Evolutionary aspects of lipoxygenases and genetic diversity of human leukotriene signaling

Abstract

Leukotrienes are pro-inflammatory lipid mediators, which are biosynthesized via the lipoxygenase pathway of the arachidonic acid cascade. Lipoxygenases form a family of lipid peroxidizing enzymes and human lipoxygenase isoforms have been implicated in the pathogenesis of inflammatory, hyperproliferative (cancer) and neurodegenerative diseases. Lipoxygenases are not restricted to humans but also occur in a large number of pro- and eucaryotic organisms. Lipoxygenase-like sequences have been identified in the three domains of life (bacteria, archaea, eucarya) but because of lacking functional data the occurrence of catalytically active lipoxygenases in archaea still remains an open question. Although the physiological and/or pathophysiological functions of various lipoxygenase isoforms have been studied throughout the last three decades there is no unifying concept for the biological importance of these enzymes. In this review we are summarizing the current knowledge on the distribution of lipoxygenases in living single and multicellular organisms with particular emphasis to higher vertebrates and will also focus on the genetic diversity of enzymes and receptors involved in human leukotriene signaling.

Evolutionary alteration of ALOX15 specificity optimizes the biosynthesis of antiinflammatory and proresolving lipoxins

“…The evolutionary concept of alox15 specificity (3) suggests that mammals ranked low in evolution (mice, rats, pigs, cattle), including lower primates (rhesus monkeys), express 12-lipoxygenating ALOX15 orthologs. In contrast, higher primates (recent and extinct humans, orangutans) express 15-lipoxygenating isoforms (3).…”

“…In contrast, higher primates (recent and extinct humans, orangutans) express 15-lipoxygenating isoforms (3). To test this concept, to characterize its mechanistic basis, and to explore the possible biological relevance of the evolutionary specificity alterations we used a research strategy involving multiple sequence alignments, cloning, and functional characterization of ALOX15 orthologs and in silico molecular dynamics (MD) simulations.…”

“…A systematic search of the currently available mammalian ALOX15 sequences (Fig. 1) suggested that lower mammals have small amino acids at either of the triad positions and thus, should function as 12-lipoxygenating enzymes (3,22,34). In contrast, highly developed mammals (H. sapiens, H. neanderthalensis, H. denisovan, P. pygmaeus) express 15-lipoxygenating enzymes as the triad positions are occupied by more space-filling amino acid residues.…”

“…Genomic LOX sequences occur in two domains (Bacteria, Eukarya) of terrestrial life (3). In mammals, LOXs have been implicated in the biosynthesis of lipid mediators (4,5), but they may also play a role in cell differentiation (6,7), apoptosis (8) and pathogenesis of inflammatory (9), hyperproliferative (10), and neurological (11) disorders.…”

Manganese lipoxygenase of F. oxysporum and the structural basis for biosynthesis of distinct 11-hydroperoxy stereoisomers

“…The proposed open reading frames of the MnLOXs from F. oxysporum 2 and C. gloeosporioides 3 were based on one intron (64 nt and 59 nt, respectively), predicted between the codons of Ile The open reading frames of Fo-and Cg-MnLOXs without their native secretion signals were ordered from GenScript in the Pichia pastoris expression vector, pPICZ ␣ A, cloned in frame with the ␣ -factor secretion signal of yeast. The expression vectors were amplifi ed in E. coli (NEB5 ␣ ), purifi ed by Nucleobond AX (Xtra Midi kit), and linearized with Pme I and Sac I, respectively.…”