Fatty Acid synthesis as a target for antimalarial drug discovery.
In biological systems, fatty acids can be synthesized by two related, but distinct de novo fatty acid synthase (FAS) pathways. Human cells rely on a type I FAS whereas plants, bacteria and other microorganisms contain type II FAS pathways. This difference exposes the type II FAS enzymes as potential targets for anti-microbial drugs that have little to no side effects in the human host. A number of inhibitors of type II FAS enzymes have been discovered - many of which have anti-bacterial activity. Extensive biochemical and structural studies have shed light on how these compounds inhibit their target enzymes, laying the foundation for the design of inhibitors with increased potency. Recent work has shown that malaria parasites do not contain a type I FAS and rely solely on a type II FAS for the de novo biosynthesis of fatty acids. The malaria FAS enzymes are therefore an exciting source of new drug targets, and are being actively exploited by several drug discovery efforts. Rapid progress has been made, largely due to the vast body of mechanistic and structural information about type II FAS enzymes from bacteria and the availability of inhibitors. Ongoing antimalarial drug discovery projects will be described in this review as well as background information about the well-studied bacterial type II FAS enzymes.
Lu
Jeff Zhiqiang
JZ
Johns Hopkins University, Bloomberg School of Public Health, Department of Molecular Microbiology and Immunology, Baltimore, MD 21205, USA.
Lee
Patricia J
PJ
Waters
Norman C
NC
Prigge
Sean T
ST
D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000737:chemistry; D000103:Acetyl-CoA Carboxylase / Q000737:chemistry; D000213:Acyl Carrier Protein / Q000737:chemistry; D051080:Acyl-Carrier Protein S-Malonyltransferase; D000217:Acyltransferases / Q000737:chemistry; D000429:Alcohol Oxidoreductases / Q000737:chemistry; D000962:Antimalarials / Q000737:chemistry*; D015195:Drug Design; D005227:Fatty Acids / Q000096:biosynthesis*; D006801:Humans; D006836:Hydro-Lyases / Q000737:chemistry
D000213:Acyl Carrier Protein; D000962:Antimalarials; D005227:Fatty Acids; D000429:Alcohol Oxidoreductases; D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase; D000217:Acyltransferases; C077402:3-ketoacyl-acyl carrier protein synthase III; D051080:Acyl-Carrier Protein S-Malonyltransferase; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D006836:Hydro-Lyases; C036180:beta-hydroxyacyl-(acyl-carrier-protein)dehydrase; D000103:Acetyl-CoA Carboxylase