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      Bioinformatics analyses provide insight into distant homology of the Keap1–Nrf2 pathway

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      Free Radical Biology and Medicine

      Elsevier BV

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          Abstract

          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.

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          Author and article information

          Journal
          Free Radical Biology and Medicine
          Free Radical Biology and Medicine
          Elsevier BV
          08915849
          November 2015
          November 2015
          : 88
          : 373-380
          Article
          10.1016/j.freeradbiomed.2015.06.015
          26117326
          © 2015

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