Melanins are complex biomolecules that provide organisms with resistance to radiation (gamma and UV), oxidation, metal toxicity, and desiccation. These properties make melanin a promising natural solution for human health applications, including skin and radiation-induced cancers, inflammation-related diseases, and environmental bioremediation. However, large-scale melanin production remains a challenge, as current sources, such as squid ink from Sepia officinalis, are costly (~$300/gram) and unsustainable. We propose using the polyextremotolerant fungus Exophialaviscosa(that we isolated and genome-sequenced)for microbial melanin production(Carr et al.,Genetics, 2023). E. viscosapossesses unique advantages: 1) it harbors all three fungal melanin biosynthetic pathways, 2) its melanin biosynthesis genes are not clustered, and 3) it naturally secretes 17 g/L of melanin when grown with organic nitrogen. We developed a genome-scale metabolic (GSM) model of E.viscosato elucidate the underlying mechanism involved in melanin production and secretion and hypothesized that melanin is essential for its survival, functioning more as a primary metabolite than a secondary metabolite. Using flux analysis andin vivo experiments, we found that E. viscosapredominantly produces DHN melanin, which is more energy-efficient than tyrosine-derived melanins. Additionally, E. viscosaoperates in an ATP maintenance state due to an incomplete TCA cycle, producing minimal ATP. Our findings suggest melanin plays a crucial role in maintaining fatty acid homeostasis and metabolic balance. Furthermore, the pks1 gene appears to regulate secondary metabolism beyond its role in melanin production. This study provides key insights into E. viscosa's melanin biosynthesis, revealing factors that enhance melanin secretion and highlighting its potential regulatory role. Future research will further investigate pks1's function to optimize E. viscosa as a genetic tool for sustainable melanin bioproduction.
