The biosynthesis pathway of Neu5Gc from Neu5Ac was discovered by Shaw and Schauer in 1988,[14] while the protein and DNA sequences for Neu5Gc, Neu5Ac, and CMAHP were described by Irie et al. in 1998.[6]
Evolution
Genomic analyses indicate that CMAH genes are present only in deuterostomes, some unicellular algae and some bacteria.[15]CMAH relatives have been lost in many other deuterostome lineages, including tunicates, many groups of fish, the axolotl, 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 functional CMAH gene do not express Neu5Gc.[15]
The absence of Neu5Gc in humans is due to a 92-bp deletion of an exon of the human gene CMAH[6]. Sequences encoding mouse, pig, and chimpanzee CMAH have been examined using cDNA cloning techniques and were found to be highly similar.[15] However, the homologous human 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 a frameshift mutation and premature termination of the polypeptide chain in humans.[6] Neu5Gc seems to be undetectable in human tissues because the truncated version of human hydroxylase mRNA cannot encode for an active enzyme.[14]
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.[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 selection may have contributed to the fixation of nonfunctional CMAH in humans.[16] 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.[16]
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.[17]
Function in humans
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 functional CMAH, 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 involves macropinocytosis, delivery to the lysosome, and export of free Neu5Gc to the cytosol via the sialin transporter.[19][13]
Because Neu5Gc differs from Neu5Ac by only one oxygen, it is handled like a native sialic acid by human biochemical 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 for atherosclerosis and epithelial 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-dependent macular degeneration, so Neu5Gc may be linked to the development of these disorders as well.[12][13]
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.[20][13] In addition, growth factors may 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 various biotherapeutics derived from animal products may impact human health and is still being studied.[12] 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.[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.[10][22] In most mammals, CMAHexpression is down-regulated in the brain, and experimental up-regulation of CMAH is lethal in mice.[10] 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.[22]
Implications for pathogenicity
The loss of Neu5Gc in humans may have contributed to resistance to generalist pathogens and increased pathogenicity of human-specific pathogens.[23] Human-specific cholera, which employs host sialic acids to trigger a gastrointestinal response, preferentially uses Neu5Ac and is inhibited by Neu5Gc.[23]
Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone. The term "sialic acid" was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this group is N-acetylneuraminic acid found in animals and some prokaryotes.
Exo-α-sialidase is a glycoside hydrolase that cleaves the glycosidic linkages of neuraminic acids:
N-Acetylneuraminic acid is the predominant sialic acid found in human cells, and many mammalian cells. Other forms, such as N-Glycolylneuraminic acid, may also occur in cells.
N-Acetylmannosamine is a hexosamine monosaccharide. It is a neutral, stable naturally occurring compound. N-Acetylmannosamine is also known as N-Acetyl-D-mannosamine monohydrate,, N-Acetyl-D-mannosamine which can be abbreviated to ManNAc or, less commonly, NAM). ManNAc is the first committed biological precursor of N-acetylneuraminic acid. Sialic acids are the negatively charged, terminal monosaccharides of carbohydrate chains that are attached to glycoproteins and glycolipids (glycans).
Siglecs(Sialic acid-binding immunoglobulin-type lectins) are cell surface proteins that bind sialic acid. They are found primarily on the surface of immune cells and are a subset of the I-type lectins. There are 14 different mammalian Siglecs, providing an array of different functions based on cell surface receptor-ligand interactions.
In enzymology, a CMP-N-acetylneuraminate monooxygenase (EC 1.14.18.2) is an enzyme that catalyzes the chemical reaction
In enzymology, a N-acylneuraminate cytidylyltransferase is an enzyme that catalyzes the chemical reaction
Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase is an enzyme that in humans is encoded by the ST8SIA1 gene.
Sialic acid-binding Ig-like lectin 12, or Siglec-XII, is a protein that in humans, is encoded by the SIGLEC12 gene.
CMP-N-acetylneuraminate-poly-alpha-2,8-sialyltransferase is an enzyme that in humans is encoded by the ST8SIA4 gene.
CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase is an enzyme that in humans is encoded by the ST3GAL4 gene.
Sialic acid-binding Ig-like lectin 5 is a protein that in humans is encoded by the SIGLEC5 gene. SIGLEC5 has also been designated CD170.
CMP-sialic acid transporter is a protein that in humans is encoded by the SLC35A1 gene.
N-acylneuraminate cytidylyltransferase is an enzyme that in humans is encoded by the CMAS gene.
Sialic acid-binding Ig-like lectin 9 is a protein that in humans is encoded by the SIGLEC9 gene.
Sialic acid synthase is an enzyme that in humans is encoded by the NANS gene.
Ajit Varki is a physician-scientist who is distinguished professor of medicine and cellular and molecular medicine, co-director of the Glycobiology Research and Training Center at the University of California, San Diego (UCSD), and co-director of the UCSD/Salk Center for Academic Research and Training in Anthropogeny (CARTA). He is also executive editor of the textbook Essentials of Glycobiology and distinguished visiting professor at the Indian Institute of Technology in Madras and the National Center for Biological Sciences in Bangalore. He is a specialist advisor to the Human Gene Nomenclature Committee.
N-Glycolylneuraminic acid (Neu5Gc) is a sialic acid molecule found in most non-human mammals. Humans cannot synthesize Neu5Gc because the human gene CMAH is irreversibly mutated, though it is found in other apes. It is absent in human tissues because of inactivation of gene encoding CMP-N-acetylneuraminic acid hydroxylase. The gene CMAH encodes for CMP-N-acetylneuraminic acid hydroxylase, which is the enzyme responsible for CMP-Neu5Gc from CMP-N-acetylneuraminic (CMP-Neu5Ac) acid. This loss of CMAH is estimated to have occurred 2-3 million years ago, just before the emergence of the genus Homo.
Racotumomab is a therapeutic cancer vaccine for the treatment of solid tumors that is currently under clinical development by Recombio, an international public-private consortium with the participation of the Center of Molecular Immunology at Havana, Cuba (CIM) and researchers from Buenos Aires University and National University of Quilmes in Argentina. It induces the patient's immune system to generate a response against a cancer-specific molecular target with the purpose of blocking tumor growth, slowing disease progression and ultimately increasing patient survival.
hCONDELs refer to regions of deletions within the human genome containing sequences that are highly conserved among closely related relatives. Almost all of these deletions fall within regions that perform non-coding functions. These represent a new class of regulatory sequences and may have played an important role in the development of specific traits and behavior that distinguish closely related organisms from each other.
1 2 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. PMID3202954.
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.
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