A single histidine residue modulates enzymatic activity in acidic mammalian chitinase.
Mammals express two active chitinases, chitotriosidase and AMCase. Only AMCase displays an extremely acidic pH optimum, consistent with its observed presence in the gastro-intestinal tract. A structural model of AMCase reveals the presence of a conserved histidine residue in the active site. Mutational analyses and molecular dynamics simulations show that His187 is responsible for the acidic optimum and suggest pH dependent modulation of the reaction mechanism that is unique to AMCases. Concluding, His187 is a crucial structural component of the active site of AMCase and this unique feature may serve as a lead for the development of specific inhibitors.
Bussink
Anton P
AP
Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.
Vreede
Jocelyne
J
Aerts
Johannes M F G
JM
Boot
Rolf G
RG
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002688:Chitinases / Q000737:chemistry* / Q000235:genetics; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry; D006596:Hexosaminidases / Q000737:chemistry / Q000235:genetics; D006639:Histidine / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008969:Molecular Sequence Data; D011487:Protein Conformation; D051381:Rats
D004791:Enzyme Inhibitors; D006639:Histidine; D006596:Hexosaminidases; C086400:chitotriosidase; C499255:AMCase, mouse; C499254:CHIA protein, human; D002688:Chitinases