CMAH
CMAHP | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Aliases | CMAHP,CMAH, CSAH, cytidine monophospho-N-acetylneuraminic acid hydroxylase, pseudogene | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | MGI:103227;GeneCards:CMAHP;OMA:CMAHP - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Cytidine monophospho-N-acetylneuraminic acid hydroxylase(Cmah) is anenzymethat is encoded by theCMAHgene.[5][6][7]In most mammals, the enzymehydroxylatesN-acetylneuraminic acid(Neu5Ac), producingN-glycolylneuraminic acid(Neu5Gc).[6]Neu5AcandNeu5Gcare mammalian glycans that compose theglycocalyx,especially insialoglycoproteins,which are part of thesialic acidfamily.[8]TheCMAHequivalent in humans is apseudogene(CMAHP);[9]there is no detectable Neu5Gc in normal human tissue.[6]This deficiency has a number of proposed effects on humans, including increased brain growth and improved self-recognition by the humanimmune system.[10][11]Incorporation of Neu5Gc from red meat and dairy into human tissues has been linked to chronic disease, includingtype-2 diabetesandchronic inflammation.[12][13]
Discovery
[edit]Thebiosynthesispathway of Neu5Gc from Neu5Ac was discovered by Shaw and Schauer in 1988,[14]while theproteinandDNA sequencesfor Neu5Gc, Neu5Ac, andCMAHPwere described by Irieet al.in 1998.[6]
Evolution
[edit]Genomic analyses indicate thatCMAHgenes are present only indeuterostomes,some unicellularalgaeand somebacteria.[15]CMAHrelatives have been lost in many other deuterostome lineages, includingtunicates,many groups of fish, theaxolotl,most reptiles, and all birds.[15]Among mammals, the gene is missing or nonfunctional in New World monkeys, the European hedgehog, ferrets, some bats, the sperm whale, and the platypus.[15]These animals lacking a functionalCMAHgene do not express Neu5Gc.[15]
The absence of Neu5Gc in humans is due to a 92-bpdeletionof anexonof the human geneCMAH[6].Sequences encoding mouse, pig, and chimpanzeeCMAHhave been examined usingcDNAcloning techniques and were found to be highly similar.[15]However, thehomologoushuman cDNA differs from these cDNAs by a 92-bp deletion in the 5' region.[15]This deletion, corresponding to exon 5 of the mouse hydroxylase gene, causes aframeshift mutationand premature termination of thepolypeptide chainin humans.[6]Neu5Gc seems to be undetectable in human tissues because the truncated version of human hydroxylasemRNAcannot encode for an active enzyme.[14]
The deletion that deactivated this gene occurred approximately 3.2mya,after the divergence of humans from the Africangreat apes,and quickly swept tofixationin the human population.[10]The lineage of this pseudogene in humans indicates another deep split in Africa dating to 2.9 mya, with a complex subsequent history.[10]
Sexual selectionmay have contributed to the fixation of nonfunctionalCMAHin humans.[16]This hypothesis has been tested in mice, with females carrying nonfunctionalCMAHexhibiting reproductive incompatibility with males carrying functionalCMAHdue to anti-Neu5Gcantibodiesmigrating to the female reproductive tract and destroying Neu5Gc-positive sperm.[16]
Function in other mammals
[edit]Sialic acids such as Neu5Ac and Neu5Gc are terminal components of the carbohydrate chains ofglycoconjugatesinvolved inligand–receptor,cell–cell,and cell–pathogen interactions.[5]Neu5Gc has been shown to be involved in a variety of processes in mice, includingprotein metabolism,signal transduction,metabolismof most organic molecules, and immunity.[8]
Cat AB blood group
[edit]Theblood typefor 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.[17]
Function in humans
[edit]Neu5Gc has been found in normal human tissue, with larger amounts found in fetal[11]and cancerous[18]tissues. Studies suggest that Neu5Gc could be an excellent cancer cell marker.[18]Since Neu5Gc can only be made by functionalCMAH,which is not present in humans, researchers have searched for alternative sources of Neu5Gc in humans.[19]Current research indicates that Neu5Gc is incorporated into human tissues through consumption of red meats and dairy.[19][12]This incorporation process involvesmacropinocytosis,delivery to thelysosome,and export of free Neu5Gc to thecytosolvia the sialin transporter.[19][13]
Because Neu5Gc differs from Neu5Ac by only one oxygen, it is handled like a native sialic acid by humanbiochemical pathways.[13]The immune system does not work the same way, however; all humans have varying amounts of a diverse spectrum of anti-Neu5Gc antibodies.[12]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.[12]These sites are also common places foratherosclerosisandepithelial carcinomas,both of which are associated with red meat and dairy consumption and are aggravated by chronic inflammation.[20]Red meat ingestion and chronic inflammation have also been associated with diseases like type-2 diabetes and age-dependentmacular degeneration,so Neu5Gc may be linked to the development of these disorders as well.[12][13]
Recent data suggests that thehypoxicconditions incarcinomascan up-regulate the expression of the lysosomal sialic acid transporter necessary for Neu5Gc incorporation into human tissues.[20][13]In addition,growth factorsmay activate enhanced macropinocytosis, which can increase Neu5Gc incorporation.[13]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.[20]
The presence of Neu5Gc in variousbiotherapeuticsderived from animal products may impact human health and is still being studied.[12]Some complications could includeimmune hypersensitivity reactions,reducedhalf-lifeof the biotherapeutic in circulation,immune complexformation, increase of Neu5Gc antibody concentration, enhancedimmunoreactivityagainst the biotherapeutic polypeptide, and directly loading more Neu5Gc into tissues.[20]
