N-Glycolylneuraminic acid

N-Glycolylneuraminic acid
Names
Other names
GcNeu; NGNA; NeuNGl; Neu5Gc
Identifiers
1113-83-3 YesY
ChEBI CHEBI:62084 N
ChemSpider 110352 N
Jmol interactive 3D Image
PubChem 123802
Properties
C11H19NO10
Molar mass 325.27 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

N-Glycolylneuraminic acid (Neu5Gc) is a sialic acid molecule found in most mammals. Humans cannot synthesize Neu5Gc because the human gene CMAH is irreversibly mutated, though it is found in apes.[1] It is absent in human tissues because of inactivation of gene encoding CMP-N-acetylneuraminic acid hydroxylase.[2] 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.[3] This loss of the CMAH was estimated to have occurred two to three millions of years ago, which occurred just before the emergence of the genus Homo.[4]

Neu5Gc is closely related to the commonly known N-acetylneuraminic acid (Neu5Ac). Neu5Ac differs by a single oxygen atom that is added in the cytosol of a cell. In many mammals, both of these molecules are transferred into the Golgi so that they may be added to many glycoconjugates. However, in humans, Neu5Gc is not present.[4]

Elimination of Neu5Gc gene in the humans

With the loss of Neu5Gc gene and gain of excess Neu5Ac, it should have affected the interactions of pathogens and humans. Humans should have been less susceptible to Neu5Gc-binding pathogens and more susceptible to Neu5Ac-binding pathogens. It is suggested that human ancestors survived a then-prevailing malaria by eliminating their Neu5Gc production. However, with the rise of Plasmodium falciparum, the parasite that causes malaria today, humans were once again endangered as this new strain of the malaria had a binding preference to the Neu5Ac-rich erythrocytes in humans.[4]

Occurrence

Neu5Gc can be found in mammals, but trace amounts can be found in humans, even though the gene to encode for production of Neu5Gc was eliminated long ago. These trace amounts come from consumption of animals in human diet. Mainly, the sources are red meats such as lamb, pork, and beef. It can also be found in dairy products, but to a lesser extent. Some 1.1% of the identified Neu5Ac is actually Neu5Gc in commercial whey protein.[5] Neu5Gc cannot be found in poultry and is found in only trace amounts in fish. This confirms that Neu5Gc is mainly found in foods of mammalian origin.[4] Lanolin in shampoo also contains Neu5Gc.[6]

Effects on humans

Even though Neu5Gc is not known by any mechanism to be produced by the human body (due to lack of genes), our bodies do interact with trillions of microorganisms that are capable of complex biological reactions. Neu5Gc is still reported to be found in concentration in human cancers, as well as found in fecal samples, suggesting a dietary source. Uptake is thought to be by macropinocytosis, and the sialic acid can be transferred to the cytosol by a sialin transporter. It is possible that the immune system then recognizes the molecule as foreign, binding of anti-Neu5Gc antibodies may cause chronic inflammation, however this assumption needs to be concretely proven. Epidemiological studies have shown a correlation between red meat consumption and increased risks of many diseases, including carcinomas, atherosclerosis, and type-2 diabetes. Although not explicitly proven that consumption of Neu5Gc is correlated with cancer in humans, it is suggested that it is the uptake of Neu5Gc from this diet that aggravates these diseases.[4] Further studies have shown humans have Neu5Gc-specific antibodies, often at high levels.[3] Additionally, Neu5Gc genetic knockout mice (to mimic human situation) have been fed Neu5Gc rich diets along with antibodies, and it has been found that this causes systemic inflammation and elevates risk fivefold of hepatocarcinomas.[7][8]

Dietary absorption and excretion

A baseline excretion of Neu5Gc exists, and it is incorporated into all body parts, some of which—mucins, hair, saliva, serum and blood, are commonly excreted. Neu5Gc is rapidly absorbed in the intestinal tract, some of which is converted to acylmannosamines by intestinal cells and bacteria, and reconverted back to Neu5Gc in the body. According to an absorption study, about 3–6% of the ingested dose of Neu5Gc was excreted within 4–6 hours, with the peak excretion rate at 2–3 h and a return to baseline levels within 24 h. In mucins, an increase was seen from day 1 to 4, with increased also found in hair after ingestion.[6] This table and this table(S3) shows levels of Neu5Gc in common foods.

