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Cytochrome P450 enzymes (P450s) are exceptional oxygenating catalysts [1] with enormous potential in drug discovery, chemical synthesis, bioremediation, and biotechnology.[2, 3] Compared to their natural counterparts, however, engineered P450s often exhibit poor catalytic and cofactor coupling efficiencies.[3] Obtaining native-like catalytic proficiencies is a mandatory first step towards utilizing the power of these versatile oxygenases in chemical synthesis. Cytochrome P450BM3 (119 kDa, B. megaterium) catalyzes the subterminal hydroxylation of long-chain (C12–C20) fatty acids.[4] Its high activity and catalytic self-sufficiency (heme and diflavin reductase domains are fused in a single polypeptide chain)[2, 4, 5] make P450BM3 an excellent platform for biocatalysis. However, despite numerous reports of the heme domain being engineered to accept nonnative substrates, including short-chain fatty acids …