Isolation and identification from common vetch of the neurotoxin beta-cyano-L-alanine, a possible factor in neurolathyrism.

Neurological effects have for centuries been observed to accompany in many instances the consumption of excessive amounts of lathyrus meal as food, particularly in parts of India and in the Mediterranean area in times of food scarcity. This condition, which is known as spontaneous clinical neurolathyrism, occurs chiefly in the male and is characterized principally by reflex irritability, weakness, spasticity, and rigidity of the leg muscles, followed sometimes by death (1). The etiology of lathyrism is unknown. However, the condition has been variously ascribed to a nutritional deficiency and to the presence of a neurotoxin in the lathyrus plant. Many studies in experimental lathyrism were made possible by the isolation of a lathyrus factor from Lathyrus pusillus (singletary pea) (2) and Lathyrus odor&s (sweet pea) (3%5), the identification of this factor as p-N-(7-~glutamyl).aminopropionitrile, and the recognition of p-aminopropionitrile as the active principle of the factor.’ However, the experimental condition produced with either the odoratus factor or with a number of synthetic compounds related to P-aminopropionitrile has resulted chiefly in abnormalities of bone and mesenchymal tissue in contradistinction to human lathyrism which is neurologic in character.1 Recently, in an investigation of a new reaction encountered in peptide synthesis, which involves conversion of asparagine to a, y-diaminobutyric acid (9), the amino acid nitrile, P-cyano-Lalanine, was synthesized (10). The latter was shown to be a likely intermediate in the conversion, arising through dehydration of the amide group of asparagine, and forming (Y ,y-diaminobutyric acid through reduction of its cyano group (10). Structurally, P-cyano-L-alanine also represents the parent amino acid which by biological decarboxylation could form the lathyrogen &aminopropionitrile. In view of the latter relationship and the prevalence and importance of biological decarboxylation reactions, p-cyano-L-alanine was tested for possible neurological activity. Fed at the 1 y0 level, this amino acid nitrile is neurotoxic to the rat, and within 3 to 5 days it results in hyperirritability, tremors, convulsions, and death (11). The D isomer at approximately 3 times the dose is also neurotoxic.2 In contrast,