Design and synthesis of aromatic inhibitors of anthranilate synthase.
Anthranilate synthase catalyses the conversion of chorismate to anthranilate, a key step in tryptophan biosynthesis. A series of 3-(1-carboxy-ethoxy) benzoic acids were synthesised as chorismate analogues, with varying functionality at C-4, the position of the departing hydroxyl group in chorismate. Most of the compounds were moderate inhibitors of anthranilate synthase, with inhibition constants between 20-30 microM. The exception was 3-(1-carboxy-ethoxy) benzoic acid, (C-4 = H), for which K(I)= 2.4 microM. These results suggest that a hydrogen bonding interaction with the active site general acid (Glu309) is less important than previously assumed for inhibition of the enzyme by these aromatic chorismate analogues.
Payne
Richard J
RJ
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UKCB2 1EW.
Bulloch
Esther M M
EM
Abell
Andrew D
AD
Abell
Chris
C
D000878:Anthranilate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002827:Chorismic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D012706:Serratia marcescens / Q000187:drug effects / Q000201:enzymology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001565:Benzoates; D004791:Enzyme Inhibitors; D000878:Anthranilate Synthase; D002827:Chorismic Acid