This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Price, A. C. Articles by White, S. W. Search for Related Content PubMed PubMed Citation Articles by Price, A. C. Articles by White, S. W.

The 1.3-Angstrom-Resolution Crystal Structure of ß-Ketoacyl-Acyl Carrier Protein Synthase II from Streptococcus pneumoniae

Departments of Structural Biology,¹ Infectious Diseases, St. Jude Children's Research Hospital,² Department of Molecular Sciences, University of Tennessee, Memphis, Tennessee 38105³

Received 3 February 2003/ Accepted 11 April 2003

The ß-ketoacyl-acyl carrier protein synthases are members of the thiolase superfamily and are key regulators of bacterial fatty acid synthesis. As essential components of the bacterial lipid metabolic pathway, they are an attractive target for antibacterial drug discovery. We have determined the 1.3 Å resolution crystal structure of the ß-ketoacyl-acyl carrier protein synthase II (FabF) from the pathogenic organism Streptococcus pneumoniae. The protein adopts a duplicated ßßßßß fold, which is characteristic of the thiolase superfamily. The two-fold pseudosymmetry is broken by the presence of distinct insertions in the two halves of the protein. These insertions have evolved to bind the specific substrates of this particular member of the thiolase superfamily. Docking of the pantetheine moiety of the substrate identifies the loop regions involved in substrate binding and indicates roles for specific, conserved residues in the substrate binding tunnel. The active site triad of this superfamily is present in spFabF as His 303, His 337, and Cys 164. Near the active site is an ion pair, Glu 346 and Lys 332, that is conserved in the condensing enzymes but is unusual in our structure in being stabilized by an Mg²⁺ ion which interacts with Glu 346. The active site histidines interact asymmetrically with Lys 332, whose positive charge is closer to His 303, and we propose a specific role for the lysine in polarizing the imidazole ring of this histidine. This asymmetry suggests that the two histidines have unequal roles in catalysis and provides new insights into the catalytic mechanisms of these enzymes.

This article has been cited by other articles:

• Christensen, C. E., Kragelund, B. B., von Wettstein-Knowles, P., Henriksen, A. (2007). Structure of the human beta-ketoacyl [ACP] synthase from the mitochondrial type II fatty acid synthase. Protein Sci. 16: 261-272 [Abstract] [Full Text]  
• Zhang, Y.-M., Hurlbert, J., White, S. W., Rock, C. O. (2006). Roles of the Active Site Water, Histidine 303, and Phenylalanine 396 in the Catalytic Mechanism of the Elongation Condensing Enzyme of Streptococcus pneumoniae. J. Biol. Chem. 281: 17390-17399 [Abstract] [Full Text]  
• Zhang, L., Joshi, A. K., Hofmann, J., Schweizer, E., Smith, S. (2005). Cloning, Expression, and Characterization of the Human Mitochondrial {beta}-Ketoacyl Synthase: COMPLEMENTATION OF THE YEAST CEM1 KNOCK-OUT STRAIN. J. Biol. Chem. 280: 12422-12429 [Abstract] [Full Text]  
• Kimber, M. S., Martin, F., Lu, Y., Houston, S., Vedadi, M., Dharamsi, A., Fiebig, K. M., Schmid, M., Rock, C. O. (2004). The Structure of (3R)-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ) from Pseudomonas aeruginosa. J. Biol. Chem. 279: 52593-52602 [Abstract] [Full Text]  
• Wang, H., Cronan, J. E. (2004). Functional Replacement of the FabA and FabB Proteins of Escherichia coli Fatty Acid Synthesis by Enterococcus faecalis FabZ and FabF Homologues. J. Biol. Chem. 279: 34489-34495 [Abstract] [Full Text]