Skip to main content

Advertisement

SpringerLink
Log in

Type II Fatty Acid Biosynthesis, a New Approach in Antimalarial Natural Product Discovery

  • Published:
Phytochemistry Reviews Aims and scope Submit manuscript

Abstract

Malaria, one of the most problematic infectious diseases worldwide, is on the rise. The absence of an effective vaccine and the spread of drug-resistant strains of Plasmodium clearly indicate the necessity for the development of new chemotherapeutic agents and the identification of novel targets. The recent discovery of a relict, non-photosynthetic plastid-like organelle, the so-called apicoplast, in Plasmodium has opened up new avenues in malaria research. It also initiated the Plasmodium falciparum genome sequencing project, which revealed a number of biochemical pathways previously unknown to Plasmodium, i.e. cytosolic shikimate pathway, apicoplastic type II fatty acid, non-mevalonate isoprene and haem biosyntheses. Since these vital biosynthetic processes are absent in humans or fundamentally different from those found in humans, they represent excellent targets for pharmaceutical interventions. We are interested in the type II fatty acid synthase (FAS II) system of malaria parasite and focus on the FabI enzyme, the only known enoyl-ACP reductase in Plasmodium involved in the final reduction step of the fatty acid chain elongation cycle. Here we describe the general aspects of fatty acid biosynthesis, its essentiality to the malaria parasite and our continuing efforts to discover in Turkish medicinal plants natural antimalarial agents, which specifically target the plasmodial FabI enzyme.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Berriman M, Ghedin E, Hertz-Fowler C, Blandin G, Renauld H, Bartholomeu DC, Lennard NJ, Caler E, Hamlin NE, Haas B, Bohme U, Hannick L, Aslett MA, Shallom J, Marcello L, Hou L, Wickstead B, Alsmark UC, Arrowsmith C, Atkin RJ, Barron AJ, Bringaud F, Brooks K, Carrington M, Cherevach I, Chillingworth TJ, Churcher C, Clark LN, Corton CH, Cronin A, Davies RM, Doggett J, Djikeng A, Feldblyum T, Field MC, Fraser A, Goodhead I, Hance Z, Harper D, Harris BR, Hauser H, Hostetler J, Ivens A, Jagels K, Johnson D, Johnson J, Jones K, Kerhornou AX, Koo H, Larke N, Landfear S, Larkin C, Leech V, Line A, Lord A, Macleod A, Mooney PJ, Moule S, Martin DM, Morgan GW, Mungall K, Norbertczak H, Ormond D, Pai G, Peacock CS, Peterson J, Quail MA, Rabbinowitsch E, Rajandream MA, Reitter C, Salzberg SL, Sanders M, Schobel S, Sharp S, Simmonds M, Simpson AJ, Tallon L, Turner CM, Tait A, Tivey AR, Van Aken S, Walker D, Wanless D, Wang S, White B, White O, Whitehead S, Woodward J, Wortman J, Adams MD, Embley TM, Gull K, Ullu E, Barry JD, Fairlamb AH, Opperdoes F, Barrell BG, Donelson JE, Hall N, Fraser CM, Melville SE and El-Sayed NM (2005). The genome of the African trypanosome Trypanosoma brucei. Science 309: 416–422

    Article  PubMed  CAS  Google Scholar 

  • Chaudhary K and Roos DS (2005). Protozoan genomics for drug discovery. Nat. Biotechnol. 23: 1089–1091

    Article  PubMed  CAS  Google Scholar 

  • Chowdhury AR, Sharma S, Mandal S, Goswami A, Mukhopadhyay S and Majumder HK (2002). Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase I. Biochem. J. 366: 653–661

    Article  PubMed  CAS  Google Scholar 

  • Coppel RL, Roos DS and Bozdech Z (2004). The genomics of malaria infection. Trends Parasitol. 20: 553–557

    Article  PubMed  CAS  Google Scholar 

  • Divo A, Sartorelli AC, Patton CL and Bia FJ (1988). Activity of fluoroquinolone antibiotics against Plasmodium falciparum in vitro. Antimicrob. Agents Chemother. 32: 1182–1186

    PubMed  CAS  Google Scholar 

  • Fitzpatrick T, Ricken S, Lanzer M, Amrhein N, Macheroux P and Kappes B (2001). Subcellular localization and characterization of chorismate synthase in the apicomplexan Plasmodium falciparum. Mol. Microbiol. 40: 65–75

    Article  PubMed  CAS  Google Scholar 

  • Foth BJ, Stimmler LM, Handman E, Crabb BS, Hodder AN and McFadden GI (2005). The malaria parasite Plasmodium falciparum has only one pyruvate dehydrogenase complex, which is located in the apicoplast. Mol. Microbiol. 55: 39–53

