Characterization of prokaryotic pantothenate kinase enzymes and the development of type-specific inhibitors
Date
2011-12
Authors
Koekemoer, Lizbe
Journal Title
Journal ISSN
Volume Title
Publisher
Stellenbosch : Stellenbosch University
Abstract
ENGLISH ABSTRACT: Pantothenate kinase (PanK) enzymes catalyze the first reaction in the five step biosynthesis of the essential cofactor coenzyme A. Enzymes representing each of the three identified PanK types have been studied and characterized and these PanK types exhibits a unique diversity between different organisms, therefore highlighting them as potential drug targets. In this study the type III PanK of specifically pathogenic bacteria were characterized with the goal of developing type-specific inhibitors. Several questions about the activity of the Mycobacterium tuberculosis enzyme was answered, which addresses the contradicting results achieved in related PanK studies performed to date. Furthermore the first inhibitors, that are competitive to the pantothenate binding site, were designed, synthesized and tested against the Pseudomonas aeruginosa enzyme. This resulted in the discovery of the most potent inhibitors of the type III PanKs to date.
AFRIKAANSE OPSOMMING: Pantoteensuurkinase-ensiem (PanK) kataliseer die eerste stap in die vyf stap biosintese van die lewens belangrike en essensiële kofaktor, koënsiem A (KoA). Die meerderheid patogeniese bakterieë, waaronder die organisme wat tuberkulose veroorsaak, besit ‘n unieke vorm van die PanK-ensiem. Gevolglik word hierdie ensieme as belangrike teikens vir die ontwikkeling van antibakteriële middels beskou. In hierdie studie is die aktiwiteit van die Mycobacterium tuberculosis ensiem gekarakteriseer wat verskeie teenstrydige bevindings oor hierdie ensiem beantwoord het. Verder is nuwe inhibitore vir die Pseudomonas aeruginosa ensiem ontwerp, gesintetiseer en getoets. Die beste inhibitore van hierdie tipe ensiem tot op hede is sodoende geïdentifiseer.
AFRIKAANSE OPSOMMING: Pantoteensuurkinase-ensiem (PanK) kataliseer die eerste stap in die vyf stap biosintese van die lewens belangrike en essensiële kofaktor, koënsiem A (KoA). Die meerderheid patogeniese bakterieë, waaronder die organisme wat tuberkulose veroorsaak, besit ‘n unieke vorm van die PanK-ensiem. Gevolglik word hierdie ensieme as belangrike teikens vir die ontwikkeling van antibakteriële middels beskou. In hierdie studie is die aktiwiteit van die Mycobacterium tuberculosis ensiem gekarakteriseer wat verskeie teenstrydige bevindings oor hierdie ensiem beantwoord het. Verder is nuwe inhibitore vir die Pseudomonas aeruginosa ensiem ontwerp, gesintetiseer en getoets. Die beste inhibitore van hierdie tipe ensiem tot op hede is sodoende geïdentifiseer.
Description
Thesis (PhD)--Stellenbosch University, 2011.
Keywords
Coenzyme A -- Biosynthesis, Pantothenate kinase, Inhibitor development, Enzymology, UCTD