title: Leukotriene signaling in the extinct human subspecies Homo denisovan and Homo neanderthalensis. Structural and functional comparison with Homo sapiens.
abstract: Mammalian lipoxygenases (LOXs) have been implicated in cell differentiation and in the biosynthesis of pro- and anti-inflammatory lipid mediators. The initial draft sequence of the Homo neanderthalensis genome (coverage of 1.3-fold) suggested defective leukotriene signaling in this archaic human subspecies since expression of essential proteins appeared to be corrupted. Meanwhile high quality genomic sequence data became available for two extinct human subspecies (H. neanderthalensis, Homo denisovan) and completion of the human 1000 genome project provided a comprehensive database characterizing the genetic variability of the human genome. For this study we extracted the nucleotide sequences of selected eicosanoid relevant genes (ALOX5, ALOX15, ALOX12, ALOX15B, ALOX12B, ALOXE3, COX1, COX2, LTA4H, LTC4S, ALOX5AP, CYSLTR1, CYSLTR2, BLTR1, BLTR2) from the corresponding databases. Comparison of the deduced amino acid sequences in connection with site-directed mutagenesis studies and structural modeling suggested that the major enzymes and receptors of leukotriene signaling as well as the two cyclooxygenase isoforms were fully functional in these two extinct human subspecies.
authors.affiliation: Institute of Biochemistry, Charite - University Medicine Berlin, Chariteplatz 1, 10117 Berlin, Germany.
authors.forename: Susan
authors.initials: S
authors.lastname: Adel
authors.affiliation: Department of Animal Biology, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500046, Andhra Pradesh, India.
authors.forename: Kumar Reddy
authors.initials: KR
authors.lastname: Kakularam
authors.affiliation: Institute of Biochemistry, Charite - University Medicine Berlin, Chariteplatz 1, 10117 Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Horn
authors.affiliation: Department of Animal Biology, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500046, Andhra Pradesh, India; National Institute of Animal Biotechnology, Hyderabad 500046, Andhra Pradesh, India.
authors.forename: Pallu
authors.initials: P
authors.lastname: Reddanna
authors.affiliation: Institute of Biochemistry, Charite - University Medicine Berlin, Chariteplatz 1, 10117 Berlin, Germany. Electronic address: hartmut.kuehn@charite.de.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kuhn
authors.affiliation: Institute of Biochemistry, Charite - University Medicine Berlin, Chariteplatz 1, 10117 Berlin, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Heydeck
mesh_terms: D000818:Animals; D030541:Databases, Genetic; D015894:Genome, Human / Q000502:physiology*; D006801:Humans; D015289:Leukotrienes / Q000235:genetics* / Q000378:metabolism; D058945:Lipoxygenases / Q000235:genetics* / Q000378:metabolism; D059125:Neanderthals / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013045:Species Specificity
chemical_list: D015289:Leukotrienes; D058945:Lipoxygenases
keywords: Eicosanoids; Evolution; H. denisovan; H. neanderthalensis; Leukotrienes; Prostaglandins