The first direct evaluation of the two-active site mechanism for chitin synthase.
Chitin synthase polymerizes UDP-GlcNAc to form chitin (poly-beta(1,4)-GlcNAc) and is essential for fungal cell wall biosynthesis. The alternating orientation of the GlcNAc residues within the chitin chain has led to the proposal that chitin synthase possesses two active sites. We report the results of the first direct test of this possibility. Two simple uridine-derived dimeric inhibitors are shown to exhibit 10-fold greater inhibition than a monomeric control, consistent with the presence of two active sites. This observation has important implications for the development of antifungal agents, as well as the understanding of polymerizing glycosyltransferases.
Yeager
Adam R
AR
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Jolla, California 92093-0358, USA.
Finney
Nathaniel S
NS
D001665:Binding Sites; D002240:Carbohydrate Sequence; D002686:Chitin / Q000096:biosynthesis; D002687:Chitin Synthase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008969:Molecular Sequence Data; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D014530:Uridine Diphosphate / Q000031:analogs & derivatives / Q000378:metabolism
D004791:Enzyme Inhibitors; D029701:Saccharomyces cerevisiae Proteins; D002686:Chitin; D014530:Uridine Diphosphate; D002687:Chitin Synthase; D003857:Deoxyuridine