CMAH: Difference between revisions

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{{Infobox_gene}}
{{Infobox_gene}}
'''Putative cytidine monophosphate-N-acetylneuraminic acid hydroxylase-like protein''' is an [[enzyme]] that in humans is encoded by the ''CMAH'' [[gene]].<ref name="pmid7608218">{{cite journal |vauthors=Kawano T, Koyama S, Takematsu H, Kozutsumi Y, Kawasaki H, Kawashima S, Kawasaki T, Suzuki A | title = Molecular [[cloning]] of cytidine monophospho-N-acetylneuraminic acid hydroxylase. Regulation of [[species]]- and tissue-specific expression of N-glycolylneuraminic acid | journal = J Biol Chem | volume = 270 | issue = 27 | pages = 16458–63 |date=Aug 1995 | pmid = 7608218 | pmc =  | doi = 10.1074/jbc.270.27.16458}}</ref><ref name="pmid9624188">{{cite journal |vauthors=Irie A, Koyama S, Kozutsumi Y, Kawasaki T, Suzuki A | title = The molecular basis for the absence of N-glycolylneuraminic acid in humans | journal = J Biol Chem | volume = 273 | issue = 25 | pages = 15866–71 |date=Jul 1998 | pmid = 9624188 | pmc =  | doi =10.1074/jbc.273.25.15866 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: CMAH cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMP-N-acetylneuraminate monooxygenase)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8418| accessdate = }}</ref>
'''Putative cytidine monophosphate-N-acetylneuraminic acid hydroxylase-like protein''' is an [[enzyme]] that in humans is encoded by the ''CMAH'' [[gene]].<ref name="pmid7608218">{{cite journal | vauthors = Kawano T, Koyama S, Takematsu H, Kozutsumi Y, Kawasaki H, Kawashima S, Kawasaki T, Suzuki A | title = Molecular cloning of cytidine monophospho-N-acetylneuraminic acid hydroxylase. Regulation of species- and tissue-specific expression of N-glycolylneuraminic acid | journal = The Journal of Biological Chemistry | volume = 270 | issue = 27 | pages = 16458–63 | date = July 1995 | pmid = 7608218 | pmc =  | doi = 10.1074/jbc.270.27.16458 }}</ref><ref name="pmid9624188">{{cite journal | vauthors = Irie A, Koyama S, Kozutsumi Y, Kawasaki T, Suzuki A | title = The molecular basis for the absence of N-glycolylneuraminic acid in humans | journal = The Journal of Biological Chemistry | volume = 273 | issue = 25 | pages = 15866–71 | date = June 1998 | pmid = 9624188 | pmc =  | doi = 10.1074/jbc.273.25.15866 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: CMAH cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMP-N-acetylneuraminate monooxygenase)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8418| access-date = }}</ref>


== Function ==
== Function ==


[[Sialic acid]]s 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.<ref name="entrez" />
[[Sialic acid]]s 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|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.<ref name="entrez" />


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 5 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.<ref name="entrez" />
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 similar. However, the homologous human cDNA differs from these cDNAs by a 92-bp deletion in the 5' region. This deletion, corresponding to exon 5 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.<ref name="entrez" />


