Tailoring enzyme strategies and functional groups in biosynthetic pathways.

Covering: 2000 to 2022Secondary metabolites are assembled by drawing off and committing some of the flux of primary metabolic building blocks to sets of enzymes that tailor the maturing scaffold to increase architectural and framework complexity, often balancing hydrophilic and hydrophobic surfaces. In this review we examine the small number of chemical strategies that tailoring enzymes employ in maturation of scaffolds. These strategies depend both on the organic functional groups present at each metabolic stage and one of two tailoring enzyme strategies. Nonoxidative tailoring enzymes typically transfer electrophilic fragments, acyl, alkyl and glycosyl groups, from a small set of thermodynamically activated but kinetically stable core metabolites. Oxidative tailoring enzymes can be oxygen-independent or oxygen-dependent. The oxygen independent oxidoreductases are often reversible nicotinamide-utilizing redox catalysts, flipping the nucleophilicity and electrophilicity of functional groups in pathway intermediates. O-dependent oxygenases, both mono- and dioxygenases, act by orthogonal, one electron strategies, generating carbon radical species. At sp substrate carbons, product alcohols may then behave as nucleophiles for subsequent waves of enzymatic tailoring. At sp carbons in olefins, electrophilic epoxides have opposite reactivity and often function as "disappearing groups", opened by intramolecular nucleophiles during metabolite maturation. "Thwarted" oxygenases generate radical intermediates that rearrange internally and are not captured oxygenatively.