Nature employs a limited and conservative set of amino acids to synthesize proteins. The ability to genetically encode an extended set of building blocks can be used in diverse applications, including approaches to study and control protein function as well as to design novel therapeutics. Non-natural amino acids (NAA) are co-translationally incorporated into proteins by orthogonal pairs consisting of aminoacyl-tRNA synthetase and cognate tRNA. However, the current repertoire can neither display the full natural diversity of NAAs and is especially limited for backbone modifications. Excitingly, we now succeeded in reverse engineering a protein ligase into a new-to-nature tRNA synthetase (aaRS-β) that can load tRNA with β-amino acids (βaa). Additionally, we derived a variant aarRS-α accepting α-amino acids that cannot be integrated into the genetic code by any other means including adavanced glycation endproducts (AGEs). Our discovery lays the foundation for understanding the role of AGEs in the development and pathogenesis of major diseases such as diabetes and atherosclerosis as well as in the process of aging. At the same time the co-translational incorporation of βaa into the nascent chain will allow the cost-effective production of antimicrobial peptides with high protease stability and increased activity against multidrug-resistant pathogens.