The results showed in TLC, HPLC, and ESI MS MS are indicative that of bifunctional activity for rPfFPPS, showing catalytic activity with DMAPP, GPP, and FPP as first substrates, ultimately yielding GGPP as final product. Based on the conservation among FPPS and GGPPS enzymes, it is tempting to sug gest that rPfFPPS mechanism Inhibitors,Modulators,Libraries of catalysis is bi bi or dered, in which binding of either DMAPP, GPP, or FPP to the free enzyme is followed by IPP binding. However, synthases, present an aromatic amino acid residue solely at the fifth position. Upon alignment of FPPS GGPPS from T. gondii and GGPPS from P. vivax it appears that these proteins share more features with other FPPS as already postulated by Ling et al. and FPPS from P. falciparum also falls in this cluster.

Accordingly, these enzymes show the apparent production of GGPP and FPP, although this is not explicitly expressed in the characterization of the P. vivax enzyme. Inhibitors,Modulators,Libraries One may argue that a hydrophilic side chain at the fifth amino acid upstream of the FARM region plays a crucial role for the production of both GGPP and FPP. Li et al. showed that the presence of a cysteine at the fifth pos ition is essential for the FPPS GGPPS bifunctionality in T. gondii. On the other hand, the methanobacterial ver sion of the enzyme contains a bulky phenylalanine at this position and also produces GGPP and FPP, turning evident that other regions may play a role in the fine specificity of product formation.

Our analyses of the CLD from 452 putative FPPS sequences show relatively high sequence conservation of other amino acids close to the FARM, and suggest the potential for the further discovery of a number of FPPS GGPPS bifunctionality in organisms as diverse as animals, fungi, amoeba, plants, and others. From the point of view of parasitism, it is reasonable to infer that a bifunctional Inhibitors,Modulators,Libraries enzyme would be a selective advantage. Considering the notoriously re duced genomes Inhibitors,Modulators,Libraries in parasitic organisms and the fact that no other enzyme with similarity to known short chain prenyl synthases has been identified in the Inhibitors,Modulators,Libraries currently se quenced Apicomplexa, this mutation has probably been advantageous selleck chemical to these parasites given the essential other sequential or random mechanisms cannot be ruled out for the P. falciparum enzyme since the results here presented do not allow the determination of its kinetic mechanism. A mandatory ordered kinetic mechanism has been described for other FPPS, including the human, T. cruzi, Staphylococcus aureus and E. coli homologues.