    Article  PubMed  CAS  Google Scholar 

  • Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, Carlton JM, Pain A, Nelson KE, Bowman S, Paulsen IT, James K, Eisen JA, Rutherford K, Salzberg SL, Craig A, Kyes S, Chan MS, Nene V, Shallom SJ, Suh B, Peterson J, Angiuoli S, Pertea M, Allen J, Selengut J, Haft D, Mather MW, Vaidya AB, Martin DMA, Fairlamb AH, Fraunholz MJ, Roos DS, Ralph SA, McFadden GI, Cummings LM, Subramanian GM, Mungall C, Venter JC, Carucci DJ, Hoffman SL, Newbold C, Davis RW, Fraser CM and Barrell B (2002). Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419: 498–511

    Article  PubMed  CAS  Google Scholar 

  • Heat RJ, White SW and Rock CO (2002). Inhibitors of fatty acid synthesis as antimicrobial chemotherapeutics. Appl. Microbiol. Biotechnol. 58: 695–703

    Article  CAS  Google Scholar 

  • Jomaa H, Wiesner J, Sanderbrand S, Altincicek B, Weidemejer C, Hintz M, Türbachova I, Eberl M, Zeidler J, Lichtenthaler HK, Soldati D and Beck E (1999). Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 285: 1573–1576

    Article  PubMed  CAS  Google Scholar 

  • Kilejian A (1975). Circular mitochondrial DNA from the avian malarial parasite Plasmodium lophurae. Biochim. Biophys. Acta 390: 267–284

    Google Scholar 

  • Kırmızıbekmez H, Çalıs I, Perozzo R, Brun R, Dönmez AA, Linden A, Rüedi P and Tasdemir D (2004). Inhibiting activities of the secondary metabolites of Phlomis brunneogaleata against parasitic protozoa and plasmodial enoyl-ACP reductase, a crucial enzyme in fatty acid biosynthesis. Planta Med. 70: 711–717

    Article  PubMed  CAS  Google Scholar 

  • Liu B, Wang Y, Fillgrove KL and Anderson VE (2002). Triclosan inhibits enoyl-reductase of type I fatty acid synthase in vitro and is cytotoxic to MCF-7 and SKBr-3 breast cancer cells. Cancer Chemother. Pharmacol. 49: 187–193

    Article  PubMed  CAS  Google Scholar 

  • McFadden GI, Reith M, Munholland J and Lang-Unnasch N (1996). Plastid in human parasites. Nature 381: 482

    Article  PubMed  CAS  Google Scholar 

  • McFadden GI and Roos DS (1999). Apicomplexan plastids as drug targets. Trends Microbiol. 7: 328–333

    Article  PubMed  CAS  Google Scholar 

  • McFadden GI (2001). Chloroplast origin and integration.. Plant Physiol. 125: 50–53

    Article  PubMed  CAS  Google Scholar 

  • McLeod R, Muench SP, Rafferty JB, Kyle DE, Mui EJ, Kirisits MJ, Mack DG, Roberts CW, Samuel BU, Lyons RE, Dorris M, Milhous WK and Rice DW (2001). Triclosan inhibits the growth of Plasmodium falciparum and Toxoplasma gondii by inhibition of apicomplexan FabI. Int. J. Parasitol. 31: 109–113

    Article  PubMed  CAS  Google Scholar 

  • Morita YS, Paul KS and Englund PT (2000). Specialized fatty acid synthesis in African trypanosomes: Myristate for GPI anchors. Science 288: 140–143

    Article  PubMed  CAS  Google Scholar 

  • Parikh SL, Xiao GP and Tonge PJ (2000). Inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis, by triclosan and isoniazid. Biochemistry 39: 7645–7650

    Article  PubMed  CAS  Google Scholar 

  • Perozzo R, Fidock DA, Kuo M, Sidhu AS, Valiyaveettil JT, Bittman R, Jacobs WR, Fidock DA and Sacchettini JC (2002). Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl acyl carrier protein reductase. J. Biol. Chem. 277: 13106–13114

    Article  PubMed  CAS  Google Scholar 

  • Ralph SA, D’Ombrain MC and McFadden GI (2001). The apicoplast as an antimalarial drug target. Drug Resist. Updat. 4: 145–151

    Article  PubMed  CAS  Google Scholar 

  • Ralph SA, Waller RF, Crawford MJ, Fraunholz MJ, Foth BJ, Tonkin CJ, Roos DS and McFadden GI (2004). Metabolic maps and functions of the Plasmodium falciparum apicoplast. Nature Rev. 2: 203–216

