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The lipoxygenase pathway of Tupaia belangeri representing Scandentia. Genomic multiplicity and functional characterization of the ALOX15 orthologs in the tree shrew
Ist Teil von
Biochimica et biophysica acta. Molecular and cell biology of lipids, 2020-02, Vol.1865 (2), p.158550-158550, Article 158550
Ort / Verlag
Netherlands: Elsevier B.V
Erscheinungsjahr
2020
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
The tree shrew (Tupaia belangeri) is a rat-sized mammal, which is more closely related to humans than mice and rats. However, the use of tree shrew to explore the patho-mechanisms of human inflammatory disorders has been limited since nothing is known about eicosanoid metabolism in this mammalian species. Eicosanoids are important lipid mediators exhibiting pro- and anti-inflammatory activities, which are biosynthesized via lipoxygenase and cyclooxygenase pathways. When we searched the tree shrew genome for the presence of cyclooxygenase and lipoxygenase isoforms we found copies of functional COX1, COX2 and LOX genes. Interestingly, we identified four copies of ALOX15 genes, which encode for four structurally distinct ALOX15 orthologs (tupALOX15a-d). To explore the catalytic properties of these enzymes we expressed tupALOX15a and tupALOX15c as catalytically active proteins and characterized their enzymatic properties. As predicted by the Evolutionary Hypothesis of ALOX15 specificity we found that the two enzymes converted arachidonic acid predominantly to 12S-HETE and they also exhibited membrane oxygenase activities. However, their reaction kinetic properties (KM for arachidonic acid and oxygen, T- and pH-dependence) and their substrate specificities were remarkably different. In contrast to mice and humans, tree shrew ALOX15 isoforms are highly expressed in the brain suggesting a role of these enzymes in cerebral function. The genomic multiplicity and the tissue expression patterns of tree shrew ALOX15 isoforms need to be considered when the results of in vivo inflammation studies obtained in this animal are translated into the human situation.
•Tupaia belangeri has four ALOX15 genes (tupALOX15a, tupALOX15b, tupALOX15c, tupALOX15d) encoding distinct ALOX15 isoenzymes.•TupAlox15a and tupALOX15c were expressed as functional N-terminal his-tag fusion proteins and were functionally characterized.•Tupaia ALOX15 isoforms follow the Evolutionary Hypothesis of ALOX15 Specificity and the Triad Concept of ALOX15 orthologs of different mammals.•TupALOX15a is high level expressed in the brain but in spleen and lungs tupALOX15c is the dominanting ALOX15 isoform.