Presented here is a structure solved by the Seattle Structural Genomics Center for Infectious Disease (SSGCID) of 3-ketoacyl-(acyl-carrier-protein) reductase or FabG from the gram-negative bacterium Rickettsia prowazekii. This parasite can only reproduce through host infection and is transmitted most commonly by contact with the saliva or feces of lice and fleas. Rickettsia prowazekii causes epidemic typhus in humans, a disease that flourishes in areas suffering from overcrowding or poor hygiene such as jails or refugee camps. Although louse control has succeeded in suppressing typhus in the modern era, recent outbreaks in the USA, Africa and Europe have once again established R. prowazekii as a re-emerging disease threat.
Owing to its small genome (about 800 protein-coding genes), this parasite relies on the mammalian host for many basic biosynthetic processes, thus hindering the identification of potential anti-pathogenic drug targets. However, like many bacteria and plants, R. prowazekii metabolism depends upon the type II fatty-acid synthesis (FAS) pathway for lipogenesis (the conversion of acetyl-CoA to fats), as opposed to the type I FAS pathway utilized by humans. FabG is the third enzyme in the FAS II pathway and the structure of FabG from Rickettsia is similar to structures from well characterized pathogens such as Mycobacterium tuberculosis and Burkholderia pseudomallei. However, the structure of this protein differs significantly from the analogous mammalian structure. Hence, drugs known to target the enzymes of pathogenic bacteria may serve as potential leads against Rickettsia. Owing to a conformational change that takes place in the FabG protein during substrate molecule binding, it has been difficult to identify suitable inhibitors for this essential and highly conserved enzyme. The SSGCID hopes that the additional structural information provided for this Rickettsia FabG protein will further aid scientists in identifying a strategy for inhibitor development. PDB ID: 3F9I.
The structure was published in the journal Acta Cryst F, as one of 30 publications comprising one special edition focused solely on SSGCID work. Reference: “Crystal Structure of 3-ketoacyl-(acyl-carrier-protein) reductase from Rickettsia prowazekii at 2.25 Ångström Resolution.” Subramanian, S., Abendroth, J., Phan, I.Q.H., Olsen, C., Staker, B.L., Napuli, A., Van Voorhis, W.C., Stacy, R., and Myler, P.J. Acta Cryst. (2011) F67, 9:1118-1122. PMID: 21904060.