Sialic acids (SA) are derivatives of neuraminic acid; they are located at the terminal position in the chains of monosaccharide residues of various glycoconjugates. SA play a dual role, they either mask recognition sites, or, on the contrary, represent biological targets that can be recognized by receptor proteins and serve as ligands. The desialylation/sialylation processes can be viewed as a dynamic modification regulated by sialyltransferases and sialidases in response to external or internal stimuli. This review describes the structural and functional diversity and the potential use of SA fractions as biomarkers for various pathological conditions. Almost any extreme effects on the body and inflammatory processes lead to an increase in the level of both total and free SA in the blood and tissues. Possible reasons for the increase of sialoglycoconjugate metabolism indicators in biological material include activation of the hepatocyte synthesis and secretion of various acute-phase proteins, many of which are sialoglycoproteins, violation of the membrane integrity and destruction of body cells, and also high activity of sialidases (neurominidases) and sialyltransferases. Most acute and chronic liver diseases are characterized by the decrease in the total level of SA in the blood serum (because many plasma proteins are synthesized and glycosylated in hepatocytes). Aberrant sialylation results in changes of sialoglycoconjugate structure, its ability to perform biological functions and half-life. Glycosylation is the most common post-translational modification of proteins in the virus, which not only promotes the formation of specific conformation of viral proteins, but also modulates their interaction with receptors and affects host cell recognition, viral replication and infectivity. Serum total SA concentration increases in some benign and inflammatory conditions, which indicates a lack of specificity and limits their use for early detection and screening of neoplastic diseases. Nevertheless, determining blood SA level and measuring concentration of existing biomarkers can be used to improve diagnostic indicators, to stage and monitor therapeutic response in some types of cancer, when the need for specificity is less than for diagnosis. Clinical and diagnostic value of determining the sialoglycoconjugate metabolic indicators, including changes in the content of both SA fractions and specific proteins in various biological fluids and tissues, lies in establishing the causes and mechanisms of biochemical changes in the body in certain diseases.
Volkhina I.V., Butolin E.G. (2022) Clinical and diagnostic significance of sialic acids determination in biological material. Biomeditsinskaya Khimiya, 68(1), 7-17.
Volkhina I.V. et al. Clinical and diagnostic significance of sialic acids determination in biological material // Biomeditsinskaya Khimiya. - 2022. - V. 68. -N 1. - P. 7-17.
Volkhina I.V. et al., "Clinical and diagnostic significance of sialic acids determination in biological material." Biomeditsinskaya Khimiya 68.1 (2022): 7-17.
Volkhina, I. V., Butolin, E. G. (2022). Clinical and diagnostic significance of sialic acids determination in biological material. Biomeditsinskaya Khimiya, 68(1), 7-17.
Blix G., Svennerholm L., Werner I., Finsnes E., Sörensen J.S., Sörensen N.A. (1952) The isolation of chondrosamine from gangliosides and from submaxillary mucin. Acta Chem. Scand., 6, 358-362. CrossRef Scholar google search
Schauer R., Kamerling J.P. (2018) Exploration of the sialic acid world. Adv. Carbohydr. Chem. Biochem., 75, 1-213. CrossRef Scholar google search