    Article  CAS  Google Scholar 

  • Roberts F, Roberts CW, Johnson JJ, Kyle DE, Krell T, Coggins JR, Coombs GH, Tzipori S, Ferguson DJP, Chakrabarti D and McLeod R (1998). Evidence for the shikimate patway in apicomplexan parasites. Nature 393: 801–805

    Article  PubMed  CAS  Google Scholar 

  • Sato S, Tews I and Wilson RJM (2000). Impact of plastid-bearing endocytobiont on apicomplexan genomes. Int. J. Parasitol. 30: 427–439

    Article  PubMed  CAS  Google Scholar 

  • Sinnis P and Sim BK (1997). Cell invasion by the vertebrate stages of Plasmodium. Trends Microbiol. 5: 52–58

    Article  PubMed  CAS  Google Scholar 

  • Sperandeo NR and Brun R (2003). Synthesis and biological evaluation of pyrazolylnaphthoquinones as new potential antiprotozoal and cytotoxic agents. Chem Bio Chem 4: 69–72

    Article  PubMed  CAS  Google Scholar 

  • Surolia N and Surolia A (2001). Triclosan offers protection against blood stages of malaria by inhibiting enoyl-ACP reductase of Plasmodium falciparum. Nature Med. 7: 167–173

    Article  PubMed  CAS  Google Scholar 

  • Surolia A, Ramya TNC, Ramya V and Surolia N (2004). FAS’t inhibition of malaria. Biochem. J. 383: 401–412

    Article  PubMed  CAS  Google Scholar 

  • Tasdemir D, Güner ND, Perozzo R, Brun R, Dönmez AA, Çalıs I and Rüedi P (2005a). Anti-protozoal and plasmodial FabI enzyme inhibiting metabolites of Scrophularia lepidota. Phytochemistry 66: 355–362

    Article  CAS  Google Scholar 

  • Tasdemir D, Brun R, Perozzo R and Dönmez AA (2005b). Evaluation of anti-protozoal and plasmodial enoyl-ACP reductase inhibition potential of Turkish medicinal plants. Phytother. Res. 19: 162–166

    Article  CAS  Google Scholar 

  • Vial HJ, Eldin P and Tielens AGM (2003). Phospholipids in parasitic protozoa. Mol. Biochem. Parasitol. 126: 143–154

    Article  PubMed  CAS  Google Scholar 

  • Waller RF, Keeling PJ, Donald RG, Striepen B, Handman E, Lang-Unnasch N, Cowman AF, Besra GS, Roos DS and McFadden GI (1998). Nuclear-encoded proteins target to the plastid in Toxoplasma gondii and Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 95: 12352–12357

    Article  PubMed  CAS  Google Scholar 

  • Waller RF, Ralph SA, Reed MB, Su V, Douglas JD, Minnikin DE, Cowman AF, Besra GS and McFadden GI (2003). A type II pathway for fatty acid biosynthesis present drug targets in Plasmodium falciparum. Antimicrob. Agents Chemother. 47: 297–301

    Article  PubMed  CAS  Google Scholar 

  • Wiesner J and Seeber F (2005). The plastid-derived organelle of protozoan human parasites as a target of established and emerging drugs. Expert Opin. Ther. Targets 9: 23–44

    Article  PubMed  CAS  Google Scholar 

  • Williams BAP and Keeling PJ (2003). Cryptic organelles in parasitic protists and fungi. Adv. Parasitol. 54: 9–68

    Article  PubMed  Google Scholar 

  • World Health Organisation Health (2000) A Precious Asset (accelerating follow-up to the World Summit for Social Development. Proposals by the World Health Organisation). WHO: 2000 HSD/HID/00.1.

Download references

Author information

Authors and Affiliations

  1. Institute of Organic Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland

    Deniz Tasdemir

  2. School of Pharmacy, Department of Pharmaceutical and Biological Chemistry Centre for Pharmacy and Phytotherapy, University of London, 29–39, Brunswick Square, WC1N 1AX, London, United Kingdom

    Deniz Tasdemir

Authors
  1. Deniz Tasdemir
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Deniz Tasdemir.

Additional information

Phytochemical Society of Europe (PSE)-Pierre Fabre Prize 2004 Lecture

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tasdemir, D. Type II Fatty Acid Biosynthesis, a New Approach in Antimalarial Natural Product Discovery. Phytochem Rev 5, 99–108 (2006). https://doi.org/10.1007/s11101-005-5297-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11101-005-5297-0

Keywords

Search

Navigation