Abstract
Natural products are usually highly complicated organic molecules with special scaffolds, and they are an important resource in medicine. Natural products with complicated structures are produced by enzymes, and this is still a challenging research field, its mechanisms requiring detailed methods for elucidation. Flavin adenine dinucleotide (FAD)-dependent monooxygenases (FMOs) catalyze many oxidation reactions with chemo-, regio-, and stereo-selectivity, and they are involved in the synthesis of many natural products. In this review, we introduce the mechanisms for different FMOs, with the classical FAD (C4a)-hydroperoxide as the major oxidant. We also summarize the difference between FMOs and cytochrome P450 (CYP450) monooxygenases emphasizing the advantages of FMOs and their specificity for substrates. Finally, we present examples of FMO-catalyzed synthesis of natural products. Based on these explanations, this review will expand our knowledge of FMOs as powerful enzymes, as well as implementation of the FMOs as effective tools for biosynthesis.
Highlights
Today, natural products (NPs) play increasingly important roles, especially in early drug development [1,2]
Compared with flavin dependent oxidase, which uses O2 as electron acceptor, flavin monooxygenase usually uses nicotinamide adenine dinucleotide phosphate (NAD(P)H) as a hydrogen donor to catalyze the binding of oxygen atoms in molecular oxygen to small molecules by forming C4a-(hydrogen) peroxide, as an intermediate stage in producing natural products with chemo, regio- and enantio-selectivity
flavin monooxygenases (FMOs) consume molecular oxygen to catalyze the insertion of one oxygen atom to an organic substrate, and the other oxygen atom is reduced to water (Scheme 1)
Summary
Natural products (NPs) play increasingly important roles, especially in early drug development [1,2]. The chemical synthesis required to achieve this goal is difficult [3] To break this bottleneck, scientists have studied in depth the natural product synthesis pathways for terpenoids, non-ribosomal peptides, and polyketides [4]. There are many enzymes utilizing oxygen as a substrate and metal as a cofactor for synthesis One class of these enzymes depends on flavin but not metal. Compared with flavin dependent oxidase, which uses O2 as electron acceptor, flavin monooxygenase usually uses nicotinamide adenine dinucleotide phosphate (NAD(P)H) as a hydrogen donor to catalyze the binding of oxygen atoms in molecular oxygen to small molecules by forming C4a-(hydrogen) peroxide, as an intermediate stage in producing natural products with chemo-, regio- and enantio-selectivity. In 2017, Tang et al systematically reviewed different types of oxidative cyclization reactions in natural product biosynthesis, involving non-free radical cyclization catalyzed by FMOs and NAD(P)H-dependent reductases [12]. Our review focuses on the application of FMOs in natural product synthesis, their differences to CYP450 monooxygenases, and their advantages in natural product synthesis
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