CMAH

Cytidine monophospho-N-acetylneuraminic acid hydroxylase (Cmah) is an enzyme that is encoded by the CMAH gene.[4][5][6] In most mammals, the enzyme hydroxylates N-acetylneuraminic acid (Neu5Ac), producing N-glycolylneuraminic acid (Neu5Gc).[5] Neu5Ac and Neu5Gc are mammalian cell surface proteins that are part of the sialic acid family.[7] The CMAH equivalent in humans is a pseudogene (CMAHP);[8] there is no detectable Neu5Gc in normal human tissue.[5] This deficiency has a number of proposed effects on humans, including increased brain growth and improved self-recognition by the human immune system.[9][10] Incorporation of Neu5Gc from red meat and dairy into human tissues has been linked to chronic disease, including type-2 diabetes and chronic inflammation.[11][12]

CMAHP
Identifiers
AliasesCMAHP, CMAH, CSAH, cytidine monophospho-N-acetylneuraminic acid hydroxylase, pseudogene
External IDsMGI: 103227 GeneCards: CMAHP
Orthologs
SpeciesHumanMouse
Entrez

8418

12763

Ensembl

ENSG00000168405

ENSMUSG00000016756

UniProt

Q9Y471

Q61419

RefSeq (mRNA)

n/a

NM_001111110
NM_001284519
NM_001284520
NM_007717

RefSeq (protein)

n/a

NP_001104580
NP_001271448
NP_001271449
NP_031743

Location (UCSC)n/aChr 13: 24.33 – 24.48 Mb
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

Discovery

The biosynthesis pathway of Neu5Gc from Neu5Ac was discovered by Shaw and Schauer in 1988,[13] while the protein and DNA sequences for Neu5Gc, Neu5Ac, and CMAHP were described by Irie et al. in 1998.[5]

Evolution

Genomic analyses indicate that CMAH genes are present only in deuterostomes, some unicellular algae and some bacteria.[14] CMAH relatives have been lost in many other deuterostome lineages, including tunicates, many groups of fish, the axolotl, most reptiles, and all birds.[14] Among mammals, the gene is missing or nonfunctional in New World monkeys, the European hedgehog, ferrets, some bats, the sperm whale, and the platypus.[14] These animals lacking a functional CMAH gene do not express Neu5Gc.[14]

The absence of Neu5Gc in humans is due to a 92-bp deletion of an exon of the human gene CMAH [5]. Sequences encoding mouse, pig, and chimpanzee CMAH have been examined using cDNA cloning techniques and were found to be highly similar.[14] However, the homologous human cDNA differs from these cDNAs by a 92-bp deletion in the 5' region.[14] This deletion, corresponding to exon 5 of the mouse hydroxylase gene, causes a frameshift mutation and premature termination of the polypeptide chain in humans.[5] Neu5Gc seems to be undetectable in human tissues because the truncated version of human hydroxylase mRNA cannot encode for an active enzyme.[13]

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.[9] The lineage of this pseudogene in humans indicates another deep split in Africa dating to 2.9 mya, with a complex subsequent history.[9]

Sexual selection may have contributed to the fixation of nonfunctional CMAH in humans.[15] This hypothesis has been tested in mice, with females carrying nonfunctional CMAH exhibiting reproductive incompatibility with males carrying functional CMAH due to anti-Neu5Gc antibodies migrating to the female reproductive tract and destroying Neu5Gc-positive sperm.[15]

Function in other mammals

Sialic acids such as Neu5Ac and Neu5Gc are terminal components of the carbohydrate chains of glycoconjugates involved in ligand–receptor, cell–cell, and cell–pathogen interactions.[4] Neu5Gc has been shown to be involved in a variety of processes in mice, including protein metabolism, signal transduction, metabolism of most organic molecules, and immunity.[7]

Cat AB blood group
See also: Blood type (non-human)

The blood type for a cat is mostly covered by the AB blood group system, determined by the CMAH alleles a cat possess. The majority A type seems to be dominant over the recessive B type, which is only found with a higher frequency in some breeds. An "AB" type seems to be expressed by a third recessive allele.[16]

Function in humans

Neu5Gc has been found in normal human tissue, with larger amounts found in fetal[10] and cancerous[17] tissues. Studies suggest that Neu5Gc could be an excellent cancer cell marker.[17] Since Neu5Gc can only be made by functional CMAH, which is not present in humans, researchers have searched for alternative sources of Neu5Gc in humans.[18] Current research indicates that Neu5Gc is incorporated into human tissues through consumption of red meats and dairy.[18][11] This incorporation process involves macropinocytosis, delivery to the lysosome, and export of free Neu5Gc to the cytosol via the sialin transporter.[18][12]