The deletion that deactivated this gene occurred approximately 3.2 [[mya (unit)|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.<ref name="pmid16272417">{{cite journal |vauthors=Hayakawa T, Aki I, Varki A, Satta Y, Takahata N | title = Fixation of the human-specific CMP-N-acetylneuraminic acid hydroxylase pseudogene and implications of haplotype diversity for human evolution | journal = Genetics | volume = 172 | issue = 2 | pages = 1139–46 |date=February 2006 | pmid = 16272417 | pmc = 1456212 | doi = 10.1534/genetics.105.046995 }}</ref> Causes of the selection against the CMAH gene could include a severe infectious disease that specifically binds to Neu5Gc, a change in binding preference of a sialic acid binding protein favoring the loss of Neu5Gc or accumulation of Neu5Ac, or protection from viruses originating in individuals with Neu5Gc due to anti-Neu5Gc antibodies in CMAH-negative individuals  <ref name="s10719">{{cite journal | author = Varki A | title = Multiple changes in sialic acid biology during human evolution | journal = Glycoconjugate Journal | volume = 26 | issue =  | pages = 231–245 | year = 2009 | pmid =  | pmc =  | doi = 10.1007/s10719-008-9813-z }}</ref>
The deletion that deactivated this gene occurred approximately 3.2 [[mya (unit)|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.<ref name="pmid16272417">{{cite journal | vauthors = Hayakawa T, Aki I, Varki A, Satta Y, Takahata N | title = Fixation of the human-specific CMP-N-acetylneuraminic acid hydroxylase pseudogene and implications of haplotype diversity for human evolution | journal = Genetics | volume = 172 | issue = 2 | pages = 1139–46 | date = February 2006 | pmid = 16272417 | pmc = 1456212 | doi = 10.1534/genetics.105.046995 }}</ref> Causes of the selection against the CMAH gene could include a severe infectious disease that specifically binds to Neu5Gc, a change in binding preference of a sialic acid binding protein favoring the loss of Neu5Gc or accumulation of Neu5Ac, or protection from viruses originating in individuals with Neu5Gc due to anti-Neu5Gc antibodies in CMAH-negative individuals  <ref name="s10719">{{cite journal | vauthors = Varki A | title = Multiple changes in sialic acid biology during human evolution | journal = Glycoconjugate Journal | volume = 26 | issue =  | pages = 231–245 | year = 2009 | pmid =  | pmc =  | doi = 10.1007/s10719-008-9813-z }}</ref>


== Effects of loss of functioning human CMAH ==
== Effects of loss of functioning human CMAH ==


The functional loss of this gene after the divergence of humans from the great apes leads to several possible implications for its role in human development, the most notable of which being less constrained brain growth. In most mammals, CMAH expression is down-regulated in the brain<ref name="pmid12192086">{{cite journal |vauthors=Chou HH, Hayakawa T, Diaz S, Krings M, Indriati E, Leakey M, Paabo S, Satta Y, Takahata N, Varki A | title = Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 99 | issue = 18 | pages = 11736–41 |date=September 2002 | pmid = 12192086 | pmc = 129338 | doi = 10.1073/pnas.182257399 }}</ref> and in fact, when higher expression of cytidine monophosphate-N-acetylneuraminic acid hydroxylase is forced in mouse brains, it proves lethal.<ref name="pmid7608218" /> Human brains are different from most primate brains in that they continue to grow for some time postnatally, unlike primate brains that stop growing soon after birth. It is therefore possible that even the small amounts of Neu5Gc present in most mammalian brains could be inhibiting their brain growth; losing the CMAH gene may have released the human brain from this constraint.<ref name="pmid12192086"/>
The functional loss of this gene after the divergence of humans from the great apes leads to several possible implications for its role in human development, the most notable of which being less constrained brain growth. In most mammals, CMAH expression is down-regulated in the brain<ref name="pmid12192086">{{cite journal | vauthors = Chou HH, Hayakawa T, Diaz S, Krings M, Indriati E, Leakey M, Paabo S, Satta Y, Takahata N, Varki A | title = Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 18 | pages = 11736–41 | date = September 2002 | pmid = 12192086 | pmc = 129338 | doi = 10.1073/pnas.182257399 }}</ref>.


