Reversible inhibition of sheep liver sorbitol dehydrogenase by the antidiabetogenic drug 2-hydroxymethyl-4-(4-N,N-dimethylaminosulfonyl-1-piperazino) pyrimidine.
The mechanism of the inhibition of sheep liver sorbitol dehydrogenase by the novel antidiabetogenic drug 2-hydroxymethyl-4-(4-N,N-dimethylaminosulfonyl-1-piperazino) pyrimidine has been investigated by steady-state kinetics over the range pH 5-10. The pyrimidine derivative exhibits mixed inhibition with respect to sorbitol, fructose and coenzyme, due to the formation of enzyme-inhibitor and enzyme-NAD(H)-inhibitor complexes. The formation of each of the binary and ternary complexes is inhibited by protonation and deprotonation of groups which, in the enzyme-inhibitor complex, have pK values of 6.6 and 8.0, respectively.
Lindstad
R I
RI
Institute of Biochemistry, University of Oslo, Blindern, Norway.
McKinley-McKee
J S
JS
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005632:Fructose / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007700:Kinetics; D007064:L-Iditol 2-Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D009243:NAD / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011522:Protons; D011743:Pyrimidines / Q000494:pharmacology*; D012756:Sheep; D013012:Sorbitol / Q000378:metabolism
D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D010879:Piperazines; D011522:Protons; D011743:Pyrimidines; C103900:SDI 158; D009243:NAD; C106112:2-hydroxymethyl-4-(4-(N,N-dimethylaminosulfonyl)-1-piperazino)pyrimidine; D005632:Fructose; D013012:Sorbitol; D007064:L-Iditol 2-Dehydrogenase; D000449:Aldehyde Reductase