Chen K., Veng Yu., Ma Zh., Li N., Han V., Zheng K., Cej Yu., Cheng D. (2015) Asp141 and hydrogenbond chain Asp141-Asn109-Asp33 are respectively essential for GT80 syalyltransferase activity and structural stability. Biohimiya, 80(8), 1289-1297. CrossRef Scholar google search
Noel M., Gilormini P.A., Cogez V., Yamakawa N., Vicogne D., Lion C., Biot C., Guérardel Y., Harduin-Lepers A. (2017) Probing the CMP-sialic acid donor specificity of two human β-d-galactoside sialyltransferases (ST3Gal I and ST6Gal I) selectively acting on O- and N-glycosylproteins. Chembiochem., 18(13), 1251-1259. CrossRef Scholar google search
Schauer R. (2004) Victor Ginsburg's influence on my research of the role of sialic acids in biological recognition. Arch. Biochem. Biophys., 426(2), 132-141. CrossRef Scholar google search
Liu R., Sreenivasan C., Yu H., Sheng Z., Newkirk S., An W., Smith D., Chen X., Wang D., Li F. (2020) Influenza D virus diverges from its related influenza C virus in the recognition of 9-O-acetylated N-acetyl- or N-glycolyl-neuraminic acidcontaining glycan receptors. Virology, 545, 16-23. CrossRef Scholar google search
Heise T., Pijnenborg J.F.A., Bull C., Hilten N., Kers-Rebel E.D., Balneger N., Elferink H., Adema G.J., Boltje T.J. (2019) Potent metabolic sialylation inhibitors based on C-5-modified fluorinated sialic acids. J. Med. Chem., 62(2), 1014-1021. CrossRef Scholar google search
Bork K., Horstkorte R., Weidemann W. (2009) Increasing the sialylation of therapeutic glycoproteins: the potential of the sialic acid biosynthetic pathway. J. Pharm. Sci., 98(10), 3499-3508. CrossRef Scholar google search
Kundra R., Kornfeld S. (1999) Asparagine-linked oligosaccharides protect Lamp-1 and Lamp-2 from intracellular proteolysis. J. Biol. Chem., 274(43), 31039-31046. CrossRef Scholar google search
Chen X., Liu X., Xiao Z., Liu J., Zhao L., Tan W.-S., Fan L. (2019) Insights into the loss of protein sialylation in an fc-fusion protein-producing CHO cell bioprocess. Appl. Microbiol. Biotechnol., 103(12), 4753-4765. CrossRef Scholar google search
Hoffmeister K.M. (2011) The role of lectins and glycans in platelet clearance. J. Thromb. Haemost., 9, 35-43. CrossRef Scholar google search
Grewal P.K., Uchiyama S., Ditto D., Varki N., Le D.T., Nizet V., Marth J.D. (2008) The Ashwell receptor mitigates the lethal coagulopathy of sepsis. Nat. Med., 14(6), 648-655. CrossRef Scholar google search
Rumjantseva V., Grewal P.K., Wandall H.H., Josefsson E.C., Sorensen A.-L., Larson G., Marth J.D., Hartwig J.H., Hoffmeister K.M. (2009) Dual roles for hepatic lectin receptors in the clearance of chilled platelets. Nat. Med., 15(11), 1273-1280. CrossRef Scholar google search
Daly J., Carlsten M., O'Dwyer M. (2019) Sugar free: novel immunotherapeutic approaches targeting siglecs and sialic acids to enhance natural killer cell cytotoxicity against cancer. Front Immunol., 10, 1047. CrossRef Scholar google search
Fougerat A., Pan X., Smutova V., Heveker N., Cairo C.W., Issad T., Larrivée B., Medin J.A., Pshezhetsky A.V. (2018) Neuraminidase 1 activates insulin receptor and reverses insulin resistance in obese mice. Mol. Metab., 12, 76-88. CrossRef Scholar google search
Hwang J.B., Hernandez J., Leduc R., Frost S.C. (2000) Alternative glycosylation of the insulin receptor prevents oligomerization and acquisition of insulin-dependent tyrosine kinase activity. Biochim. Biophys. Acta, 1499(1-2), 74-84. CrossRef Scholar google search
Pshezheckij A.V., Ashmarina L.I. (2013) Desialylation of surface receptors as a new dimension in cell signaling. Biohimiya, 78(7), 949-961. CrossRef Scholar google search
