CMP-N-acetylneuraminic acid hydroxylase (CMAH)

CMP-N-acetylneuraminic acid hydroxylase (CMAH) is the rate-limiting enzyme responsible for the biochemical conversion of CMP-N-acetylneuraminic acid (CMP-Neu5Ac) to CMP-N-glycolylneuraminic acid (CMP-Neu5Gc) [1]. While most mammals express a functional CMAH enzyme, humans possess a pseudogenized version of the gene due to a 92-bp deletion, rendering them unable to synthesize Neu5Gc endogenously [2]. Consequently, Neu5Gc is recognized as a foreign xenoantigen by the human immune system, leading to the production of circulating anti-Neu5Gc antibodies. The metabolic incorporation of dietary Neu5Gc from red meat into human tissues can trigger a chronic inflammatory response known as xenosialitis, which is linked to an increased risk of cancer and cardiovascular disease [3]. In the context of biotechnology, CMAH is a primary target for genetic knockout in donor animals, such as pigs, to eliminate Neu5Gc expression and prevent hyperacute rejection in xenotransplantation [4]. Although no small-molecule drugs currently target CMAH in clinical practice, it remains a critical focus for gene-editing therapies and the development of Neu5Gc-free biopharmaceuticals [5].

Other names

Cytidine monophosphate-N-acetylneuraminic acid hydroxylaseCMP-Neu5Ac hydroxylaseCMAH

Genetic knockout or enzymatic inhibition to prevent the synthesis of the immunogenic sialic acid N-glycolylneuraminic acid (Neu5Gc) from N-acetylneuraminic acid (Neu5Ac).