The loss of CMAH has also played a role in human viral history. On one side, it has made humans more susceptible to some viruses by decreasing sialic acid diversity.<ref name="ajpa10018">{{cite journal | author =  Varki A | title = Loss of N-Glycolylneuraminic Acid in Humans: Mechanisms, Consequences, and Implications for Hominid Development | journal = Yearbook of Physical Anthropology | volume = 44 | issue =  | pages = 54–69 | year = 2001 | pmid =  | pmc =  | doi = 10.1073/10.1002/ajpa.10018 }}</ref> Viruses that bind to Neu5Ac before entering the cell will see their binding enhanced via the cluster glycoside effect,<ref name="cr000418f">{{cite journal | vauthors = Lundquist JL, Toone EJ | title = The cluster glycoside effect | journal = Chemical Reviews | volume = 102 | issue = 2 | pages = 555–578 |date=January 2002 | pmid =  11841254 | doi = 10.1021/cr000418f }}</ref> which wouldn't be seen as strongly if other sialic acids like Neu5Gc were also present. A potential example of this is the most serious form of [[malaria]] in humans, ''P. falciparum'',<ref name="s10719" /> which initially targets Neu5Ac on red blood cells for binding.<ref name="ajpa10018" /> Oppositely though, losing CMAH should protect humans against any virus that targets Neu5Gc, such as those that cause certain diarrheal diseases in livestock,<ref name="ajpa10018" /> ''E. coli'' K99, transmissible gastroenteritis coronavirus, and simian virus 40 (SV40).<ref name="s10719" /> Interestingly, another form of malaria, ''P. reichenowii'', may have been the original selecting agent against Neu5Gc. Thus only organisms negative for Neu5Gc would survive, with the outcome being humans who are completely resistant. Further support from this idea comes from the fact that ''P. falciparum'' malaria appears to have evolved in the last tens of thousands of years.<ref name="s10719" />
In fact, when higher expression of CMAH is forced in mouse brains, it proves lethal.<ref name="pmid7608218" /> Human brains are different from most primate brains in that they continue to grow for some time postnatally, unlike primate brains that stop growing soon after birth. It is therefore possible that even the small amounts of Neu5Gc present in most mammalian brains could be inhibiting their brain growth; losing the CMAH gene may have released the human brain from this constraint.<ref name="pmid12192086"/>


Even though humans do not have a functioning CMAH gene, Neu5Gc has been found present in normal human tissue, with larger amounts found in both fetal<ref name="ajpa10018" /> and cancerous <ref name="pmid9624188" /><ref name="ajpa10018" /> tissues. In fact, studies suggest that it could be an excellent cancer cell marker.<ref name="pmid9624188" /> Since Neu5Gc can only be made by functioning cytidine monophosphate-N-acetylneuraminic acid hydroxylase, another explanation of how it comes to be found in human tissue is needed. Current research indicates it is incorporated into human tissues through food sources, most notably from red meats (beef, pork, lamb) and to a lesser extent, dairy. This incorporation process involves macropinocytosis, delivery to the lysosome, and export of free Neu5Gc to the cytosol via the sialin transporter.<ref name="pnas0914634107">{{cite journal | author = Varki A | title = Uniquely human evolution of sialic acid genetics and biology | journal = Proceedings of the National Academy of Sciences | volume = 107 | issue = suppl. 2 | pages = 8939–8946 |date=May 2010 | pmid = 20445087| pmc = 3024026| doi = 10.1073/pnas.0914634107 }}</ref> Because Neu5Gc differs from Neu5Ac by only one oxygen, it is handled like a native sialic acid by human biochemical pathways.<ref name="pnas0914634107" /> The immune system does not work the same way, however; all humans have varying, though still significant, amounts of a diverse spectrum of anti-Neu5Gc antibodies, with the commonest being from the IgG class; these, in combination with constant incorporation of Neu5Gc into tissue, can be a source of chronic inflammation, especially in blood vessels and the linings of hollow organs. 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.<ref name="s10719" /> 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.<ref name="pnas0914634107" />
The loss of CMAH has also played a role in human viral history. On one side, it has made humans more susceptible to some viruses by decreasing sialic acid diversity.<ref name="ajpa10018">{{cite journal | vauthors =  Varki A | title = Loss of N-Glycolylneuraminic Acid in Humans: Mechanisms, Consequences, and Implications for Hominid Development | journal = Yearbook of Physical Anthropology | volume = 44 | issue =  | pages = 54–69 | year = 2001 | pmid =  | pmc =  | doi = 10.1073/10.1002/ajpa.10018 }}</ref> Viruses that bind to Neu5Ac before entering the cell will see their binding enhanced via the cluster glycoside effect,<ref name="cr000418f">{{cite journal | vauthors = Lundquist JJ, Toone EJ | title = The cluster glycoside effect | journal = Chemical Reviews | volume = 102 | issue = 2 | pages = 555–78 | date = February 2002 | pmid = 11841254 | doi = 10.1021/cr000418f }}</ref> which wouldn't be seen as strongly if other sialic acids like Neu5Gc were also present. A potential example of this is the most serious form of [[malaria]] in humans, ''P. falciparum'',<ref name="s10719" /> which initially targets Neu5Ac on red blood cells for binding.<ref name="ajpa10018" /> Oppositely though, losing CMAH should protect humans against any virus that targets Neu5Gc, such as those that cause certain diarrheal diseases in livestock,<ref name="ajpa10018" /> ''E. coli'' K99, transmissible gastroenteritis coronavirus, and simian virus 40 (SV40).<ref name="s10719" /> Another form of malaria, ''P. reichenowii'', may have been the original selecting agent against Neu5Gc. Thus only organisms negative for Neu5Gc would survive, with the outcome being humans who are completely resistant. Further support from this idea comes from the fact that ''P. falciparum'' malaria appears to have evolved in the last tens of thousands of years.<ref name="s10719" />
 
