CMAH
Putative cytidine monophosphate-N-acetylneuraminic acid hydroxylase-like protein is an enzyme that in humans is encoded by the CMAH gene.[1][2][3]
Sialic acids are terminal components of the carbohydrate chains of glycoconjugates involved in ligand–receptor, cell–cell, and cell–pathogen interactions. The two most common forms of sialic acid found in mammalian cells are N-acetylneuraminic acid (Neu5Ac) and its hydroxylated derivative, N-glycolylneuraminic acid (Neu5Gc). Studies of sialic acid distribution show that Neu5Gc is not detectable in normal human tissues although it was an abundant sialic acid in other mammals. Neu5Gc is, in actuality, immunogenic in humans.[3]
The absence of Neu5Gc in humans is due to a deletion within the human gene CMAH encoding cytidine monophosphate-N-acetylneuraminic acid hydroxylase, an enzyme responsible for Neu5Gc biosynthesis. Sequences encoding the mouse, pig, and chimpanzee hydroxylase enzymes were obtained by cDNA cloning and found to be highly homologous. However, the homologous human cDNA differs from these cDNAs by a 92-bp deletion in the 5' region. This deletion, corresponding to exon 6 of the mouse hydroxylase gene, causes a frameshift mutation and premature termination of the polypeptide chain in human. It seems unlikely that the truncated human hydroxylase mRNA encodes for an active enzyme explaining why Neu5Gc is undetectable in normal human tissues.[3]
The deletion that deactivated this gene occurred approximately 3.2 mya, after the divergence of humans from the African great apes, and quickly swept to fixation in the human population. The lineage of this pseudogene in humans indicates another deep split in Africa dating to 2.9 Mya, with a complex subsequent history.[4]
References
- ^ Kawano T, Koyama S, Takematsu H, Kozutsumi Y, Kawasaki H, Kawashima S, Kawasaki T, Suzuki A (Aug 1995). "Molecular cloning of cytidine monophospho-N-acetylneuraminic acid hydroxylase. Regulation of species- and tissue-specific expression of N-glycolylneuraminic acid". J Biol Chem 270 (27): 16458–63. doi:10.1074/jbc.270.27.16458. PMID 7608218.
- ^ Irie A, Koyama S, Kozutsumi Y, Kawasaki T, Suzuki A (Jul 1998). "The molecular basis for the absence of N-glycolylneuraminic acid in humans". J Biol Chem 273 (25): 15866–71. doi:10.1074/jbc.273.25.15866. PMID 9624188.
- ^ a b c "Entrez Gene: CMAH cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMP-N-acetylneuraminate monooxygenase)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8418.
- ^ Hayakawa, T; Aki, I; Varki, A; Satta, Y; Takahata, N (Feb 2006). "Fixation of the Human-Specific CMP-N-Acetylneuraminic Acid Hydroxylase Pseudogene and Implications of Haplotype Diversity for Human Evolution". Genetics 172 (2): 1139–46. doi:10.1534/genetics.105.046995. ISSN 0016-6731. PMC 1456212. PMID 16272417. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1456212.
Further reading
- Varki A (2002). "N-glycolylneuraminic acid deficiency in humans". Biochimie 83 (7): 615–22. doi:10.1016/S0300-9084(01)01309-8. PMID 11522390.
- Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
- Irie A, Suzuki A (1998). "CMP-N-Acetylneuraminic acid hydroxylase is exclusively inactive in humans". Biochem. Biophys. Res. Commun. 248 (2): 330–3. doi:10.1006/bbrc.1998.8946. PMID 9675135.
- Chou HH, Takematsu H, Diaz S et al. (1998). "A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence". Proc. Natl. Acad. Sci. U.S.A. 95 (20): 11751–6. doi:10.1073/pnas.95.20.11751. PMC 21712. PMID 9751737. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=21712.
- Muchmore EA, Diaz S, Varki A (1999). "A structural difference between the cell surfaces of humans and the great apes". Am. J. Phys. Anthropol. 107 (2): 187–98. doi:10.1002/(SICI)1096-8644(199810)107:2<187::AID-AJPA5>3.0.CO;2-S. PMID 9786333.
- Hayakawa T, Satta Y, Gagneux P et al. (2001). "Alu-mediated inactivation of the human CMP- N-acetylneuraminic acid hydroxylase gene". Proc. Natl. Acad. Sci. U.S.A. 98 (20): 11399–404. doi:10.1073/pnas.191268198. PMC 58741. PMID 11562455. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=58741.
- Chou HH, Hayakawa T, Diaz S et al. (2002). "Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution". Proc. Natl. Acad. Sci. U.S.A. 99 (18): 11736–41. doi:10.1073/pnas.182257399. PMC 129338. PMID 12192086. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=129338.
- Strausberg RL, Feingold EA, Grouse LH et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241.
- Mungall AJ, Palmer SA, Sims SK et al. (2003). "The DNA sequence and analysis of human chromosome 6". Nature 425 (6960): 805–11. doi:10.1038/nature02055. PMID 14574404.
- Bighignoli B, Niini T et al. (2008). "Cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) mutations associated with the domestic cat AB blood group". BMC Genetics 8: 27. doi:10.1186/1471-2156-8-27.