Oxidoreductase-mediated biotransformation often requires the consumption of a secondary sacrificial co-substrate and an additional auxiliary enzyme to drive cofactor regeneration, which leads to the generation of undesirable by-products. Here we report on a highly atomic, self-sufficient hydride shuttle cascade to simultaneously obtain two pharmaceutically important building blocks (7,12-dioxo-lithocholic acid and L-tert-leucine) in which the oxidation of cholic acid (CA) and Die reductive amination of trimethylpyruvic acid has been integrated for redox self-recycling. In this cascade, the cofactor acts as a hydride shuttle that connects the two synthetically relevant reactions at the expense of only inorganic ammonium as a sacrificial agent and creates water as the greenest by-product. The preparative biotransformation using a whole-cell biocatalyst in the absence of an exogenous cofactor showed a space-time yield of 768 g L.−1 d−1 and a Total Sales Number (TTN) of 20,363 for NAD+ Recycling. This is the highest reported cofactor TTN for the bio-oxidation of CA, which indicates the great potential of this self-sufficient cofactor and redox bioprocess for cost-effective and sustainable bioproduction of products with high added value.