Transketolase variant enzymes and brain damage.

Human red blood cell transketolase has been resolved into two components by gel filtration. One component has its thiamine diphosphate coenzyme firmly bound whilst the other variant of the enzyme is a smaller molecule which is inactive without added thiamine diphosphate, for which it has a reduced affinity. It is concluded that the failure to detect an increase in activation in the commonly used clinical test of red cell transketolase activation by raising the thiamine diphosphate concentration above about 0.3 mmol/l is likely to be due to masking of the effect of activation of the low affinity variant in haemolysates from normal red blood cells by the inhibitory effect of excess thiamine diphosphate upon the activity of the high affinity form of the enzyme with which it is mixed. Increased activation by higher thiamine diphosphate concentrations is sometimes seen in haemolysates from the blood of chronic alcoholics, as well as in the low molecular weight fraction separated from normal haemolysates. It is considered likely that there are at least two variants of the enzyme and that the low molecular weight variant represents a damaged form of the enzyme normally present in small amounts but formed in larger proportions in vivo in abnormal conditions like chronic alcoholism and thiamine deficiency as well as by enzyme breakdown in vitro. In the light of these conclusions some recently proposed hypotheses regarding the role of transketolase in the genesis of brain damage in thiamine deficiency are reconsidered and a modified mechanism is proposed consistent with these and other recent findings.