Lipoxygenase pathways in Homo neanderthalensis: functional comparison with Homo sapiens isoforms

Pavlos Chaitidis,Susan Adel,Monika Anton,Dagmar Heydeck,Hartmut Kuhn,Thomas Horn

doi:10.1194/jlr.m035626

Abstract

Lipoxygenases (LOX) have been implicated in biosynthesis of pro- and anti-inflammatory mediators, and a previous report suggested compromised leukotriene signaling in H. neanderthalensis. To search for corresponding differences in leukotriene biosynthesis, we screened the Neandertal genome for LOX genes and found that, as modern humans, this archaic hominid contains six LOX genes (nALOX15, nALOX12, nALOX5, nALOX15B, nALOX12B, and nALOXE3) and one pseudogene. In the Neandertal genome, 60-75% of the amino acids of the different human LOX isoforms have been identified, and the degree of identity varies between 96 and 99%. Most functional amino acids (iron ligands, specificity determinants, calcium and ATP-binding sites, membrane-binding determinants, and phosphorylation sites) are well conserved in the Neandertal LOX isoforms, and expression of selected neandertalized human LOX mutants revealed no major functional defects. However, in nALOX12 and nALOXE3, two premature stop codons were found, leading to inactive enzyme species. These data suggest that ALOX15, ALOX5, ALOX15B, and ALOX12B should have been present as functional enzymes in H. neanderthalensis and that in contrast to lower nonhuman primates (M. mulatta) and other mammals (mice, rats), this ancient hominid expressed a 15-lipoxygenating ALOX15. Expression of ALOXE3 and ALOX12 was compromised, which might have caused problems in epidermal differentiation.

Highlights

Lipoxygenases (LOX) have been implicated in biosynthesis of pro- and anti-inflammatory mediators, and a previous report suggested compromised leukotriene signaling in H. neanderthalensis
For those amino acids, which were specified in both genomes, the degree of sequence identity varied between 96% and 99% for the different ALOX isoforms (Table 1), but even for the most similar enzyme, we found a number of amino acid exchanges that might have impacted the functionality of the enzymes
For each LOX isoform, these amino acid differences were categorized according to their degree of reliability in three different groups (Table 1): i) Confirmed differences (+++, blue background in the figures; these amino acid differences were found in two of the three sequenced individual Neandertal fossil specimens); ii) unconfirmed differences (++, green background in the figures; these differences were observed in only one fossil specimen; for the other fossil specimens, there were no sequence data for the corresponding genomic region); and iii) uncertain differences (+, yellow background in the figures; these differences were observed in only one fossil specimen; the difference was localized at the beginning or at the end of a sequence fragment; the likelihood of a sequencing artifact appears to be higher)

Summary

Introduction

Lipoxygenases (LOX) have been implicated in biosynthesis of pro- and anti-inflammatory mediators, and a previous report suggested compromised leukotriene signaling in H. neanderthalensis. Lipoxygenases (LOX) constitute a heterogeneous family of lipid-peroxidizing enzymes that catalyze dioxygenation of free and/or esterified polyunsaturated fatty acids to their corresponding hydroperoxy derivatives [1,2,3]. In mammals they have been implicated in cell development and maturation, but they play a role in inflammatory and hyperproliferative diseases [1]. The recently published draft sequence of the nuclear genome suggests that Neandertals are likely to have had a role in the genetic ancestry of today’s humans outside of Africa [19]. No direct functional studies have been carried out, the sequence data suggest that Neandertals might have suffered from compromised leukotriene signaling [19]

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Results

Conclusion