384 2. ANALOGS OF ENZYME KEACTION COMPONENTS 



OH H OH 



an) (IV) 



There is some evidence that the enolic tautomer II is not important and the 

 behavior with enzymes might favor structure I. Hynd (1927) at St. Andrews 

 tested D-glucosone to determine if it could counteract insulin hypoglycemic 

 convulsions, as glucose does, but found that, if anything, the effect of 

 insulin is increased. Glucosone was then administered to normal mice giving 

 toxic symptoms within 5 min and a well-developed insulin-like reaction in 

 20 min. The lethal dose range is very narrow, 2.4 mg/kg being nonlethal and 

 2.6 mg/kg generally lethal. Glucose injected before or with the glucosone 

 reduces the effects somewhat. Moribund mice following lethal doses show 

 an elevation in blood glucose from 0.161 to around 0.240 mg%; thus the 

 symptoms are not due to a hypoglycemia. Although these results would 

 point to glucosone interference with the utilization of glucose, Hynd un- 

 fortunately assumed that glucosone is formed from glucose by the action 

 of insulin and that, indeed, it is responsible for the effects of insulin, the 

 raised blood glucose levels being unexplained. Similar reactions to glucosone 

 are seen in several species (Herring and Hynd, 1928). The theory that insulin 

 induces glucosone formation was made untenable by Dixon and Harrison 

 (1932), who found no glucosone in the blood during insulin convulsions. 



The problem rested at this stage for 20 years and then was taken up at St. 

 Andrews (Bayne, 1952; Mitchell and Bayne, 1952; Johnstone and Mitchell, 

 1953), but the results were published in a series of short and incomplete 

 communications without adequate data. D-Glucosone effects in mice were 

 not seen with up to 10 mg/kg of any other osone, including D-galactosone, 

 D-arabinosone, D-xylosone, L-glucosone, and 3-methyl-D-glucosone. Turning 

 to yeast glucose fermentation, they found no inhibition by 50 mM D-gluco- 

 sone but marked inhibition at 200 mM, whereas L-glucosone has no effect 

 at 200 mM. Becker (1954) reported almost complete inhibition of the aero- 

 bic and anaerobic utilization of glucose by yeast when (glucosone)/(glu- 

 cose) = 5. 



It was realized finally by Eeg-Larsen and Laland (1954) in Oslo that the 

 structural similarity of glucosone to glucose might allow the former to 

 interfere with the utilization of the latter by blocking its phosphorylation. 

 This was demonstrated with ox brain hexokinase; glucosone is not phospho- 

 rylated but inhibits glucose phosphorylation 50% at 0.35 mM and 100% 

 at 2.4 mM when glucose is 2.4 mM. They concluded that the inhibition is 

 noncompetitive, but the small range of glucose concentrations used makes 



