A new branch of mammalian vitamin B 6 metabolism: AKR1C ‐mediated conversion of pyridoxal to pyridoxine and 4‐pyridoxolactone

Pyridoxal 5′‐phosphate (PLP), the coenzyme form of vitamin B 6 , 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 B 6 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 B 6 vitamer profiles. Moreover, we show that elevated PL levels suppress AKR1C activities toward non‐B 6 substrates, indicating reciprocal cross‐talk between vitamin B 6 metabolism and other AKR1C‐dependent metabolic processes. This study expands the current framework of mammalian vitamin B 6 metabolism, highlighting AKR1Cs as metabolic hubs with broad regulatory implications.