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An essential requirement for the evolution of early eukaryotic life was the development
of effective means to protect against metabolic oxidative stress and exposure to environmental
toxicants. In present-day mammals, the master transcription factor Nrf2 regulates
basal level homeostasis and inducible expression of numerous detoxifying and antioxidant
genes. To examine early evolution of the Keap1-Nrf2 pathway, we present bioinformatics
analyses of distant homology of mammalian Keap1 and Nrf2 proteins across the Kingdoms
of Life. Software written for this analysis is made freely available on-line. Furthermore,
utilizing protein modeling and virtual screening methods, we demonstrate potential
for Nrf2 activation by competitive inhibition of its binding to Keap1, specifically
by UV-protective fungal mycosporines and marine mycosporine-like amino acids (MAAs).
We contend that coevolution of Nrf2-activating secondary metabolites by fungi and
other extant microbiota may provide prospective compound leads for the design of new
therapeutics to target activation of the human Keap1-Nrf2 pathway for treating degenerative
diseases of ageing.