Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.2.1.7 (BAL)
 1,977 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of dithiol compounds with different spacing between the thiol (SH) groups to protect against and reversed the action of alloxan on islet tissue permeability, and their ability to inhibit the reaction between alloxan and glutathione (which results in the formation of a compound with a 305 nm absorption maximum) have been examined. Treatment of toadfish islet slices with alloxan markedly increased their permeability to D-mannitol-1-14C, which normally is restricted to the extracellular space. Pretreatment of the slices with 2,3-dimercaptopropanol (BAL) or 1,4-dimercaptobutane (DMB) before treatment with alloxan completely protected them against this action of alloxan, whereas 1,5-dimercaptopentane (DMP) and 1,6-dimercaptohexane (DMH) partially protected and 1,8-dimercapto-octane (DMO) had no effect. When islets were first treated with alloxan and then treated with the dithiols, BAL and DMB reverse the action of alloxan to the greatest extent, DMP was less effective, and DMH had no effect. The effect of the dithiols on the reaction between alloxan and glutathione was consistent with their effects on the alloxan-induced increase in islet permeability; BAL and DMB were the strongest inhibitors, DMP and DMH inhibited to a lesser degree and DMO did not inhibit. These studies support the hypothesis that alloxan damages islet cell membranes by reacting with membrane dithiols formed by two SH groups which are relatively close together.
 ...
PMID:Effect of alloxan on islet tissue permeability: protection and reversal by dithiols. 79 16

Alloxan inhibited hexokinase activity in cytoplasmic fractions of transplantable radiation-induced rat islet cell tumours, ob/ob mouse pancreatic islets, rat liver and rat kidney. Half maximal inhibitory concentrations of alloxan were greater than those previously found for half maximal inhibition of pancreatic islet or liver glucokinase. D-glucose, preferentially the alpha-anomer, and D-mannose protected hexokinase activity against alloxan inhibition. 1,4-Dithiothreitol completely protected against and partially reversed the alloxan inhibition of hexokinase. The ability of various dithiols to reverse the inhibition of hexokinase by alloxan was dependent on the spacing between the SH (thiol) groups. Only dithiols with intermediate spacing between the SH groups were effective. Dithiols with two vicinal SH groups such as 1,2-dimercaptoethane and 2,3-dimercaptopropanol (BAL) and dithiols with more widely spaced SH groups such as 1,5-dimercaptopentane were ineffective. Thus a reaction of alloxan with two SH groups in the sugar binding site of the hexokinase with the formation of a disulfide bond may be involved in the reversible inhibition of the enzyme. Ninhydrin also inhibited hexokinase from all four tissues studied. The half maximal inhibitory concentrations of ninhydrin were lower than those of alloxan. Inhibition of hexokinase may be an important factor in the general cytotoxic action of ninhydrin. However, inhibition of pancreatic islet hexokinase is unlikely to be the initial event in the pancreatic B-cell toxic action of alloxan, even if inhibition of hexokinase by high concentrations of alloxan may contribute to the B-cell toxic action.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Alloxan and ninhydrin inhibition of hexokinase from pancreatic islets and tumoural insulin-secreting cells. 218 63

Alloxan is known to inhibit pancreatic B cell and liver glucokinase and glucose protects the enzyme against inhibition. The dithiol 1,4-dithiothreitol (1,4-DTT) protected against and reversed the inhibition of glucokinase by alloxan. An investigation into the structure-activity relationship using a variety of different dithiols demonstrated that the ability of the dithiols to protect against and to reverse the inhibition of glucokinase by alloxan was dependent on the spacing between the SH (thiol) groups of the various dithiols. Only 1,3-dimercaptopropane, 1,4-dimercaptobutane, 1,4-dithioerythritol, and 1,4-DTT, with intermediate spacing between the SH groups, reversed the inhibition of glucokinase induced by alloxan. Dithiols with two vicinal SH groups such as 1,2-dimercaptoethane and 2,3-dimercaptopropanol (BAL) were ineffective in the same way as dithiols with more widely spaced SH groups such as 1,5-dimercaptopentane and 1,6-dimercaptohexane. Except for 1,6-dimercaptohexane, all dithiols also protected glucokinase against the inhibition of alloxan. The monothiol cysteine, but not glutathione, a tripeptide monothiol, also protected glucokinase against alloxan inhibition but both were unable to reverse the inhibition. Like alloxan, other dithiol reagents such as ninhydrin, N-ethylmaleimide, and maleimide inhibited glucokinase. Glucose and 1,4-DTT protected glucokinase against this inhibition. 1,4-DTT partially reversed this inhibition. It is concluded, therefore, that the mechanism of inhibition of glucokinase by alloxan is a reaction of alloxan with two adjacent SH groups in the depth of the sugar-binding site of the glucokinase, with formation of a disulfide bond and concomitant inactivation of the enzyme. Because glucokinase can couple changes in the blood glucose concentration to changes in the glycolytic flux rate and corresponding changes in the rate of insulin secretion, it may function as a glucose signal recognition enzyme in the pancreatic B cell. This mechanism of interaction of alloxan with glucokinase may thereby provide an explanation for the ability of alloxan to inhibit glucose-induced insulin secretion.
 ...
PMID:Inhibition of glucokinase by alloxan through interaction with SH groups in the sugar-binding site of the enzyme. 341 26