Gu T.J., Gu X.B., Ariga T., Yu R.K. (1990) Purification and characterization of CMP-NeuAc:GM1 (Gal beta 1-4GalNAc) alpha 2-3 sialyltransferase from rat brain. FEBS Lett., 275(1-2), 83-96. CrossRef Scholar google search
Glanz V.Y., Myasoedova V.A., Grechko A.V., Orekhov A.N. (2019) Sialidase activity in human pathologies. Eur. J. Pharmacol., 842, 345-350. CrossRef Scholar google search
Shakireyanova R.M. (1962) On differential diagnosis of chronic tonsillogenic intoxication from relapsed rheumatism by serum sialic acid levels. Kazanskij Med. Zh., 5, 40-41. Scholar google search
Afanas'ev E.N. (1963) Determination of sialic acid and diphenylamine reaction in the serum of children with rheumatism and chronic tonsillitis. Pediatriya, 42, 24-28. Scholar google search
Fedrova M.K. (1964) Comparative studies of proteinogram, glucidogram and sialic acid in clinical rheumatism and rheumatoid arthritis. Klinicheskaya Khimiya, 10, 986-990. CrossRef Scholar google search
Sharaev P.N., Ryabov V.I., Gumyarova G.H., Vol'hina I.V. (1993) Determination of free and bound forms of sialic acids in biological objects. Klinicheskaya Laboratornaya Diagnostika, 4, 44-46. Scholar google search
Bhagava N.V. (2002) Heteropolysaccharides: glycoproteins and glycolipids. Medical Biochemistry, 4, 153-171. CrossRef Scholar google search
Volkhina I.V., Butolin E.G. (2020) Influence of lipoic acid on the exchange of sialic acids in small intestine of rats with alloxan diabetes. Pediatr. SPb, 11(1), 37-42. CrossRef Scholar google search
Strelkov N.S., Sharaev P.N., Volkhina I.V. (1997) On the exchange of sialose compounds in the development of chronic osteomyelitis. Byulleten' Eksperimental'noj Biologii i Mediciny, 123(6), 607-608. CrossRef Scholar google search
Volkhina I.V., Naumova N.G. (2012) The comparative analysis of changes of indicators of the exchange of biopolymers of the connective tissue in the stomach wall at immobilization at rats with different reaction to stress. Vestnik UdGU, 1, 55-58. Scholar google search
Maslak A.S., Kostyuk O.V., Mashejko I.V., Brazaluk A.Z. (2013) Contents of α1-acid glycoprotein and sialic acids in biological fluids in patients with chronic myeloproliferative diseases. Zhurnal Grodnenskogo Gosudarstvennogo Medicinskogo Universiteta, 1, 39-41. Scholar google search
Naryzhnyj S.N., Legina O.K. (2021) Gaptoglobin as biomarker. Biomeditsinskaya Khimiya, 67(2), 105-118. CrossRef Scholar google search
Appenheimer M.M., Huang R.-Y., Chandrasekaran E.V., Dalziel M., Hu Y.P., Soloway P.D., Wuensch S.A., Matta K.L., Lau J.T.Y. (2003) Biologic contribution of P1 promotermediated expression of ST6Gal I sialyltransferase. Glycobiology, 13(8), 591-600. CrossRef Scholar google search
Yasukawa Z., Sato C., Kitajima K. (2005) Inflammationdependent changes in α2,3-, α2,6-, and α2,8-sialic acid glycotopes on serum glycoproteins in mice. Glycobiology, 15(9), 827-837. CrossRef Scholar google search
Gunnarsson P., Levander L., Pahlsson P., Grenegard M. (2007) The acute-phase protein 1-acid glycoprotein (AGP) induces rises in cytosolic Ca2+ in neutrophil granulocytes via sialic acid binding immunoglobulin-like lectins (Siglecs). FASEB J., 21(14), 4059-4069. CrossRef Scholar google search
Süer G.S., Kazezoğlu C., Sunar B., Özçelik F., Güngör Ö., Yorulmaz F., Gülen Ş. (2006) Relationship between serum sialic acids, sialic acid-rich inflammation-sensitive proteins and cell damage in patients with acute myocardial infarction. Clinical Chemistry and Laboratory Medicine (CCLM), 44(2), 199-206. CrossRef Scholar google search
