[Psychosine: a "toxin" produced in the brain--its mechanism of action]

Psychosine (galactosylsphingosine) is enzymatically synthesized from UDP-galactose and sphingosine and degraded by galactosylceramidase. Galactosylceramidase is genetically deficient in Krabbe disease (globoid cell leukodystrophy) and psychosine accumulates in the brain of humans, dogs or mice affected by the disease. Psychosine has a very potent inhibitory effect on cytochrome c oxidase (COX) in mitochondria. When COX is purified, psychosine does not suppress the enzyme activity. However, a clear inhibitory effect is seen when the enzyme is "reconstituted" with sonicated phosphatidylcholine, suggesting that the inhibition of the enzymatic activity is caused by perturbation of the environment of COX in the mitochondrial membrane. Studies using analogues suggest that the free amino group in the sphingosine moiety plays an important role in exerting the effects of psychosine. The effects of psychosine are not only potent but fast and reversible. It is noteworthy that a powerful inhibitor of cellular respiration is synthesized in mammals' brain, an organ vulnerable to hypoxia.