Even though humans do not have a functioning CMAH gene, Neu5Gc has been found present in normal human tissue, with larger amounts found in both fetal<ref name="ajpa10018" /> and cancerous <ref name="pmid9624188" /><ref name="ajpa10018" /> tissues. In fact, studies suggest that it could be an excellent cancer cell marker.<ref name="pmid9624188" /> Since Neu5Gc can only be made by functioning cytidine monophosphate-N-acetylneuraminic acid hydroxylase, another explanation of how it comes to be found in human tissue is needed. Current research indicates it is incorporated into human tissues through food sources, most notably from red meats (beef, pork, lamb) and to a lesser extent, dairy. This incorporation process involves macropinocytosis, delivery to the lysosome, and export of free Neu5Gc to the cytosol via the sialin transporter.<ref name="pnas0914634107">{{cite journal | vauthors = Varki A | title = Colloquium paper: uniquely human evolution of sialic acid genetics and biology | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 Suppl 2 | issue = suppl. 2 | pages = 8939–46 | date = May 2010 | pmid = 20445087 | pmc = 3024026 | doi = 10.1073/pnas.0914634107 }}</ref> Because Neu5Gc differs from Neu5Ac by only one oxygen, it is handled like a native sialic acid by human biochemical pathways.<ref name="pnas0914634107" /> The immune system does not work the same way, however; all humans have varying, though still significant, amounts of a diverse spectrum of anti-Neu5Gc antibodies, with the commonest being from the IgG class; these, in combination with constant incorporation of Neu5Gc into tissue, can be a source of chronic inflammation, especially in blood vessels and the linings of hollow organs. 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.<ref name="s10719" /> 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.<ref name="pnas0914634107" />


