Hexapeptide repeat proteins display tandem repeated copies of a six- residue amino acid sequence generally described as (LIV)-(GAED)-X2- (STAV)-X. These proteins display a unique three-dimensional structural motif termed a Left-Handed Parallel beta Helix (LbetaH). Hexapeptide enzymes frequently function as acyltransferases in a variety of processes, including bacterial cell wall biosynthesis, amino acid metabolism and antibiotic inactivation. In this proposal, the three- dimensional structure of at least two members of the largest class of these proteins, the hexapeptide acetyltransferases, will be determined by x-ray crystallography in the presence and absence of ligands. This structural information will be combined with steady state kinetic data in order to define the order of addition of substrates, the identity of catalytically important functional groups and the chemical mechanism of action of these enzymes. This information will be used to characterize the function of this newly recognized superfamily of enzymes and to provide a structural and mechanistic framework for the design of antibiotics directed against bacterial pathogens.

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National Institute of Allergy and Infectious Diseases (NIAID)
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Biochemistry Study Section (BIO)
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Albert Einstein College of Medicine
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Pereira, Mark P; Blanchard, Jan E; Murphy, Cecilia et al. (2009) High-throughput screening identifies novel inhibitors of the acetyltransferase activity of Escherichia coli GlmU. Antimicrob Agents Chemother 53:2306-11
Guan, Rong; Roderick, Steven L; Huang, Bin et al. (2008) Roles of histidines 154 and 189 and aspartate 139 in the active site of serine acetyltransferase from Haemophilus influenzae. Biochemistry 47:6322-8
Olsen, Laurence R; Vetting, Matthew W; Roderick, Steven L (2007) Structure of the E. coli bifunctional GlmU acetyltransferase active site with substrates and products. Protein Sci 16:1230-5
Andreassi 2nd, John L; Bilder, Patrick W; Vetting, Matthew W et al. (2007) Crystal structure of the Streptococcus pneumoniae mevalonate kinase in complex with diphosphomevalonate. Protein Sci 16:983-9
Roderick, Steven L (2005) The lac operon galactoside acetyltransferase. C R Biol 328:568-75
Johnson, Corey M; Roderick, Steven L; Cook, Paul F (2005) The serine acetyltransferase reaction: acetyl transfer from an acylpantothenyl donor to an alcohol. Arch Biochem Biophys 433:85-95
Olsen, Laurence R; Huang, Bin; Vetting, Matthew W et al. (2004) Structure of serine acetyltransferase in complexes with CoA and its cysteine feedback inhibitor. Biochemistry 43:6013-9
Johnson, Corey M; Huang, Bin; Roderick, Steven L et al. (2004) Chemical mechanism of the serine acetyltransferase from Haemophilus influenzae. Biochemistry 43:15534-9
Wang, Xing-Guo; Olsen, Laurence R; Roderick, Steven L (2002) Structure of the lac operon galactoside acetyltransferase. Structure 10:581-8
Sugantino, Michele; Roderick, Steven L (2002) Crystal structure of Vat(D): an acetyltransferase that inactivates streptogramin group A antibiotics. Biochemistry 41:2209-16

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