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Title: Characterisation of some of the steps involved in haem and sirohaem biosynthesis in a number of pathogens
Author: Scott, Alan Francis
ISNI:       0000 0004 2747 3465
Awarding Body: University of Kent
Current Institution: University of Kent
Date of Award: 2012
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Enzymes involved in haem and sirohaem synthesis are potential drug targets. A number of these enzymes from various pathogens have been overproduced using recombinant technology and characterised. HemC is a haem synthesis enzyme th-at produces hydroxymethylbilane, a linear tetrapyrrole which rapidly cyclises into uroporphyrinogen I in the absence of the next enzyme in the pathway. This is HemD, which inverts ringD during cyclisation of hydroxymethylbilane to form uroporphyrinogen Ill. A recent publication claimed that Plasmodium falciparum HemC contains HemD activity in addition to its normal function. This has been refuted by the use of a complementation study which shows that the P. falciparum hemC gene cannot compliment a defined E. coli nemir mutant. Additionally, biochemical analysis of the reaction product identifies it (in its oxidised form) as uroporphyrin I. Demonstrating that the enzyme is mono-functional has shown that it is a less attractive drug target as it would be too similar to the human enzyme. Staphylococcus aureus HemY was expected to catalyse protoporphyrinogen IX oxidation - the penultimate step in haem synthesis. However, purified HemY failed to exhibit this activity but could oxidise coproporphyrinogen III into coproporphyrin Ill, suggesting that haem synthesis in S. aureus may proceed via a novel pathway. The addition of HemQ, a haem synthesis protein of unclear function, failed to activate _______ protoporphyrinoqen IX oxidase .. activity .in S. aureus HemY. A low throughput drug screen identified potent inhibitors of HemY which are based around the diphenyl-ether herbicides. These inhibitors could become leads for the development of novel anti- infectives.~--~---- Bacterial frataxin CyaY has been recently shown to be a negative regulator of iron- sulphur cluster formation. The possibility that CyaY may also regulate other iron- utilisation pathways was investigated with studies on the sirohaem ferrocheletase activity of CysG. However, CyaY failed to alter the activity of the enzyme in response to iron concentration.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available