title: Bioinformatics analyses provide insight into distant homology of the Keap1-Nrf2 pathway.
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.
authors.affiliation: Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Ranko
authors.initials: R
authors.lastname: Gacesa
authors.affiliation: Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, UK.
authors.forename: Walter C
authors.initials: WC
authors.lastname: Dunlap
authors.affiliation: 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.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Long
mesh_terms: D000818:Animals; D019295:Computational Biology; D030541:Databases, Genetic; D019143:Evolution, Molecular; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D051267:NF-E2-Related Factor 2 / Q000737:chemistry* / Q000378:metabolism*; D010802:Phylogeny; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology; D012984:Software
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D051267:NF-E2-Related Factor 2
keywords: Adaptation of microbiota; Distant Homology Search Pipeline; Mycosporine-like amino acids; Mycosporines; Protein modeling; Sordariomycetes; Taxonomy Landscape Mapper; Virtual screening