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Plasmodium vivax farnesyl pyrophosphate synthase

PDB Code 2IHI Protein Family Malaria Target Pv-PF11_0295 Alias n/a Disease Area/Function parasitic disease Date Deposited 2006-09-26 Authors A.DONG, J.DUNFORD, J.LEW, A.K.WERNIMONT, H.REN, Y.ZHAO, I.KOEIERADZKI, U.OPPERMAN, M.SUNDSTROM, J.WEIGELT, A.M.EDWARDS, C.H.ARROWSMITH, A.BOCHKAREV, R.HUI, J.D.ARTZ, STRUCTURALGENOMICS CONSORTIUM (SGC) Related Structure 3CC9

About this structure

Isoprenoids such as sterols and ubiquinones are a diverse and universal family of natural products. Their biosynthesis typically involves condensation of different numbers of isopentenyl diphosphate units (IPP).1 In mammals, IPP is produced by means of the mevalonate pathway with eponymous mevalonic acid as the starting metabolite. Simpler organisms, including eubacteria, algae and some plants, undergo an alternative non-mevalonate mechanism involving conversion of glyceraldehyde 3-phosphate (G3P) and pyruvate to 1-deoxy-D-xylulose 5-phosphate (DOXP) and subsequently to 2-C-methyl-D-erythritol 4-phosphate (MEP), giving rise to the DOXP pathway or the MEP pathway.

With studies uncovering the ineffectiveness of inhibitors of the mevalonate pathway, identification of enzymes such as DOXP synthase and DOXP reductoisomerase, as well as effectiveness of fosmidomycin in curing malaria in mice,2 it has been established that Plasmodium parasites produce IPP by means of the MEP pathway. Specifically, it has been shown that this pathway takes place inside the apicoplast organelle in both Plasmodium and Toxoplasma parasites.

Once IPP and its isomer dimethylallyl diphosphate (DMAPP) are produced, they are converted to first geranyl pyrophosphate (GPP) and finally the isoprenoid precursor farnesyl pyrophosphate (FPP) by the catalytic action of farnesyl pyrophosphate synthase (FPPS). This is a well characterized enzyme which is also a validated drug target for osteoporosis in humans and considered a potential drug target in protozoan parasites. Specifically, nitrogen-containing bisphosphonates, which are non-hydrolyzable pyrophosphate analogues and proven FPPS inhibitors (with some compounds currently available as drugs against osteoporosis), have been found to have nanomolar to low micro-molar activity in vitro against Trypanosoma, Leishmania, Toxoplasma and Plasmodium parasites.3

We have solved the structure of a Plasmodium vivax enzyme who is homologous by sequence to human FPPS and GGPPS. Enzymatic characterization showed that this enzyme produced exclusively GGPP but was inhibited at mid-nanomolar concentrations by N-BPs, which is uncommon for a geranylgeranyl pyrophosphate synthase. This structure will aid in further elucidation of the isoprenoid pathway in Plasmodium parasites and provide the basis for structure guided optimization of FPPS inhibitors as anti-malarials.

See also

  • SGC's human FPPS structure with in complex with risedronate and zoledronate
  • SGC's Cryptosporidium parvum structure of polyprenyl pyrophosphate synthase in complex with zoledronate

References

  1. Rohmer, M. (2003) "Mevalonate-independent methylerythritol phosphate pathway for isoprenoid biosynthesis. Elucidation and distribution." Pure Appl. Chem., Vol. 75, Nos. 2–3, pp. 375–387.
  2. Jomaa, H.,Wiesner, J., Sanderbrand, S., Altincicek, B., Weidemeyer, C., Hintz, M., Tu¬rbachova, I., Eberl, M., Zeidler, J., Lichtenthaler, H., Soldati, D. and Beck, E. (1999) "Inhibitors of the Nonmevalonate Pathway of Isoprenoid Biosynthesis as Antimalarial Drugs." Science, Vol. 285, No 3, pp. 1573-6.
  3. Martin, M.B., Grimley, J.S., Lewis, J.C., Heath, III, H.T., Bailey, B.N., Kendrick, H., Yardley, V., Caldera, A., Renee Lira, R., Urbina, J.A., Moreno, S.N.J., Docampo, R., Croft, S.L. and Oldfield, E. (2001). "Bisphosphonates Inhibit the Growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum: A Potential Route to Chemotherapy." J. Med. Chem.