Mechanism of uptake

Sialic acids are negatively charged and hydrophilic, so they don’t readily cross the lipid, hydrophobic membranes of cells. It is because of this that the uptake of Neu5Gc must occur through an endocytic pathway. More specifically, exogenous Neu5Gc molecules enter cells through clathrin-independent endocytic pathways with help from pinocytosis. After the Neu5Gc has entered the cell via pinocytosis, the molecule is released by lysosomal sialidase. The molecule is then transferred into the cytosol by the lysosomal sialic acid transporter. From here, Neu5Gc are available for activation and addition to glycoconjugates. Because Neu5Gc appears to be enhanced in naturally occurring tumors and fetal tumors, it is suggested that this uptake mechanism is enhanced by growth factors.[9]

See also

References

  1. ↑ Chou, Hsun-Hua; Takematsu, Hiromu; Diaz, Sandra; Iber, Jane; Nickerson, Elizabeth; Wright, Kerry L.; Muchmore, Elaine A.; Nelson, David L.; Warren, Stephen T.; Varki, Ajit (1998). "A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence". Proceedings of the National Academy of Sciences 95 (20): 11751–6. Bibcode:1998PNAS...9511751C. doi:10.1073/pnas.95.20.11751. JSTOR 49259. PMC 21712. PMID 9751737. Lay summary – UCSD Health Sciences (September 25, 1998).
  2. ↑ Varki, Ajit (2001). "Loss of N-glycolylneuraminic acid in humans: Mechanisms, consequences, and implications for hominid evolution". American Journal of Physical Anthropology 116 (Suppl 33): 54–69. doi:10.1002/ajpa.10018. PMID 11786991.
  3. 1 2 Ghaderi, Darius; Taylor, Rachel E; Padler-Karavani, Vered; Diaz, Sandra; Varki, Ajit (2010). "Implications of the presence of N-glycolylneuraminic acid in recombinant therapeutic glycoproteins". Nature Biotechnology 28 (8): 863–7. doi:10.1038/nbt.1651. PMID 20657583.
  4. 1 2 3 4 5 Varki, Ajit (2010). "Uniquely human evolution of sialic acid genetics and biology". Proceedings of the National Academy of Sciences 107 (Suppl 2): 8939–46. Bibcode:2010PNAS..107.8939V. doi:10.1073/pnas.0914634107. PMC 3024026. PMID 20445087.
  5. ↑ http://www.academia.edu/2658765/N-and_O-glycosylation_of_a_commercial_bovine_whey_protein_product
  6. 1 2 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC218710/
  7. ↑ Samraj, AN; Pearce, OM; Läubli, H; Crittenden, AN; Bergfeld, AK; Banda, K; Gregg, CJ; Bingman, AE; Secrest, P; Diaz, SL; Varki, NM; Varki, A (2015). "A red meat-derived glycan promotes inflammation and cancer progression". Proceedings of the National Academy of Sciences 112 (2): 542–7. doi:10.1073/pnas.1417508112. JSTOR 49259. PMC 4299224. PMID 25548184.
  8. ↑ http://health.ucsd.edu/news/releases/Pages/2014-12-29-sugar-molecule-in-red-meat-linked-to-cancer.aspx
  9. ↑ Bardor, Muriel; Nguyen, Dzung H.; Diaz, Sandra; Varki, Ajit (2004). "Mechanism of Uptake and Incorporation of the Non-human Sialic Acid N-Glycolylneuraminic Acid into Human Cells". Journal of Biological Chemistry 280 (6): 4228–37. doi:10.1074/jbc.m412040200. PMID 15557321.

Further reading

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