As for accounting for the larger amounts of Neu5Gc found in tumors, recent data suggests that the hypoxic conditions in carcinomas can up-regulate the expression of the lysosomal sialic acid transporter necessary for Neu5Gc incorporation.<ref name="s10719" /><ref name="pnas0914634107" /> In addition, growth factors may activate enhanced macropinocytosis, which can also augment Neu5Gc incorporation in tissues.<ref name="pnas0914634107" /> Studies have shown that fetal tissues are also capable of taking up Neu5Gc from maternal dietary sources, which may explain elevated levels there.<ref name="s10719" />
As for accounting for the larger amounts of Neu5Gc found in tumors, recent data suggests that the hypoxic conditions in carcinomas can up-regulate the expression of the lysosomal sialic acid transporter necessary for Neu5Gc incorporation.<ref name="s10719" /><ref name="pnas0914634107" /> In addition, growth factors may activate enhanced macropinocytosis, which can also augment Neu5Gc incorporation in tissues.<ref name="pnas0914634107" /> Studies have shown that fetal tissues are also capable of taking up Neu5Gc from maternal dietary sources, which may explain elevated levels there.<ref name="s10719" />
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The presence of Neu5Gc in various biotherapeutics derived from mammals or animal products may also be an issue, and indeed, short- and long-term effects of these are still being studied. Some complications could include immune hypersensitivity reactions, reduced half-life of the biotherapeutic in circulation, immune-complex formation, boosting of Neu5Gc antibody levels, enhancing immune reactivity against the underlying biotherapeutic polypeptide and directly loading more Neu5Gc into tissues.<ref name="s10719" />
The presence of Neu5Gc in various biotherapeutics derived from mammals or animal products may also be an issue, and indeed, short- and long-term effects of these are still being studied. Some complications could include immune hypersensitivity reactions, reduced half-life of the biotherapeutic in circulation, immune-complex formation, boosting of Neu5Gc antibody levels, enhancing immune reactivity against the underlying biotherapeutic polypeptide and directly loading more Neu5Gc into tissues.<ref name="s10719" />


==References==
Genomic analyses indicate that the gene ''CMAH is'' present only in deuterostomes, some unicellular algae and some bacteria. In addition to humans, the ''CMAH'' gene has been lost also in many other deuterostome lineages, including tunicates, many groups of fish, the axolotl, most reptiles, and all birds. Among mammals, the gene is missing or inactivated in New World monkeys, the European hedgehog, ferrets, some bats, the sperm whale, and the platypus <ref>{{cite journal | vauthors = Peri S, Kulkarni A, Feyertag F, Berninsone PM, Alvarez-Ponce D | title = Phylogenetic Distribution of CMP-Neu5Ac Hydroxylase (CMAH), the Enzyme Synthetizing the Proinflammatory Human Xenoantigen Neu5Gc | journal = Genome Biology and Evolution | volume = 10 | issue = 1 | pages = 207–219 | date = January 2018 | pmid = 29206915 | pmc = 5767959 | doi = 10.1093/gbe/evx251 }}</ref>. These animals lacking a functional ''CMAH'' gene are not expected to exhibit endogenous Neu5Gc.
 