Because Neu5Gc differs from Neu5Ac by only one oxygen, it is handled like a native sialic acid by human biochemical pathways.[12] The immune system does not work the same way, however; all humans have varying amounts of a diverse spectrum of anti-Neu5Gc antibodies.[11] If Neu5Gc is constantly being incorporated into tissues due to a diet heavy in red meats and dairy, anti-Neu5Gc antibodies cause chronic inflammation, especially in blood vessels and the linings of hollow organs.[11] These sites are also common places for atherosclerosis and epithelial carcinomas, both of which are associated with red meat and dairy consumption and are aggravated by chronic inflammation.[19] Red meat ingestion and chronic inflammation have also been associated with diseases like type-2 diabetes and age-dependent macular degeneration, so Neu5Gc may be linked to the development of these disorders as well.[11][12]

Recent data suggests that the hypoxic conditions in carcinomas can up-regulate the expression of the lysosomal sialic acid transporter necessary for Neu5Gc incorporation into human tissues.[19][12] In addition, growth factors may activate enhanced macropinocytosis, which can increase Neu5Gc incorporation.[12] Studies have shown that fetal tissues are also capable of taking up Neu5Gc from maternal dietary sources, which may explain elevated levels of Neu5Gc in the human fetus.[19]

The presence of Neu5Gc in various biotherapeutics derived from animal products may impact human health and is still being studied.[11] Some complications could include immune hypersensitivity reactions, reduced half-life of the biotherapeutic in circulation, immune complex formation, increase of Neu5Gc antibody concentration, enhanced immunoreactivity against the biotherapeutic polypeptide, and directly loading more Neu5Gc into tissues.[19]

Implications for human evolution

Pseudogenes such as CMAH can be used to study allele fixation and demographic history.[20] Analyses of CMAH haplotype diversity have been used to examine human demographic history during the Plio-Pleistocene.[20]

The functional loss of CMAH after the divergence of humans from the great apes has several implications for its role in human development, including less constrained brain growth and increased running endurance, two traits thought to be important to human evolution.[9][21] In most mammals, CMAH expression is down-regulated in the brain, and experimental up-regulation of CMAH is lethal in mice.[9] Experimental CMAH loss in mice increases running endurance and decreases muscle fatigue, which could have been beneficial to ancestral Homo during the gene's fixation.[21]

Implications for pathogenicity

The loss of Neu5Gc in humans may have contributed to resistance to generalist pathogens and increased pathogenicity of human-specific pathogens.[22] Human-specific cholera, which employs host sialic acids to trigger a gastrointestinal response, preferentially uses Neu5Ac and is inhibited by Neu5Gc.[22]

Nonfunctionialization of CMAH has made humans more susceptible to some viruses by decreasing sialic acid diversity.[10] Viruses that bind to Neu5Ac before entering the cell are enhanced by the high density of Neu5Ac, which would be reduced if other sialic acids were present on human cell membranes.[10] For example, the most serious form of malaria in humans, P. falciparum, binds to Neu5Ac on the membrane of red blood cells.[10][19] In contrast to these negative effects, losing CMAH should actually protect humans against any virus that targets Neu5Gc, such as those that cause diarrheal diseases in livestock[10] , E. coli K99, transmissible gastroenteritis coronavirus (TGEV),[19] and simian virus 40 (SV40).[19]

