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N-Glycolylneuraminic acid

January 01, 1970

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]

N-Glycolylneuraminic acid
Names
Other names
GcNeu; NGNA; NeuNGl; Neu5Gc
Identifiers
  • 1113-83-3 Y
3D model (JSmol)
  • Interactive image
ChEBI
  • CHEBI:62084 N
ChemSpider
  • 110352 N
  • 123802
UNII
  • NB446XTC7L Y
  • 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 N
    Key: FDJKUWYYUZCUJX-AJKRCSPLSA-N 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
  • 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
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 YN ?)

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 edit

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 edit

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 edit

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 edit

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 edit

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 edit

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]

See also edit

References edit

  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.
    • "Difference Between Humans and Apes Linked to a Missing Oxygen Atom". UCSD Health Sciences (Press release). 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. PMC 7159735. PMID 11786991.
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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 edit

  • Samraj, Annie N.; Pearce, Oliver M. T.; Läubli, Heinz; Crittenden, Alyssa N.; Bergfeld, Anne K.; Banda, Kalyan; Gregg, Christopher J.; Bingman, Andrea E.; Secrest, Patrick; Diaz, Sandra L.; Varki, Nissi M.; Varki, Ajit (2014). "A red meat-derived glycan promotes inflammation and cancer progression". Proceedings of the National Academy of Sciences. 112 (2): 542–547. Bibcode:2015PNAS..112..542S. doi:10.1073/pnas.1417508112. PMC 4299224. PMID 25548184.

January 01, 1970
glycolylneuraminic, acid, neu5gc, sialic, acid, molecule, found, most, human, mammals, humans, cannot, synthesize, neu5gc, because, human, gene, cmah, irreversibly, mutated, though, found, other, apes, gene, cmah, encodes, acetylneuraminic, acid, hydroxylase, . 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 N Glycolylneuraminic acid Names Other names GcNeu NGNA NeuNGl Neu5Gc Identifiers CAS Number 1113 83 3 Y 3D model JSmol Interactive image ChEBI CHEBI 62084 N ChemSpider 110352 N PubChem CID 123802 UNII NB446XTC7L Y 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 NKey FDJKUWYYUZCUJX AJKRCSPLSA N NInChI 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 s1Key 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 N verify what is Y N Infobox references 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 Contents 1 Elimination of the Neu5Gc gene in humans 2 Occurrence 3 Effects on humans 3 1 Dietary absorption and excretion 3 2 Cancer 4 Mechanism of uptake 5 See also 6 References 7 Further readingElimination of the Neu5Gc gene in humans editWith 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 editNeu5Gc 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 editEven 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 edit 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 edit 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 editSialic 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 See also editN Acetylneuraminic acid Neuraminic acid Sialic acidReferences edit 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 Bohm 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 Further reading editSamraj Annie N Pearce Oliver M T Laubli Heinz Crittenden Alyssa N Bergfeld Anne K Banda Kalyan Gregg Christopher J Bingman Andrea E Secrest Patrick Diaz Sandra L Varki Nissi M Varki Ajit 2014 A red meat derived glycan promotes inflammation and cancer progression Proceedings of the National Academy of Sciences 112 2 542 547 Bibcode 2015PNAS 112 542S doi 10 1073 pnas 1417508112 PMC 4299224 PMID 25548184 Retrieved from https en wikipedia org w index php title N Glycolylneuraminic acid amp oldid 1223169657, wikipedia, wiki, book, books, library,

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