Browsing by Author "Macuamule, Cristiano Joao"

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    Coenzyme a biosynthesis and utilization in Plasmodium falciparum : drug targets for antimalarial chemotherapy
    (Stellenbosch : Stellenbosch University, 2014-12) Macuamule, Cristiano Joao; Strauss, Erick; Saliba, Kevin J.; Stellenbosch University. Faculty of Science. Dept. of Biochemistry.
    ENGLISH ABSTRACT: Pantothenate (also known as Vitamin B5) is the sole precursor of the essential enzyme cofactor coenzyme A (CoA) that is required in several metabolic reactions virtually in all living organisms including the human malaria parasite Plasmodium falciparum. While the parasite has the capacity to generate CoA from pantothenate, it cannot produce this nutrient de novo, and as a result depends on external supplies. Processes in the CoA metabolic pathway have been identified as possible targets for drug development and pantothenate analogues as agents that can interfere with those processes to block parasite development. In this dissertation it is shown that the class of pantothenate analogues known as Nsubstituted pantothenamides (PanAms) and N‐substituted pantoyltauramides, inhibit the growth of intraerythrocytic‐stage P. falciparum parasites at sub‐ and low micromolar concentrations respectively. In both cases, the compounds inhibited parasite proliferation through inhibition of pantothenate‐dependent processes. It is also shown that the antiplasmodial potency of PanAms can be strengthened through structural modifications rendering the compounds less susceptible to degradation by enzymes known as pantetheinases, which occur natural and ubiquitously in mammals, particularly in the serum. Finally it is also shown that the antiplasmodial mode of action of PanAms results from the compounds serving as alternative substrates for pantothenate kinase (PanK), the first enzyme intervening in the CoA biosynthesis pathway, thus interfering with the phosphorylation of the natural substrate – pantothenate. In addition, it negatively affects the production of functional CoA and acyl carrier proteins (ACPs) which are required in various cellular metabolic processes.