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Ancient mammals possess active eicosanoid metabolism, expressing functional ALOX15B but lacking ALOX15 genes. This suggests ALOX15 evolved from ALOX15B after the Prototheria-Metatheria split.

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Area of Science:

  • Biochemistry
  • Evolutionary Biology
  • Genomics

Background:

  • Eicosanoids are crucial lipid mediators in cell function and disease pathogenesis.
  • Mammalian eicosanoid biosynthesis is well-studied in advanced species, but poorly understood in ancient mammals (Prototheria).

Purpose of the Study:

  • To investigate the presence and function of lipoxygenase (ALOX) and prostaglandin synthase (PTGS) genes in Prototheria.
  • To characterize the evolutionary origins of ALOX15 and ALOX15B genes in mammals.

Main Methods:

  • Genomic analysis of platypus and echidna for ALOX and PTGS genes.
  • Expression and functional characterization of prototherian ALOX15B isoforms.
  • Enzyme activity comparison with human and mouse orthologs using mutagenesis.

Main Results:

  • Prototherian genomes contain intact ALOX5, ALOX12, ALOX12B, ALOXE3, PTGS1, and PTGS2 genes.
  • Two ALOX15B genes were identified, with one corrupted in echidnas; ALOX15 genes were absent.
  • Prototherian ALOX15B isoforms showed conserved reaction specificity, with Jisaka determinant modification altering catalytic properties.

Conclusions:

  • Prototheria exhibit active eicosanoid metabolism with functional ALOX15B orthologs but lack ALOX15 genes.
  • ALOX15 likely arose from ALOX15B gene duplication during the Prototheria-Metatheria transition.
  • This study sheds light on early mammalian lipid mediator evolution.