N-Glycolylneuraminic acid
| N-Glycolylneuraminic acid | |
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Other names
GcNeu; NGNA; NeuNGl; Neu5Gc |
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| Identifiers | |
| CAS number | 1113-83-3  |
| PubChem | 123802 |
| Properties | |
| Molecular formula | C11H19NO10 |
| Molar mass | 325.27 g/mol |
 (verify) (what is:  / ?)Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) |
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| 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 in the humans
With the loss of Neu5Gc 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 NHH 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. 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]
Effects on humans
Even though Neu5Gc cannot be produced by humans, it is still reported to be found in human cancers and fetal samples. This suggests that these Neu5Gc molecules must enter the human pathways through external sources, like through diets. As found in the observation of cultured human cells, the cells expressed Neu5Gc due to their uptake of animal products in the medium. By macropinocytosis, the sialic acid can be transferred to the cytosol by a sialin transporter. Due to the fact that Neu5Gc differs from the human Neu5Ac by only one oxygen atom, cells will uptake the molecule as if it were native to the cell. Although the biochemical pathways don’t recognize this molecule as foreign the immune system does, which can bring about many problems.Epidemiological studies have shown a correlation between red meat consumption and increased risks of many diseases. These diseases include carcinomas, atherosclerosis, and type-2 diabetes. Although not explicitly proven, it is suggested that it is the uptake of Neu5Gc from this diet that aggravates these diseases. Because of the anti-Neu5Gc antibodies that the human body carries, ingestion of Neu5Gc causes chronic inflammation.[4]
In recent findings, it has been discovered that all humans have Neu5Gc-specific antibodies, often at high levels.[3]
Mechanism of uptake
Sialic acids are negatively charged and hydrophillic, 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.[5]
References
- ^ Difference Between Humans and Apes Linked to a Missing Oxygen Atom
- ^ Varki, A (2001). "Loss of N-glycolylneuraminic acid in humans: Mechanisms, consequences, and implications for hominid evolution". American Journal of Physical Anthropology. Suppl 33: 54–69. doi:10.1002/ajpa.10018. PMID 11786991.
- ^ a b Ghaderi, Darius; Taylor, R. Padler-Karavani, V. (25). "Implications of the presence of N-glycolylneuraminic acid in recombinant therapeutic glycoproteins". Nature Biotechnology 28 (8): 863–867. Retrieved 11 November 2011.
- ^ a b c d e Varki, Ajit (11). "Uniquely human evolution of sialic acid genetics and biology". PNAS 107: 8939–8946. Retrieved 16 November 2011.
- ^ Bardor, Muriel; Nguyen,D. Diaz,S. Varki,A. (22). "Mechanism of Uptake and Incorporation of the Non-human Sialic Acid N-Glycolylneuraminic Acid into Human Cells". The Journal of Biological Chemistry 280 (6): 4228–4237. Retrieved 16 November 2011.
