Apicoplast fatty acid biosynthesis as a target for medical intervention in apicomplexan parasites.
New chemotherapies for human and animal apicomplexan infections are needed as a component of future strategies to deal with these diseases. An extensive search for new treatments exploring the unique developmental physiology, metabolism and molecular structures of Apicomplexa is under way. The description of the full complement of about 5,300 Plasmodium falciparum genes and fast growing sequence databases for other Apicomplexa allow reconstruction of metabolic pathways of these parasites and thus accelerate identification and biochemical analysis of potential targets. The apicoplast de novo fatty acid biosynthetic pathway shows great potential as a target for small-molecule inhibitors in a stand-alone or combination chemotherapy. Three enzymatic activities, acetyl-CoA carboxylase, beta-ketoacyl-ACP synthase and enoyl-ACP reductase, respond to inhibitors previously identified for bacteria and plants, and deserve to be explored in depth. In this connection, screening systems have been established to seek more potent and specific antiparasitic compounds that are harmless to the host. To this end the interconnections of fatty acid biosynthesis in Apicomplexa with other metabolic and cellular processes must be investigated.
Gornicki
Piotr
P
Department of Molecular Genetics and Cell Biology, University of Chicago, 920 East 58th Street, Chicago IL 60637, USA. pg13@midway.uchicago.edu
D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors; D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors; D000818:Animals; D016782:Apicomplexa / Q000378:metabolism* / Q000502:physiology; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D004791:Enzyme Inhibitors / Q000627:therapeutic use; D064429:Fatty Acid Synthases / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis*; D006790:Host-Parasite Interactions; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008018:Life Cycle Stages; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010273:Parasitic Diseases, Animal / Q000188:drug therapy; D011528:Protozoan Infections / Q000188:drug therapy* / Q000469:parasitology; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D012107:Research Design
D004791:Enzyme Inhibitors; D005227:Fatty Acids; D007527:Isoenzymes; D011768:Pyruvate Dehydrogenase Complex; D010088:Oxidoreductases; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D064429:Fatty Acid Synthases; D000103:Acetyl-CoA Carboxylase