Implications for human evolution
[edit]Pseudogenes such asCMAHcan be used to studyallelefixation anddemographic history.[21]Analyses ofCMAHhaplotypediversity have been used to examine human demographic history during thePlio-Pleistocene.[21]
The functional loss ofCMAHafter 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.[10][22]In most mammals,CMAHexpressionis down-regulated in the brain, and experimental up-regulation ofCMAHis lethal in mice.[10]ExperimentalCMAHloss in mice increases running endurance and decreases muscle fatigue, which could have been beneficial to ancestralHomoduring the gene's fixation.[22]
Implications for pathogenicity
[edit]The loss of Neu5Gc in humans may have contributed to resistance to generalistpathogensand increasedpathogenicityof human-specific pathogens.[23]Human-specificcholera,which employs host sialic acids to trigger a gastrointestinal response, preferentially uses Neu5Ac and is inhibited by Neu5Gc.[23]
NonfunctionializationofCMAHhas made humans more susceptible to somevirusesby decreasing sialic acid diversity.[11]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 humancell membranes.[11]For example, the most serious form ofmalariain humans,P. falciparum,binds to Neu5Ac on the membrane ofred blood cells.[11][20]In contrast to these negative effects, losingCMAHshould actually protect humans against any virus that targets Neu5Gc, such as those that causediarrheal diseasesin livestock[11],E. coliK99,transmissible gastroenteritis coronavirus(TGEV),[20]andsimian virus 40(SV40).[20]
References
[edit]- ^abcGRCh38: Ensembl release 89: ENSG00000168405–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000016756–Ensembl,May 2017
- ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^abKawano 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.PMID7608218.
- ^abcdefIrie 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.PMID9624188.
- ^"Entrez Gene: CMAH cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMP-N-acetylneuraminate monooxygenase)".
- ^abKwon 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.PMC4167996.PMID25229777.
- ^"CMAHP cytidine monophospho-N-acetylneuraminic acid hydroxylase, pseudogene [Homo sapiens (human)]".NCBI GenBank.12 Oct 2019.
- ^abcdeChou 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.PMC129338.PMID12192086.
- ^abcdefVarki A (2001)."Loss of N-glycolylneuraminic acid in humans: Mechanisms, consequences, and implications for hominid evolution".American Journal of Physical Anthropology.Suppl 33 (Suppl): 54–69.doi:10.1002/ajpa.10018.PMC7159735.PMID11786991.
- ^abcdefPadler-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.PMC2586336.PMID18669916.
- ^abcdefVarki 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.PMC3024026.PMID20445087.
- ^abShaw 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.PMID3202954.
- ^abcdefPeri S, Kulkarni A, Feyertag F, Berninsone PM, Alvarez-Ponce D (January 2018)."Phylogenetic Distribution of CMP-Neu5Ac Hydroxylase (CMAH), the Enzyme Synthetizing [sic] the Proinflammatory Human Xenoantigen Neu5Gc ".Genome Biology and Evolution.10(1): 207–219.doi:10.1093/gbe/evx251.PMC5767959.PMID29206915.
- ^abGhaderi 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.PMC3203784.PMID21987817.
- ^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.PMC1913925.PMID17553163.
- ^abMalykh 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.PMID11522391.
- ^abcTangvoranuntakul 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.PMC218710.PMID14523234.
- ^abcdefgVarki 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.PMC7087641.PMID18777136.S2CID13169985.
- ^abHayakawa 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.PMC1456212.PMID16272417.
- ^abOkerblom 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.PMC6158528.PMID30209232.
- ^abAlisson-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.PMC6023241.PMID29912959.
Further reading
[edit]- Varki A (July 2001). "N-glycolylneuraminic acid deficiency in humans".Biochimie.83(7): 615–22.doi:10.1016/S0300-9084(01)01309-8.PMID11522390.
- Bonaldo MF, Lennon G, Soares MB (September 1996)."Normalization and subtraction: two approaches to facilitate gene discovery".Genome Research.6(9): 791–806.doi:10.1101/gr.6.9.791.PMID8889548.
- Irie A, Suzuki A (July 1998). "CMP-N-Acetylneuraminic acid hydroxylase is exclusively inactive in humans".Biochemical and Biophysical Research Communications.248(2): 330–3.doi:10.1006/bbrc.1998.8946.PMID9675135.
- Chou HH, Takematsu H, Diaz S, Iber J, Nickerson E, Wright KL, et al. (September 1998)."A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence".Proceedings of the National Academy of Sciences of the United States of America.95(20): 11751–6.Bibcode:1998PNAS...9511751C.doi:10.1073/pnas.95.20.11751.PMC21712.PMID9751737.
- Muchmore EA, Diaz S, Varki A (October 1998). "A structural difference between the cell surfaces of humans and the great apes".American Journal of Physical Anthropology.107(2): 187–98.doi:10.1002/(SICI)1096-8644(199810)107:2<187::AID-AJPA5>3.0.CO;2-S.PMID9786333.
- Hayakawa T, Satta Y, Gagneux P, Varki A, Takahata N (September 2001)."Alu-mediated inactivation of the human CMP- N-acetylneuraminic acid hydroxylase gene".Proceedings of the National Academy of Sciences of the United States of America.98(20): 11399–404.Bibcode:2001PNAS...9811399H.doi:10.1073/pnas.191268198.PMC58741.PMID11562455.
- 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.PMC129338.PMID12192086.