In this study, we leverage lysine as a smart donor in transaminase-catalyzed DKR reactions to effect the synthesis of β-branched noncanonical amino acids (ncAAs, Scheme 1C), privileged building blocks that can imbue proteolytic stability and enhance binding interactions of bioactive peptides with a biological target. Although lysine is the native substrate of several wild-type enzymes, it has not, to our knowledge, been recognized nor leveraged as a smart donor in synthetic biocatalysis. Our mechanistic investigation suggests that spontaneous cyclization of the 6-amino-2-oxohexanoic acid byproduct to the corresponding imine 1 drives the equilibrium, enabling significantly reduced amine donor stoichiometry and thus a straightforward isolation procedure at scale. We accessed a suite of β-branched ncAAs in high yield, overcoming substrate limitations previously encountered, with diastereo-and enantioselectivities that exceed the traditional chemical methods. Furthermore, we show that lysine exhibits promising transaminase compatibility, rendering this inexpensive, readily available proteinogenic amino acid an exceedingly practical smart donor.