== References ==
{{reflist}}
{{reflist}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
*{{cite journal | author=Varki A |title=N-glycolylneuraminic acid deficiency in humans |journal=Biochimie |volume=83 |issue= 7 |pages= 615–22 |year= 2002 |pmid= 11522390 |doi=10.1016/S0300-9084(01)01309-8 }}
* {{cite journal | vauthors = Varki A | title = N-glycolylneuraminic acid deficiency in humans | journal = Biochimie | volume = 83 | issue = 7 | pages = 615–22 | date = July 2001 | pmid = 11522390 | doi = 10.1016/S0300-9084(01)01309-8 }}
*{{cite journal |vauthors=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery |journal=Genome Res. |volume=6 |issue= 9 |pages= 791–806 |year= 1997 |pmid= 8889548 |doi=10.1101/gr.6.9.791 }}
* {{cite journal | vauthors = Bonaldo MF, Lennon G, Soares MB | title = Normalization and subtraction: two approaches to facilitate gene discovery | journal = Genome Research | volume = 6 | issue = 9 | pages = 791–806 | date = September 1996 | pmid = 8889548 | doi = 10.1101/gr.6.9.791 }}
*{{cite journal |vauthors=Irie A, Suzuki A |title=CMP-N-Acetylneuraminic acid hydroxylase is exclusively inactive in humans |journal=Biochem. Biophys. Res. Commun. |volume=248 |issue= 2 |pages= 330–3 |year= 1998 |pmid= 9675135 |doi= 10.1006/bbrc.1998.8946 }}
* {{cite journal | vauthors = Irie A, Suzuki A | title = CMP-N-Acetylneuraminic acid hydroxylase is exclusively inactive in humans | journal = Biochemical and Biophysical Research Communications | volume = 248 | issue = 2 | pages = 330–3 | date = July 1998 | pmid = 9675135 | doi = 10.1006/bbrc.1998.8946 }}
*{{cite journal | author=Chou HH |title=A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue= 20 |pages= 11751–6 |year= 1998 |pmid= 9751737 |doi=10.1073/pnas.95.20.11751 | pmc=21712  |name-list-format=vanc| author2=Takematsu H  | author3=Diaz S  | display-authors=3  | last4=Iber  | first4=J  | last5=Nickerson  | first5=E  | last6=Wright  | first6=KL  | last7=Muchmore  | first7=EA  | last8=Nelson  | first8=DL  | last9=Warren  | first9=ST  }}
* {{cite journal | vauthors = Chou HH, Takematsu H, Diaz S, Iber J, Nickerson E, Wright KL, Muchmore EA, Nelson DL, Warren ST, Varki A | title = A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 20 | pages = 11751–6 | date = September 1998 | pmid = 9751737 | pmc = 21712 | doi = 10.1073/pnas.95.20.11751 }}
*{{cite journal |vauthors=Muchmore EA, Diaz S, Varki A |title=A structural difference between the cell surfaces of humans and the great apes |journal=Am. J. Phys. Anthropol. |volume=107 |issue= 2 |pages= 187–98 |year= 1999 |pmid= 9786333 |doi= 10.1002/(SICI)1096-8644(199810)107:2<187::AID-AJPA5>3.0.CO;2-S }}
* {{cite journal | vauthors = Muchmore EA, Diaz S, Varki A | title = A structural difference between the cell surfaces of humans and the great apes | journal = American Journal of Physical Anthropology | volume = 107 | issue = 2 | pages = 187–98 | date = October 1998 | pmid = 9786333 | doi = 10.1002/(SICI)1096-8644(199810)107:2<187::AID-AJPA5>3.0.CO;2-S }}
*{{cite journal | author=Hayakawa T |title=Alu-mediated inactivation of the human CMP- N-acetylneuraminic acid hydroxylase gene |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=98 |issue= 20 |pages= 11399–404 |year= 2001 |pmid= 11562455 |doi= 10.1073/pnas.191268198 | pmc=58741  |name-list-format=vanc| author2=Satta Y  | author3=Gagneux P  | display-authors=3  | last4=Varki  | first4=A  | last5=Takahata  | first5=N }}
* {{cite journal | vauthors = Hayakawa T, Satta Y, Gagneux P, Varki A, Takahata N | title = Alu-mediated inactivation of the human CMP- N-acetylneuraminic acid hydroxylase gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 20 | pages = 11399–404 | date = September 2001 | pmid = 11562455 | pmc = 58741 | doi = 10.1073/pnas.191268198 }}
*{{cite journal | author=Chou HH |title=Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 18 |pages= 11736–41 |year= 2002 |pmid= 12192086 |doi= 10.1073/pnas.182257399  | pmc=129338 |name-list-format=vanc| author2=Hayakawa T  | author3=Diaz S  | display-authors=3  | last4=Krings  | first4=M  | last5=Indriati  | first5=E  | last6=Leakey  | first6=M  | last7=Paabo  | first7=S  | last8=Satta  | first8=Y  | last9=Takahata  | first9=N }}
* {{cite journal | vauthors = Chou HH, Hayakawa T, Diaz S, Krings M, Indriati E, Leakey M, Paabo S, Satta Y, Takahata N, Varki A | title = Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 18 | pages = 11736–41 | date = September 2002 | pmid = 12192086 | pmc = 129338 | doi = 10.1073/pnas.182257399 }}
*{{cite journal  | author=Strausberg RL |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899  | pmc=139241  |name-list-format=vanc| author2=Feingold EA  | author3=Grouse LH  | display-authors=3  | last4=Derge  | first4=JG  | last5=Klausner  | first5=RD  | last6=Collins  | first6=FS  | last7=Wagner  | first7=L  | last8=Shenmen  | first8=CM  | last9=Schuler  | first9=GD }}
* {{cite journal | vauthors = Bighignoli B, Niini T, Grahn RA, Pedersen NC, Millon LV, Polli M, Longeri M, Lyons LA | title = Cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) mutations associated with the domestic cat AB blood group | journal = BMC Genetics | volume = 8 | pages = 27 | date = June 2007 | pmid = 17553163 | doi = 10.1186/1471-2156-8-27 }}
*{{cite journal | author=Mungall AJ |title=The DNA sequence and analysis of human chromosome 6 |journal=Nature |volume=425 |issue= 6960 |pages= 805–11 |year= 2003 |pmid= 14574404 |doi= 10.1038/nature02055  |name-list-format=vanc| author2=Palmer SA  | author3=Sims SK  | display-authors=3  | last4=Edwards  | first4=C. A.  | last5=Ashurst  | first5=J. L.  | last6=Wilming  | first6=L.  | last7=Jones  | first7=M. C.  | last8=Horton  | first8=R.  | last9=Hunt  | first9=S. E. }}
*{{cite journal | author=Bighignoli B |title=Cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) mutations associated with the domestic cat AB blood group |journal=BMC Genetics |volume=8 |year=2008 |doi=10.1186/1471-2156-8-27 |name-list-format=vanc| author2=Niini T | display-authors=2 | last3=Grahn | first3=Robert A | last4=Pedersen | first4=Niels C | last5=Millon | first5=Lee V | last6=Polli | first6=Michele | last7=Longeri | first7=Maria | last8=Lyons | first8=Leslie A | pages=27 }}
{{refend}}
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Latest revision as of 19:41, 4 August 2018

