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Functional Characterization of Genetic Enzyme Variations in Human Lipoxygenases

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Functional Characterization of Genetic Enzyme Variations in Human Lipoxygenases Redox Biology 1 (2013) 566–577 Contents lists available at ScienceDirect Redox Biology journal homepage: www.elsevier.com/locate/redox Functional characterization of genetic enzyme variations in human lipoxygenases Thomas Horn a,n, Kumar Reddy Kakularam b, Monika Anton a, Constanze Richter c, Pallu Reddanna b,d, Hartmut Kuhn a a Institute of Biochemistry, University Medicine Berlin—Charité, Charitéplatz 1, D-10117 Berlin, Germany b Department of Animal Sciences, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500046, Andhra Pradesh, India c Institute of Nutrition Technology and Nutrition Chemistry, TU Berlin, Gustav-Meyer-Allee 25, D-13355 Berlin, Germany d National Institute of Animal Biotechnology, Hyderabad 500046, Andhra Pradesh, India article info abstract Article history: Mammalian lipoxygenases play a role in normal cell development and differentiation but they have also been Received 28 October 2013 implicated in the pathogenesis of cardiovascular, hyperproliferative and neurodegenerative diseases. As lipid Accepted 1 November 2013 peroxidizing enzymes they are involved in the regulation of cellular redox homeostasis since they produce lipid hydroperoxides, which serve as an efficient source for free radicals. There are various epidemiological Keywords: correlation studies relating naturally occurring variationsinthesixhumanlipoxygenasegenes(SNPsorrare Eicosanoids mutations) to the frequency for various diseases in these individuals, but for most of the described variations no Leukotrienes functional data are available. Employing a combined bioinformatical and enzymological strategy, which Lipoxygenases included structural modeling and experimental site-directed mutagenesis, we systematically explored the Gene polymorphism structural and functional consequences of non-synonymous genetic variations in four different human SNP lipoxygenase genes (ALOX5, ALOX12, ALOX15, and ALOX15B) that have been identified in the human 1000 genome project. Due to a lack of a functional expression system we resigned to analyze the functionality of genetic variations in the hALOX12B and hALOXE3 gene. We found that most of the frequent non-synonymous coding SNPs are located at the enzyme surface and hardly alter the enzyme functionality. In contrast, genetic variations which affect functional important amino acid residues or lead to truncated enzyme variations (nonsense mutations) are usually rare with a global allele frequencyo0.1%. This data suggest that there appears to be an evolutionary pressure on the coding regions of the lipoxygenase genes preventing the accumulation of loss-of-function variations in the human population. & 2013 The Authors. Published by Elsevier B.V. Open access under CC BY-NC-ND license. Introduction cis,cis-1,4-pentadiene structure [1]. Together with various oxygen activating enzymes LOXs increase the cellular oxidizing potential by Lipoxygenases (LOXs) are lipid-peroxidizing enzymes that cata- biosynthesizing lipid hydroperoxides, which serve as an efficient lyze the dioxygenation of poly-unsaturated fatty acids containing a source for free radicals unless they are reduced by peroxide reducing enzymes to the corresponding alcohols [2,3]. LOXs are widely distributed in terrestrial life since they occur in bacteria, fungi, lower marine organisms, plants and higher animals [4,5]. In humans six functional LOX genes (ALOX5, ALOX12, ALOX15, ALOX15B, ALOX12B, and ALOXE3) have been identified [1]. The crystal structures of three Abbreviations: LOXs, lipoxygenases; ALOX, arachidonate lipoxygenase; 5-H(p)ETE, different mammalian LOX isoforms (human ALOX5, rabbit ALOX15, (6E,8Z,11Z,14Z)-5-hydroperoxyeicosa-6,8,11,14-tetraenoic acid; 15-H(p)ETE, porcine ALOX15) have been solved [6–8] and despite subtle struc- (5Z,8Z,11Z,13E)-15-hydroperoxyeicosa-5,8,11,13-tetraenoic acid; 12-H(p)ETE, tural differences there is a high degree of structural similarity (5Z,8Z,10E,14Z)-12-hydroperoxyeicosa-5,8,10,14-tetraenoic acid; 8-H(p)ETE, between different LOX isoforms. Human LOXs (hALOX) have been (5Z,9E,11Z,14Z)-8-hydroperoxyeicosa-5,9,11,14-tetraenoic acid; IPTG, Isopropyl-β-D- fl thiogalactopyranosid; HETE, hydroxyeicosatetraenoic acid; H(p)ETE, implicated in the pathogenesis of cardiovascular and in ammatory hydroperoxyeicosatetraenoic acid; LTA4, 4-[(2S,3S)-3-[(1E,3E,5Z,8Z)-tetradeca-1,3,5, diseases as well as in various forms of cancer but the detailed 8-tetraen-1-yl]oxiran-2-yl]butanoic acid; LTB4, 5(S),12(R)-dihydroxy-6,8,10,14-(Z,E,E,Z)- mechanistic basis for their pathophysiological roles is still a matter eicosatetraenoic acid; LTC4, (5S,6R,7E,9E,11Z,14Z)-6-{[(2R)-2-[(4S)-4-amino-4-carboxy- of discussion [9–12]. butanamido]-2-[(carboxymethyl) carbamoyl]ethyl]sulfanyl}-5-hydroxyeicosa-7,9,11, 14-tetraenoic acid; UTR, untranslated region In different epidemiological correlation studies genetic varia- n Corresponding author. Tel.: þ49 30 450 528 040; fax: þ49 30 450 528 905. tions in hALOX genes have been related to an increased risk of E-mail address: [email protected] (T. Horn). colorectal cancer [13,14], stroke [15], bronchial asthma [16] and 2213-2317 & 2013 The Authors. Published by Elsevier B.V. Open access under CC BY-NC-ND license. http://dx.doi.org/10.1016/j.redox.2013.11.001 T. Horn et al. / Redox Biology 1 (2013) 566–577 567 atherosclerosis [17]. Unfortunately, most of these variations occur Sigma Aldrich (Hamburg, Germany), HPLC standards of 5(7)- either in intronic, in the promoter or in other non-coding DNA HETE, 8(7)-HETE, 11(7)-HETE, 12(7)-HETE, 13(7)-HODE, regions and thus, functional characterization of these genetic varia- and 15(7)-HETE from Cayman Chem. (distributed by Biomol, tionsisdifficult. However, there are scattered reports, in which the Hamburg, Germany), sodium borohydride from Aldrich (Steinheim, functionality of some genetic variations has been studied: (i) A non- Germany), ampicillin from Life Technologies, Inc. (Eggenstein, synonymous SNP in the hALOX12 gene (rs28395860) has been Germany), kanamycin and isopropyl-β-thiogalactopyranoside (IPTG) identified, which leads to a non-conservative Gln261Arg exchange. from Carl Roth GmbH (Karlsruhe, Germany). HPLC solvents were This mutation has been correlated to the pathogenesis of osteoporo- ordered from Baker (Deventer, Netherlands) or VWR International sis, breast cancer and schizophrenia [18–20].Unfortunately, func- GmbH (Darmstadt, Germany). Restriction enzymes were purchased tional data on the recombinant enzyme indicated that this mutation from Fermentas (St. Leon-Rot, Germany). Oligonucleotide synthesis did hardly impact the in vitro enzyme function [21]. (ii) Heterozygous was performed at BioTez (Berlin, Germany) and DNA sequencing was allele carriers of the hALOX15 Thr560Met SNP (rs34210653) have a carried out at Eurofins MWG Operon (Ebersberg, Germany). The E. significant higher risk for coronary artery disease (CAD) [22]. In vitro coli strain XL-1 blue was purchased from Stratagene (La Jolla, CA), the mutagenesis studies indicated that this amino acid exchange leads to E. coli strain BL21(DE3)pLysS and the fluorescent dye SYPRO Oranges anearnullvariantoftheenzymeandthemolecularbasisfortheloss were purchased from Invitrogen (Carlsbad, California, USA). The in the enzyme activity has been explored in detail [23].Asimilar EnBase fed batch system was obtained from the company Biosilta naturally occurring near null variant (rs61099320) of this enzyme has (Oulu, Finland). recently been described but because of its low occurrence frequency no epidemiological correlation study has yet been carried out [24]. (iii) Inactive enzyme variations in hALOX12B and hALOXE3 have Methods been associated with a rare skin dysfunction called autosomal recessive congenital ichthyosis (ARCI) [25]. (iv) In a recent report Recombinant expression and purification of hALOX15, hALOX5, the non-synonymous SNP rs2228065, which leads to a Glu254Lys hALOX12 and hALOX15B exchange in hALOX5, was significantly associated with a higher risk of bronchial asthma [26], whereas it was not associated with an In order to express hALOX15 as a His-tag fusion protein, the increased risk of breast cancer [27]. Unfortunately, no functional data coding region of the corresponding cDNA was first amplified by arecurrentlyavailableforthis particular enzyme variant. RT-PCR from human blood and then cloned into the pET28b Completion of the human 1000 Genome project provided an expression vector between the SalI (N-terminus) and HindIII integrated map of genetic variations in 1092 individuals from all (C-terminus) restriction sites. For the wild-type enzyme and for over the world [28] and the corresponding database (www.1000ge- each mutant a 0.5 l fed batch liquid culture (EnBase, Biosilta) of E. nomes.org) also includes a large number of genetic variations in coli BL12(DE3)pLysS was grown overnight at 30 1C until an OD600 enzymes and receptors of the arachidonic acid cascade. Although of about 15 was reached. Expression of the recombinant protein this database does not sufficiently cover the genetic diversity in all was then induced by addition of 1 mM IPTG (final concentration) parts of the world, particularly in Southeast Asia [29],itservesasa and the culture was kept for 24 h at 23 1C until a final OD600 of suitable source for detailed studies on the functionality of naturally 25–30. Bacteria were centrifuged (3,600g,41C, 10 min) and resus- occurring genetic variants of enzymes, hormones, receptors, and pended in 45 ml phosphate buffered saline (PBS). Cells were lysed structural
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