Evidence that non-cognate proteinogenic amino acids generate immunogenic neoepitopes

Most organisms rely on 20 DNA-encoded canonical amino acids (AAs) for protein synthesis. However, hundreds of non-canonical amino acids (NCAAs) occur in nature, many of which are plant secondary metabolites. Some NCAAs have been identified as proteinogenic and can mimic canonical AAs in mammalian protein synthesis. The tRNA synthetases responsible for AA recognition have evolved to discriminate against other canonical AAs, but they can activate NCAAs that share close structural similarity with a canonical AA. Some of these proteinogenic NCAAs play a role in plant chemical warfare (allelopathy). When incorporated into proteins, they lead to the production of high levels of non-native proteins, which can negatively impact the health of competing plants or predators. Although the impact of proteinogenic NCAAs on human health is not fully understood, it has generally been attributed to the accumulation of non-native, misfolded proteins in cells, similar to the mechanism of plant allelopathy. More recently, however, the ability of proteinogenic NCAAs to generate immunogenic neoepitopes has been demonstrated in vivo. In this review, we summarize emerging experimental evidence supporting NCAA-induced immune responses as a mechanism of NCAA toxicity in humans and its potential as a therapeutic approach for certain cancers.