Cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) (CMAH)

Cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) is the enzyme responsible for the biosynthesis of N-glycolylneuraminic acid (Neu5Gc), a common sialic acid found in most mammals but absent in humans due to an evolutionary gene mutation (UniProt: P51911). In pigs, CMAH converts CMP-N-acetylneuraminic acid (CMP-Neu5Ac) into CMP-Neu5Gc, which is then incorporated into cell surface glycoproteins and glycolipids. Because humans lack this enzyme, they produce natural antibodies against the Neu5Gc epitope, making it a major xenoantigen in porcine-to-human xenotransplantation (PubMed: 15703225). When porcine organs are transplanted into humans, these anti-Neu5Gc antibodies trigger hyperacute rejection by activating the complement system and causing vascular damage. To overcome this barrier, CMAH is a primary target for gene-editing technologies like CRISPR-Cas9, which are used to create CMAH-knockout pigs that do not express the Neu5Gc epitope (PubMed: 29033138). Beyond transplantation, the metabolic incorporation of dietary Neu5Gc into human tissues is associated with chronic inflammation and an increased risk of cancer and cardiovascular diseases (PubMed: 30643246).

Other names

CMP-N-acetylneuraminic acid hydroxylaseCMP-Neu5Ac hydroxylaseN-glycolylneuraminic acid synthaseNeu5Gc synthase

Genomic inactivation (knockout) of the CMAH gene to eliminate the synthesis of the Neu5Gc epitope, thereby preventing antibody-mediated hyperacute rejection in xenotransplantation.