References
  1. GRCm38: Ensembl release 89: ENSMUSG00000016756 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. Kawano T, Koyama S, Takematsu H, Kozutsumi Y, Kawasaki H, Kawashima S, et al. (July 1995). "Molecular cloning of cytidine monophospho-N-acetylneuraminic acid hydroxylase. Regulation of species- and tissue-specific expression of N-glycolylneuraminic acid". The Journal of Biological Chemistry. 270 (27): 16458–63. doi:10.1074/jbc.270.27.16458. PMID 7608218.
  5. Irie A, Koyama S, Kozutsumi Y, Kawasaki T, Suzuki A (June 1998). "The molecular basis for the absence of N-glycolylneuraminic acid in humans". The Journal of Biological Chemistry. 273 (25): 15866–71. doi:10.1074/jbc.273.25.15866. PMID 9624188.
  6. "Entrez Gene: CMAH cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMP-N-acetylneuraminate monooxygenase)".
  7. Kwon DN, Chang BS, Kim JH (2014). "Gene Expression and Pathway Analysis of Effects of the CMAH Deactivation on Mouse Lung, Kidney and Heart". PLOS ONE. 9 (9): 1–13. Bibcode:2014PLoSO...9j7559K. doi:10.1371/journal.pone.0107559. PMC 4167996. PMID 25229777.
  8. "CMAHP cytidine monophospho-N-acetylneuraminic acid hydroxylase, pseudogene [Homo sapiens (human)]". NCBI GenBank. 12 Oct 2019.
  9. Chou HH, Hayakawa T, Diaz S, Krings M, Indriati E, Leakey M, et al. (September 2002). "Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution". Proceedings of the National Academy of Sciences of the United States of America. 99 (18): 11736–41. Bibcode:2002PNAS...9911736C. doi:10.1073/pnas.182257399. PMC 129338. PMID 12192086.
  10. Varki A (2001). "Loss of N-glycolylneuraminic acid in humans: Mechanisms, consequences, and implications for hominid evolution". American Journal of Physical Anthropology. Suppl 33: 54–69. doi:10.1002/ajpa.10018. PMC 7159735. PMID 11786991.
  11. Padler-Karavani V, Yu H, Cao H, Chokhawala H, Karp F, Varki N, et al. (October 2008). "Diversity in specificity, abundance, and composition of anti-Neu5Gc antibodies in normal humans: potential implications for disease". Glycobiology. 18 (10): 818–30. doi:10.1093/glycob/cwn072. PMC 2586336. PMID 18669916.
  12. Varki A (May 2010). "Colloquium paper: uniquely human evolution of sialic acid genetics and biology". Proceedings of the National Academy of Sciences of the United States of America. 107 Suppl 2 (suppl. 2): 8939–46. Bibcode:2010PNAS..107.8939V. doi:10.1073/pnas.0914634107. PMC 3024026. PMID 20445087.
  13. Shaw L, Schauer R (June 1988). "The biosynthesis of N-glycoloylneuraminic acid occurs by hydroxylation of the CMP-glycoside of N-acetylneuraminic acid". Biological Chemistry Hoppe-Seyler. 369 (6): 477–86. doi:10.1515/bchm3.1988.369.1.477. PMID 3202954.
  14. Peri S, Kulkarni A, Feyertag F, Berninsone PM, Alvarez-Ponce D (January 2018). "Phylogenetic Distribution of CMP-Neu5Ac Hydroxylase (CMAH), the Enzyme Synthetizing the Proinflammatory Human Xenoantigen Neu5Gc". Genome Biology and Evolution. 10 (1): 207–219. doi:10.1093/gbe/evx251. PMC 5767959. PMID 29206915.
  15. Ghaderi D, Springer SA, Ma F, Cohen M, Secrest P, Taylor RE, Varki A, Gagneux P (2011). "Sexual Selection by Female Immunity against Paternal Antigens Can Fix Loss of Function Alleles". Proceedings of the National Academy of Sciences of the United States of America. 108 (43): 17743–48. Bibcode:2011PNAS..10817743G. doi:10.1073/pnas.1102302108. PMC 3203784. PMID 21987817.
  16. Bighignoli B, Niini T, Grahn RA, Pedersen NC, Millon LV, Polli M, et al. (June 2007). "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. PMC 1913925. PMID 17553163.
  17. Malykh YN, Schauer R, Shaw L (2001). "N-Glycolylneuraminic Acid in Human Tumours". Biochimie. 83 (7): 623–34. doi:10.1016/s0300-9084(01)01303-7. PMID 11522391.
  18. Tangvoranuntakul P, Gagneux P, Diaz S, Bardor M, Varki N, Varki A, Muchmore E (October 2003). "Human uptake and incorporation of an immunogenic nonhuman dietary sialic acid". Proceedings of the National Academy of Sciences of the United States of America. 100 (21): 12045–50. Bibcode:2003PNAS..10012045T. doi:10.1073/pnas.2131556100. PMC 218710. PMID 14523234.
  19. Varki A (April 2009). "Multiple changes in sialic acid biology during human evolution". Glycoconjugate Journal. 26 (3): 231–45. doi:10.1007/s10719-008-9183-z. PMC 7087641. PMID 18777136. S2CID 13169985.
  20. Hayakawa T, Aki I, Varki A, Satta Y, Takahata N (2005). "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. PMC 1456212. PMID 16272417.
  21. Okerblom J, Fletes W, Patel HH, Schenk S, Varki A, Breen EC (2018). "Human-like Cmah Inactivation in Mice Increases Running Endurance and Decreases Muscle Fatigability: Implications for Human Evolution". Proceedings of the Royal Society B: Biological Sciences. 285 (1886): 20181656. doi:10.1098/rspb.2018.1656. PMC 6158528. PMID 30209232.
  22. Alisson-Silva F, Liu JZ, Diaz SL, Deng L, Gareau MG, Marchelletta R, Chen X, et al. (2018). "Human Evolutionary Loss of Epithelial Neu5Gc Expression and Species-Specific Susceptibility to Cholera". PLOS Pathogens. 14 (6): 1–20. doi:10.1371/journal.ppat.1007133. PMC 6023241. PMID 29912959.

Further reading
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