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Origin of the Slow‐Binding Inhibition of Aldolase by D‐ glycero ‐Tetrulose 1‐Phosphate (D‐Erythrulose 1‐Phosphate) from the Comparison with the Isosteric Phosphonate Analog
Author(s) -
Page Patrick,
Blonski Casimir,
Périé Jacques
Publication year - 1999
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/(sici)1099-0690(199911)1999:11<2853::aid-ejoc2853>3.0.co;2-0
Subject(s) - chemistry , aldolase a , phosphonate , stereochemistry , phosphate , dihydroxyacetone phosphate , enzyme , non competitive inhibition , substrate (aquarium) , enamine , fructose bisphosphate aldolase , biochemistry , catalysis , oceanography , geology
The mechanistic reaction pathway for the slow‐binding inhibition of rabbit muscle aldolase by D ‐ glycero ‐tetrulose 1‐phosphate ( D ‐erythrulose 1‐phosphate) was investigated through the use of its phosphonomethyl isoster 4 which was synthezised for this study. The latter is not a substrate nor a slow‐binding inhibitor but interferes in the enzyme‐catalyzed reaction with the substrate fructose 1,6‐diphosphate in a competitive manner. It was found that phosphonate 4 forms an iminium ion with aldolase and undergoes subsequent α‐proton abstraction to form an enamine intermediate. We show from these results that enzyme slow‐binding inhibition by D ‐erythrulose 1‐phosphate is consistent with a phosphate β‐elimination reaction through the enamine intermediate. This mechanism takes into account the stereochemical features known for aldolase, the parallel between enzyme activity recovery and phosphate release after action of D ‐erythrulose 1‐phosphate, and also the same reaction from dihydroxyacetone phosphate.