Phylogenetic distribution of CMP-Neu5Ac hydroxylase (CMAH), the enzyme synthetizing the pro-inflammatory human xeno-antigen Neu5Gc

Abstract

The enzyme CMP-N-acetylneuraminic acid hydroxylase (CMAH) is responsible for thesynthesis of N-glycolylneuraminic acid (Neu5Gc), a sialic acid present on the cell surfaceproteins of most deuterostomes. The CMAH gene is thought to be present in mostdeuterostomes, but it has been inactivated in a number of lineages, including humans. Theinability of humans to synthesize Neu5Gc has had several evolutionary and biomedicalimplications. Remarkably, Neu5Gc is a xeno-antigen for humans, and consumption ofNeu5Gc-containing foods, such as red meats, may promote inflammation, arthritis andcancer. Likewise, xenotransplantation of organs producing Neu5Gc can result ininflammation and organ rejection. Therefore, knowing what animal species contain afunctional CMAH gene, and are thus capable of endogenous Neu5Gc synthesis, haspotentially far-reaching implications. In addition to humans, other lineages are known, orsuspected, to have lost CMAH; however, to date reports of absent and pseudogenic CMAHgenes are restricted to a handful of species. Here, we analyze all available genomic datafor non-deuterostomes, and 322 deuterostome genomes, to ascertain the phylogeneticdistribution of CMAH. Among non-deuterostomes, we found CMAH homologs in twogreen algae and a few prokaryotes. Within deuterostomes, putatively functional CMAHhomologs are present in 184 of the studied genomes, and a total of 31 independent genelosses/pseudogenization events were inferred. Our work produces a list of animals inferredto be free from endogenous Neu5Gc based on the absence of CMAH homologs and arethus potential candidates for human consumption, xenotransplantation research, and modelorganisms for investigation of human diseases.