Phylogenetic Distribution of CMP-Neu5Ac Hydroxylase (CMAH), the Enzyme Synthetizing the Proinflammatory Human Xenoantigen Neu5Gc

Abstract

The enzyme CMP-N-acetylneuraminic acid hydroxylase (CMAH) is responsible for the synthesis of N-glycolylneuraminic acid (Neu5Gc), a sialic acid present on the cell surface proteins of most deuterostomes. The CMAH gene is thought to be present in most deuterostomes, but it has been inactivated in a number of lineages, including humans. The inability of humans to synthesize Neu5Gc has had several evolutionary and biomedical implications. Remarkably, Neu5Gc is a xenoantigen for humans, and consumption of Neu5Gc-containing foods, such as red meats, may promote inflammation, arthritis, and cancer. Likewise, xenotransplantation of organs producing Neu5Gc can result in inflammation and organ rejection. Therefore, knowing what animal species contain a functional CMAH gene, and are thus capable of endogenous Neu5Gc synthesis, has potentially far-reaching implications. In addition to humans, other lineages are known, or suspected, to have lost CMAH; however, to date reports of absent and pseudogenic CMAH genes are restricted to a handful of species. Here, we analyze all available genomic data for nondeuterostomes, and 322 deuterostome genomes, to ascertain the phylogenetic distribution of CMAH. Among nondeuterostomes, we found CMAH homologs in two green algae and a few prokaryotes. Within deuterostomes, putatively functional CMAH homologs are present in 184 of the studied genomes, and a total of 31 independent gene losses/pseudogenization events were inferred. Our work produces a list of animals inferred to be free from endogenous Neu5Gc based on the absence of CMAH homologs and are thus potential candidates for human consumption, xenotransplantation research, and model organisms for investigation of human diseases.

De-O-Acetylation of mucin-derived sialic acids by recombinant NanS-p esterases of Escherichia coli O157:H7 strain EDL933

“…N-glycolylneuraminic acid (Neu5Gc) is the hydroxylated derivative of Neu5Ac carrying an OH-group in the N-acetyl chain at carbon C5. Neu5Gc is generated by the enzyme CMP-Neu5Ac-hydroxylase, which is expressed as functional enzyme in all mammals except humans, who produce an inactive enzyme due a deletion in the corresponding chromosome (Peri et al, 2018). Although humans lack a functioning CMP-Neu5Ac-hydroxylase, Neu5Gc has been found in low quantities in human mucins most likely due to catabolic incorporation from nutritional Neu5Gc derived from red meat (Varki and Schauer, 2009).…”

Influenza Viruses in Mice: Deep Sequencing Analysis of Serial Passage and Effects of Sialic Acid Structural Variation

“…Humans and ferrets lack a functional CMAH so that Neu5Gc is not displayed in cells of those hosts, while CMAH is active in other natural influenza hosts such as swine and horses, and Neu5Gc is also displayed at high levels in many tissues of mice (31,32). Other chemical modifications of Sia that have the potential to impact virus-Sia interactions are also abundant 115 and diverse across vertebrate species, and include the addition of acetyl groups on the 4, 7, 8 and/or 9 positions, as well as potential lactyl or sulfate modifications of the glycerol side chain (33)(34)(35).…”

The desirable donor pig to eliminate all xenoreactive antigens

“…Pigs, and many other mammals, synthesize two carbohydrates, galactose-α-1,3-galactose (α-Gal) and N-glycolylneuraminic acid (Neu5Gc), that are lacking in humans. 1,2 Consequently, these sugars can be targeted by natural human antibodies which likely arise following exposure to various environmental antigens. Though α-Gal and Neu5Gc were recognized as antigens for quite some time, initial genetic engineering efforts only eliminated α-Gal.…”