Zhang Z., Wuhrer M., Holst S. (2018) Serum sialylation changes in cancer. Glycoconj. J., 35(2), 139-160. CrossRef Scholar google search
Schauer R. (1985) Sialic acids and their role as biological masks. Trends. Biochem. Sci., 10(9), 357-360. CrossRef Scholar google search
Nicol B.M., Prasad S.B. (2002) Sialic acid changes in Dalton's lymphoma-bearing mice after cyclophosphamide and cisplatin treatment. Braz. J. Med. Biol. Res., 35(5), 549-553. CrossRef Scholar google search
Dao T.L., Ip C., Patel J. (1980) Serum sialyltransferase and 5′-nucleotidase as reliable biomarkers in women with breast cancer. J. Nat. Cancer Inst., 65(3), 529-534. Scholar google search
Glavey S.V., Manier S., Natoni A., Sacco A., Moschetta M., Reagan M.R., Murillo L.S., Sahin I., Wu P., Mishima Y., Zhang Y., Zhang W., Zhang Y., Morgan G., Joshi I., Roccaro A.M., Ghobrial I.M., Dwyer M. (2014) The sialyltransferase ST3GAL6 influences homing and survival in multiple myeloma. Blood, 124, 1765-1776. CrossRef Scholar google search
Miyagi T. (2008) Aberrant expression of sialidase and cancer progression. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci., 84, 407-418. CrossRef Scholar google search
Zazdravnaya A.V. (2016) Cancer markers and their clinical significance. Zdravoohranenie Yugry: Opyt i Innovacii, 2, 26-32. Scholar google search
Gao L., Linden L., Parsons N.J., Cole J.A., Smith H. (2000) Uptake of metabolites by gonococci grown with lactate in a medium containing glucose: evidence for a surface location of the sialyltransferase. Microb. Pathog., 28(5), 257-266. CrossRef Scholar google search
Vimr E., Lichtensteiger C. (2002) To sialylate, or not to sialylate: that is the question. Trends. Microbiol., 10(6), 254-257. CrossRef Scholar google search
Gong Y., Qin S., Dai L., Tian Z. (2021) The glycosylation in SARS-CoV-2 and its receptor ACE2. Signal Transduct. Target. Ther., 6(1), 396. CrossRef Scholar google search
Teppa R.E., Petit D., Plechakova O., Cogez V., Harduin-Lepers A. (2016) Phylogenetic-derived insights into the evolution of sialylation in eukaryotes: comprehensive analysis of vertebrate β-galactoside α2,3/6-sialyltransferases (ST3Gal and ST6Gal). Int. J. Mol. Sci., 17(8), 1286. CrossRef Scholar google search
Yao H., Song Y., Chen Y., Wu N., Xu J., Sun C., Zhang J., Weng T., Zhang Z., Wu Z. (2020) Molecular architecture of the SARS-CoV-2 virus. Cell, 183(3), 730-738. CrossRef Scholar google search
Casalino L., Gaieb Z., Goldsmith J.A., Hjorth C.K., Dommer A.C., Harbison A.M., Fogarty C.A., Barros E.P., Taylor B.C., McLellan J.S. (2020) Beyond shielding: the roles of glycans in the SARS-CoV-2 spike protein. ACS Cent. Sci., 6, 1722-1734. CrossRef Scholar google search
Wang O., Wang Y., Yang S., Lin C., Aliyu L., Chen Y., Parsons L., Tian Y., Jia H., Pekosz A., Betenbaugh M.J., Cipollo J.F. (2021) A linkage-specific sialic acid labeling strategy reveals different site-specific glycosylation patterns in SARS-CoV-2 spike protein produced in CHO and HEK cell substrates. Front. Chem., 9, 735558. CrossRef Scholar google search
Lan J., Ge J., Yu J., Shan S., Zhou H., Fan S., Zhang Q., Shi X., Wang Q., Zhang L., Wang X. (2020) Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature, 581(7807), 215-220. CrossRef Scholar google search
Shajahan A., Archer-Hartmann S., Supekar N.T., Gleinich A.S., Heiss C., Azadi P. (2021) Comprehensive characterization of N- and O- glycosylation of SARS-CoV-2 human receptor angiotensin converting enzyme 2. Glycobiology, 31(4), 410-424. CrossRef Scholar google search
