Nagaraja, Viswanathan Arun and Arumugam, Rajavel and Chandra, Nagasuma R and Prasad, Dasari and Rangarajan, Pundi N and Padmanaban, Govindarajan (2009) Localisation of Plasmodium falciparum uroporphyrinogen III decarboxylase of the heme-biosynthetic pathway in the apicoplast and characterisation of its catalytic properties. In: International Journal for Parasitology, 39 (5). pp. 559-568.
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Uroporphyrinogen decarboxylase (UROD) is a key enzyme in the heme-biosynthetic pathway and in Plasmodium falciparum it occupies a strategic position in the proposed hybrid pathway for heme biosynthesis involving shuttling of intermediates between different subcellular compartments in the parasite. In the present study, we demonstrate that an N-terminally truncated recombinant P. falciparum UROD (r(Δ)PfUROD) over-expressed and purified from Escherichia coli cells, as well as the native enzyme from the parasite were catalytically less efficient compared with the host enzyme, although they were similar in other enzyme parameters. Molecular modeling of PfUROD based on the known crystal structure of the human enzyme indicated that the protein manifests a distorted triose phosphate isomerase (TIM) barrel fold which is conserved in all the known structures of UROD. The parasite enzyme shares all the conserved or invariant amino acid residues at the active and substrate binding sites, but is rich in lysine residues compared with the host enzyme. Mutation of specific lysine residues corresponding to residues at the dimer interface in human UROD enhanced the catalytic efficiency of the enzyme and dimer stability indicating that the lysine rich nature and weak dimer interface of the wild-type PfUROD could be responsible for its low catalytic efficiency. PfUROD was localised to the apicoplast, indicating the requirement of additional mechanisms for transport of the product coproporphyrinogen to other subcellular sites for its further conversion and ultimate heme formation.
|Item Type:||Journal Article|
|Additional Information:||Copyright of this article belongs to Elsevier Science.|
|Keywords:||Uroporphyrinogen decarboxylase;Heme;Plasmodium falciparum; Apicoplast;Catalytic efficiency;Weak dimer.|
|Department/Centre:||Division of Information Sciences > Supercomputer Education & Research Centre
Division of Biological Sciences > Biochemistry
Division of Information Sciences > BioInformatics Centre
|Date Deposited:||28 Aug 2009 15:38|
|Last Modified:||19 Sep 2010 05:30|
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