Origin and diversification of the L-amino oxidase family in innate immune defenses of animals.

L-amino acid oxidases (LAOs), because they produce hydrogen peroxide as a by-product, function in innate immune defenses of both vertebrates and mollusks. Phylogenetic analysis revealed two major subfamilies of LAOs: (1) a subfamily including LAOs from vertebrates and mainly from Terrabacteria and (2) a subfamily including LAOs from mollusks and Hydrobacteria. These subfamilies thus originated early in the history of life, implying that their innate immune functions in vertebrates and mollusks have evolved separately. Mammalian LAOs were found to belong to three separate clades: (1) LAO1, (2) LAO2, and (3) IL4I1. Phylogenetic analysis supported the hypothesis that LAO1 and LAO2 arose by a gene duplication prior to the divergence of marsupials from placental mammals, while IL4I1 duplicated from the ancestor of the LAO1 and LAO2 prior to the divergence of tetrapods from bony fishes. Mammalian IL4I1 clustered with LAOs from bony fishes, and these molecules shared a number of unique sequence features, including both amino acid replacements and a unique two-codon deletion. It is certain such unique features may be functionally important, especially three unique amino acid replacements in close proximity to the putative active site.