amino acid-residue situated at the opening of the substrate access-channel followed by long-range electron-transfer (LRET) to the active site (i.e. Phe68 in HRP; Pro115/Ala114→sheet A→helix 2 or Pro424→sheet E→helix 13 in LPO). Peroxidases are likely to be partially responsible for the inactivation of hydroxamic acid-based drugs in vivo. These data reported here may be considered in drug design.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry