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

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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 Radic. Biol. Med.
          Free radical biology & medicine
          Elsevier BV
          1873-4596
          0891-5849
          Nov 2015
          : 88
          : Pt B
          Affiliations
          [1 ] Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, UK.
          [2 ] Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, UK; Department of Chemistry, King's College London, 150 Stamford Street, London SE1 9NH, UK. Electronic address: paul.long@kcl.ac.uk.
          Article
          S0891-5849(15)00283-X
          10.1016/j.freeradbiomed.2015.06.015
          26117326

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