A new branch of mammalian vitamin B₆ metabolism: AKR1C-mediated conversion of pyridoxal to pyridoxine and 4-pyridoxolactone.

Pyridoxal 5'-phosphate (PLP), the coenzyme form of vitamin B₆, is indispensable for diverse metabolic processes, especially amino acid metabolism. In mammals, PLP is primarily synthesized via a salvage pathway involving pyridoxal kinase (PLK), pyridoxine/pyridoxamine 5'-phosphate oxidase (PNPO), and pyridoxal phosphate phosphatase (PLPP). However, recent evidence suggests the presence of additional, yet unidentified, enzymatic contributors to this pathway. Here, we identify aldo-keto reductase family 1 member C (AKR1C) isozymes as previously unrecognized enzymes involved in vitamin B₆ metabolism. We demonstrate that AKR1Cs catalyze two novel reactions: an NADPH-dependent pyridoxal reductase (PLR) activity that converts pyridoxal (PL) to pyridoxine (PN), and an NADP⁺-dependent pyridoxal dehydrogenase (PLD) activity that oxidizes PL to 4-pyridoxolactone (4-PLA). Both reactions occur under physiological conditions and significantly impact intracellular vitamin B₆ vitamer profiles. Moreover, we show that elevated PL levels suppress AKR1C activities toward non-B₆ substrates, indicating reciprocal cross-talk between vitamin B₆ metabolism and other AKR1C-dependent metabolic processes. This study expands the current framework of mammalian vitamin B₆ metabolism, highlighting AKR1Cs as metabolic hubs with broad regulatory implications.