Fungal Dihydroxynaphthalene-Melanin: Diversity-Oriented Biosynthesis through Enzymatic and Non-enzymatic Transformations

Abstract

Tetrahydroxynaphthalene reductase (T4HNR) from Magnaporthe grisea catalyzes the reduction of polyhydroxynaphthalenes, hydroxynaphthoquinones, and 1,4-diketones, with extensive ramifications for the biosynthesis of (shunt) metabolites related to 1,8-dihydroxynaphthalene (DHN)-melanin biosynthesis. Hence, an extended model for DHN-melanin biosynthesis has been developed which is based on a screening hypothesis involving non-enzymatic transformations such as oxidations and tautomerism. This has led to the broadening of the functions of several short-chain dehydrogenases/reductases (SDRs) capable of reducing polyhydroxyanthracenes, polyhydroxynaphthalenes, and polyhydroxybenzenes. Our work, broadening the scope of enzymatic dearomatization reactions, provides access to the biocatalytic synthesis of a variety of natural and natural-like products. Furthermore, the results described in this account provide the basis for the identification of other SDRs amenable to reducing aromatic compounds, and thus enable the identification of biosynthetic gene clusters most likely involved in the biosynthesis of aromatic polyketides.1 Introduction2 Biosynthesis of 1,8-Dihydroxynaphthalene (DHN)3 Biosynthesis of Shunt Metabolites and the Origin of Molecular Diversity3.1 Role of Spontaneous Non-enzymatic Oxidations3.2 Role of T4HNR and T3HNR3.3 Role of Tautomerism in the Biosynthesis of (Shunt) Metabolites4 Extended Melanin Biosynthesis: A Screening Hypothesis5 Useful Outcomes of the Newly Identified Melanin Biosynthetic Pathway5.1 NADP+ Regeneration Using Lawsone as Mediator5.2 Anthrahydroquinone as an Intermediate in the Biosynthesis of Chrysophanol and Other Anthraquinone-Derived Products5.3 Combination of T3HNR and GDH To Access trans-Ketodiols5.4 Phloroglucinol Reductases (PGRs) To Dearomatize Monomeric Phenols6 Conclusion