N-Glycolylneuraminic acid

N-Glycolylneuraminic acid
Names
	Other names GcNeu; NGNA; NeuNGl; Neu5Gc
Identifiers
CAS Number	1113-83-3 ;
3D model (JSmol)	Interactive image;
ChEBI	CHEBI:62084 ;
ChemSpider	110352 ;
PubChem CID	123802;
UNII	NB446XTC7L ;
	InChI InChI=1S/C11H19NO10/c13-2-5(16)8(18)9-7(12-6(17)3-14)4(15)1-11(21,22-9)10(19)20/h4-5,7-9,13-16,18,21H,1-3H2,(H,12,17)(H,19,20)/t4-,5+,7+,8+,9+,11-/m0/s1 Key: FDJKUWYYUZCUJX-AJKRCSPLSA-N ; InChI=1/C11H19NO10/c13-2-5(16)8(18)9-7(12-6(17)3-14)4(15)1-11(21,22-9)10(19)20/h4-5,7-9,13-16,18,21H,1-3H2,(H,12,17)(H,19,20)/t4-,5+,7+,8+,9+,11-/m0/s1 Key: FDJKUWYYUZCUJX-AJKRCSPLBU;
	SMILES C1[C@@H]([C@H]([C@@H](O[C@@]1(C(=O)O)O)[C@@H]([C@@H](CO)O)O)NC(=O)CO)O;
Properties
Chemical formula	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). verify (what is ?) Infobox references

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.^[1]^[2] The gene CMAH encodes CMP-N-acetylneuraminic acid hydroxylase, which is the enzyme responsible for CMP-Neu5Gc from CMP-N-acetylneuraminic (CMP-Neu5Ac) acid.^[3] This loss of CMAH is estimated to have occurred two to three million years ago, 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 by the CMAH enzyme in the cytosol of a cell. In many mammals, both of these molecules are transferred into the Golgi apparatus so that they may be added to many glycoconjugates. However, in humans, Neu5Gc is not present.^[4]^[5]

Elimination of the Neu5Gc gene in humans

With the loss of the Neu5Gc gene and the gain of excess Neu5Ac, interactions between pathogens and human ancestors would have been affected. There would have been less susceptibility to Neu5Gc-binding pathogens, and more susceptibility to Neu5Ac-binding pathogens. It is suggested that human ancestors lacking Neu5Gc production survived a then-prevailing malaria epidemic. However, with the rise of Plasmodium falciparum, the parasite that causes malaria today, humans were once again endangered, as this new strain of malaria had a binding preference to the Neu5Ac-rich erythrocytes in humans.^[4] The latest research shows that humans who lack Neu5Ac on their red blood cells are less likely to get malaria from the parasites that cause it.^{[citation needed]}

Occurrence

Neu5Gc is found in most mammals, with exceptions like humans, ferrets, the platypus, western dog breeds and New World monkeys.^[6] 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. 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.^[7]

In 2017, scientists succeeded in indirectly identifying the presence of Neu5Gc from multiple ancient animal fossils dated to over a million years ago, the oldest of which was dated to around 4 Mya.^[8]

Effects on humans

Even though Neu5Gc is not known to be produced by any mechanism in 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 reported to be found in concentration in human cancers, as well as in fecal samples, suggesting that humans ingest Neu5Gc as part of their diets. Uptake is thought to be by macropinocytosis, and the sialic acid can be transferred to the cytosol by a sialin transporter. Humans have Neu5Gc-specific antibodies, often at high levels.

Dietary absorption and excretion

Ingested Neu5Gc 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, with some of it converted to acylmannosamines by intestinal cells and bacteria, and then 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 days 1 to 4, with an increase also found in hair after ingestion.^[7] This table and this table (S3) show levels of Neu5Gc in common foods.

Cancer

Neu5Gc has been suggested as a mechanism linking processed meat and red meat consumption with colorectal cancer risk.^[9]^[10]^[11]^[12]

Mechanism of uptake

Sialic acids are negatively charged and hydrophilic, so they don't readily cross the hydrophobic regions of cellular membranes. 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.^[13]

References

^
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.
- "Difference Between Humans and Apes Linked to a Missing Oxygen Atom". UCSD Health Sciences (Press release). September 25, 1998.
^ 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. PMC 7159735. PMID 11786991.
^ 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. PMC 3077421. PMID 20657583.
^ ^a ^b ^c ^d 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.
^ Dankwa, Selasi (4 April 2016). "Ancient human sialic acid variant restricts an emerging zoonotic malaria parasite". Nature Communications. 7: 11187. Bibcode:2016NatCo...711187D. doi:10.1038/ncomms11187. PMC 4822025. PMID 27041489.
^ Ng, Preston S.K.; Böhm, Raphael; Hartley-Tassell, Lauren E.; Steen, Jason A.; Wang, Hui; Lukowski, Samuel W.; Hawthorne, Paula L.; Trezise, Ann E.O.; Coloe, Peter J.; Grimmond, Sean M.; Haselhorst, Thomas; von Itzstein, Mark; Paton, Adrienne W.; Paton, James C.; Jennings, Michael P. (2014). "Ferrets exclusively synthesize Neu5Ac and express naturally humanized influenza A virus receptors". Nature Communications. 5: 5750. Bibcode:2014NatCo...5.5750N. doi:10.1038/ncomms6750. PMC 4351649. PMID 25517696.
^ ^a ^b Tangvoranuntakul, P; Gagneux, P; Diaz, S; Bardor, M; Varki, N; Varki, A; Muchmore, E (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.
^ Bergfeld, Anne K.; Lawrence, Roger; Diaz, Sandra L.; Pearce, Oliver M. T.; Ghaderi, Darius; Gagneux, Pascal; Leakey, Meave G.; Varki, Ajit (2017). "N-glycolyl groups of nonhuman chondroitin sulfates survive in ancient fossils". Proceedings of the National Academy of Sciences of the United States of America. 114 (39): E8155–E8164. Bibcode:2017PNAS..114E8155B. doi:10.1073/pnas.1706306114. ISSN 0027-8424. PMC 5625913. PMID 28893995.
^ Alisson-Silva, F.; Kawanishi, K.; Varki, A. (2016). "Human risk of diseases associated with red meat intake: Analysis of current theories and proposed role for metabolic incorporation of a non-human sialic acid". Molecular Aspects of Medicine. 51: 16–30. doi:10.1016/j.mam.2016.07.002. PMC 5035214. PMID 27421909.
^ Demeyer, D.; Mertens, B.; De Smet, S.; Ulens, M. (2016). "Mechanisms Linking Colorectal Cancer to the Consumption of (Processed) Red Meat: A Review". Critical Reviews in Food Science and Nutrition. 56 (16): 2747–2766. doi:10.1080/10408398.2013.873886. hdl:1854/LU-8518004. PMID 25975275.
^ Wang, J.; Shewell, L.K.; Day, C.J.; Jennings, M.P. (2023). "N-glycolylneuraminic acid as a carbohydrate cancer biomarker". Translational Oncology. 31: 101643. doi:10.1016/j.tranon.2023.101643. hdl:10072/428860. PMID 36805917.
^ Liang, M.; Wu, J.; Li, H.; Zhu, Q. (2024). "N-glycolylneuraminic acid in red meat and processed meat is a health concern: A review on the formation, health risk, and reduction". Comprehensive Reviews in Food Science and Food Safety. 32 (2): e13314. doi:10.1111/1541-4337. PMID 38389429.
^ 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.