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Putative cytidine monophosphate-N-acetylneuraminic acid hydroxylase-like protein is an enzyme that in humans is encoded by the CMAH gene.[1][2][3]

Function

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 similar. However, the homologous human cDNA differs from these cDNAs by a 92-bp deletion in the 5' region. This deletion, corresponding to exon 5 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] Causes of the selection against the CMAH gene could include a severe infectious disease that specifically binds to Neu5Gc, a change in binding preference of a sialic acid binding protein favoring the loss of Neu5Gc or accumulation of Neu5Ac, or protection from viruses originating in individuals with Neu5Gc due to anti-Neu5Gc antibodies in CMAH-negative individuals [5]

Effects of loss of functioning human CMAH

The functional loss of this gene after the divergence of humans from the great apes leads to several possible implications for its role in human development, the most notable of which being less constrained brain growth. In most mammals, CMAH expression is down-regulated in the brain[6].

In fact, when higher expression of CMAH is forced in mouse brains, it proves lethal.[1] Human brains are different from most primate brains in that they continue to grow for some time postnatally, unlike primate brains that stop growing soon after birth. It is therefore possible that even the small amounts of Neu5Gc present in most mammalian brains could be inhibiting their brain growth; losing the CMAH gene may have released the human brain from this constraint.[6]

The loss of CMAH has also played a role in human viral history. On one side, it has made humans more susceptible to some viruses by decreasing sialic acid diversity.[7] Viruses that bind to Neu5Ac before entering the cell will see their binding enhanced via the cluster glycoside effect,[8] which wouldn't be seen as strongly if other sialic acids like Neu5Gc were also present. A potential example of this is the most serious form of malaria in humans, P. falciparum,[5] which initially targets Neu5Ac on red blood cells for binding.[7] Oppositely though, losing CMAH should protect humans against any virus that targets Neu5Gc, such as those that cause certain diarrheal diseases in livestock,[7] E. coli K99, transmissible gastroenteritis coronavirus, and simian virus 40 (SV40).[5] Another form of malaria, P. reichenowii, may have been the original selecting agent against Neu5Gc. Thus only organisms negative for Neu5Gc would survive, with the outcome being humans who are completely resistant. Further support from this idea comes from the fact that P. falciparum malaria appears to have evolved in the last tens of thousands of years.[5]

