A comprehensive review of the proline mimic azetidine-2-carboxylic acid (A2C)

The imino acid azetidine-2-carboxylic acid (A2C), a proline homologue, was first identified in liliaceous plants in 1955. Its ability to exchange for proline in protein synthesis is responsible for its teratogenic effects and has made it a very useful tool for generating non-native proteins to study proteotoxic stress and ER stress. The tRNA synthetases from some A2C-producing plants can discriminate between proline and A2C, but for most plants and for mammalian cells, A2C is mistakenly used in protein synthesis in place of proline and can avoid cell proof-reading mechanisms. Human exposure to A2C would be very limited had it not been for the development of sugar beets as an alternative source of dietary sucrose to sugar cane, and the widespread use of the plentiful byproducts as livestock fodder. Fodder beets, a very high yielding forage crop, are also used as livestock fodder particularly for lactating cows. It is therefore possible for A2C to enter the human food chain and impact human health. It was hypothesised that its ability to replace proline in protein synthesis generates immunogenic neo-epitopes in myelin basic protein and could therefore be a causative factor for multiple sclerosis. In this review we discuss the distribution of A2C in nature, what is known about its toxicity, and the impact of the proline to A2C exchange on protein structure and function and in particular the proteins collagen and myelin basic protein. We summarise analytical approaches that can be used to quantify A2C in complex biological samples and the adaptations made by some organisms to avoid its toxic effects. We summarise the evidence for human exposure to A2C and the geographical and temporal links to higher incidences of MS. Finally, we highlight gaps in our knowledge that require addressing before we can determine if this non-protein amino acid is a threat to human health.