Establishing the Photoenzyme CvFAP as Platform for New-to-Nature Radical Biotransformations

In its natural reaction, the fatty acid photodecarboxylase from Chlorella variabilis (CvFAP) catalyzes the light-driven, redox-neutral decarboxylation of fatty acids via carbon-centered radical intermediates. Here, we systematically repurpose this radical pathway to unlock new reactivities, establishing CvFAP as a versatile platform for photobiocatalytic radical transformations. We expand its photocatalytic reaction portfolio by four new reactions: (i) the intermolecular Giese-type coupling of fatty acids with cycloalkenones, (ii) the intramolecular decarboxylative radical cyclization via nucleophilic radicals and isolated C=C bonds of the same philicity, (iii) a cysteine-mediated (Z)→(E) photoisomerization of unsaturated fatty acids, and (iv) a radical carbohydroxylation reaction that demonstrates the enzyme’s capability of olefin bis-functionalization. Enzyme Engineering, using computational modelling as basis, enhanced cyclization efficiency, demonstrating the evolvability of CvFAP towards new reactivities. The study expands the enzymatic repertoire of radical chemistry and demonstrates how photobiocatalysis can channel reactive intermediates to selective, new-to-nature bond-forming transformations, and pave the way toward enzyme-controlled radical couplings using abundant carboxylic acid feedstocks.