Even though humans do not have a functioning CMAH gene, Neu5Gc has been found present in normal human tissue, with larger amounts found in both fetal[7] and cancerous [2][7] tissues. In fact, studies suggest that it could be an excellent cancer cell marker.[2] Since Neu5Gc can only be made by functioning cytidine monophosphate-N-acetylneuraminic acid hydroxylase, another explanation of how it comes to be found in human tissue is needed. Current research indicates it is incorporated into human tissues through food sources, most notably from red meats (beef, pork, lamb) and to a lesser extent, dairy. This incorporation process involves macropinocytosis, delivery to the lysosome, and export of free Neu5Gc to the cytosol via the sialin transporter.[9] Because Neu5Gc differs from Neu5Ac by only one oxygen, it is handled like a native sialic acid by human biochemical pathways.[9] The immune system does not work the same way, however; all humans have varying, though still significant, amounts of a diverse spectrum of anti-Neu5Gc antibodies, with the commonest being from the IgG class; these, in combination with constant incorporation of Neu5Gc into tissue, can be a source of chronic inflammation, especially in blood vessels and the linings of hollow organs. 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.[5] 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.[9]

As for accounting for the larger amounts of Neu5Gc found in tumors, recent data suggests that the hypoxic conditions in carcinomas can up-regulate the expression of the lysosomal sialic acid transporter necessary for Neu5Gc incorporation.[5][9] In addition, growth factors may activate enhanced macropinocytosis, which can also augment Neu5Gc incorporation in tissues.[9] Studies have shown that fetal tissues are also capable of taking up Neu5Gc from maternal dietary sources, which may explain elevated levels there.[5]

The presence of Neu5Gc in various biotherapeutics derived from mammals or animal products may also be an issue, and indeed, short- and long-term effects of these are still being studied. Some complications could include immune hypersensitivity reactions, reduced half-life of the biotherapeutic in circulation, immune-complex formation, boosting of Neu5Gc antibody levels, enhancing immune reactivity against the underlying biotherapeutic polypeptide and directly loading more Neu5Gc into tissues.[5]

Genomic analyses indicate that the gene CMAH is present only in deuterostomes, some unicellular algae and some bacteria. In addition to humans, the CMAH gene has been lost also in many other deuterostome lineages, including tunicates, many groups of fish, the axolotl, most reptiles, and all birds. Among mammals, the gene is missing or inactivated in New World monkeys, the European hedgehog, ferrets, some bats, the sperm whale, and the platypus [10]. These animals lacking a functional CMAH gene are not expected to exhibit endogenous Neu5Gc.

References

  1. ↑ 1.0 1.1 Kawano T, Koyama S, Takematsu H, Kozutsumi Y, Kawasaki H, Kawashima S, Kawasaki T, Suzuki A (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.
  2. ↑ 2.0 2.1 2.2 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.
  3. ↑ 3.0 3.1 3.2 "Entrez Gene: CMAH cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMP-N-acetylneuraminate monooxygenase)".
  4. ↑ Hayakawa T, Aki I, Varki A, Satta Y, Takahata N (February 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. PMC 1456212. PMID 16272417.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 Varki A (2009). "Multiple changes in sialic acid biology during human evolution". Glycoconjugate Journal. 26: 231–245. doi:10.1007/s10719-008-9813-z.
  6. ↑ 6.0 6.1 Chou HH, Hayakawa T, Diaz S, Krings M, Indriati E, Leakey M, Paabo S, Satta Y, Takahata N, Varki A (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. doi:10.1073/pnas.182257399. PMC 129338. PMID 12192086.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Varki A (2001). "Loss of N-Glycolylneuraminic Acid in Humans: Mechanisms, Consequences, and Implications for Hominid Development". Yearbook of Physical Anthropology. 44: 54–69. doi:10.1073/10.1002/ajpa.10018.
  8. ↑ Lundquist JJ, Toone EJ (February 2002). "The cluster glycoside effect". Chemical Reviews. 102 (2): 555–78. doi:10.1021/cr000418f. PMID 11841254.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 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. doi:10.1073/pnas.0914634107. PMC 3024026. PMID 20445087.
  10. ↑ 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.

Further reading

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