Sun X.-L. (2021) The role of cell surface sialic acids for SARS-CoV-2 infection. Glycobiology, 31(10), 1245-1253. CrossRef Scholar google search
Muller E., Schroder C., Schauer R., Sharon N. (1983) Binding and phagocytosis of sialidase-treated rat erythrocytes by a mechanism independent of opsonins. Hoppe Seylers Z. Physiol. Chem., 364(10), 1419-1429. CrossRef Scholar google search
Gruszewska E., Cylwik B., Gudowska M., Panasiuk A., Flisiak R., Chrostek L. (2019) The concentration of total sialic acid in chronic hepatitis B and C. Ann. Clin. Biochem., 56(1), 118-122. CrossRef Scholar google search
Gruszewska E., Cylwik B., Panasiuk A., Szmitkowski M., Flisiak R., Chrostek L. (2014) Total and free serum sialic acid concentration in liver diseases. Biomed. Res. Int., 2014, 876096. CrossRef Scholar google search
Dotz V., Wuhrer M. (2019) N-glycome signatures in human plasma: associations with physiology and major diseases. FEBS Lett., 593(21), 2966-2976. CrossRef Scholar google search
Romppanen J., Punnonen K., Anttila P., Jakobsson T., Blake J., Niemelä O. (2002) Serum sialic acid as a marker of alcohol consumption: effect of liver disease and heavy drinking. Alcohol. Clin. Exp. Res., 26, 1234-1238. CrossRef Scholar google search
Ivanov D.O., Novikova V.P., Pohlebkina A.A. (2018) Congenital disorders of glycosylation. Pediatr, 9(3), 5-15. CrossRef Scholar google search
Chang I.J., He M., Lam C.T. (2018) Congenital disorders of glycosylation. Ann. Transl. Med., 6(24), 477. CrossRef Scholar google search
Chrostek L., Cylwik B., Szmitkowski M., Korcz W. (2006) The diagnostic accuracy of carbohydrate-deficient transferrin, sialic acid and commonly used markers of alcohol abuse during abstinence. Clin. Chim. Acta, 364(1-2), 167-171. CrossRef Scholar google search
Horynova M.S., Vrablikova A., Stewart T.J., Takahashi K., Czernekova L., Yamada K., Suzuki H., Julian B.A., Renfrow M.B., Novak J., Raska M. (2015) N-acetylgalactosaminide α2,6-sialyltransferase II is a candidate enzyme for sialylation of galactose-deficient IgA1, the key autoantigen in IgA nephropathy. Nephrol. Dial. Transplan., 30(2), 234-238. CrossRef Scholar google search
Knoppova B., Reily C., King R.G., Julian B.A., Novak J., Todd J., Green T.J. (2021) Pathogenesis of IgA nephropathy: current understanding and implications for development of disease-specific treatment. J. Clin. Med., 10(19), 4501. CrossRef Scholar google search
Mehta A.S., Long R.E., Comunale M.A., Wang M., Rodemich L., Krakover J., Philip R., Marrero J.A., Dwek R.A., Block T.M. (2008) Increased levels of galactose-deficient anti-Gal immunoglobulin G in the sera of hepatitis C virus-infected individuals with fibrosis and cirrhosis. J. Virol., 82(3), 1259-1270. CrossRef Scholar google search
Markina Yu.V., Markin A.M., Sobenin I.A., Orekhov A.N. (2020) Prospects for the use of sialylated immunoglobulins in the treatment of different diseases. Fund. Clin. Med., 5(2), 112-118. CrossRef Scholar google search
Khan A., Sergi C. (2018) Sialidosis: a review of morphology and molecular biology of a rare pediatric disorder. Diagnostics (Basel), 8(2), 29. CrossRef Scholar google search
Ahn J.H., Kim A.R., Lee C., Kim N.K.D., Kim N.-S., Park W.-Y., Kim M., Youn J., Cho J.W., Kim J.S. (2019) Type 1 sialidosis patient with a novel deletion mutation in the NEU1 gene: case report and literature review. Cerebellum, 18(3), 659-664. CrossRef Scholar google search
Leroy J.C., Seppala R., Huizing M., Dacremont G., de Simpel H., van Coster R.N., Orvisky E., Krasnewich D.M., Gahl W.A. (2001) Dominant inheritance of sialuria, an inborn error of feedback inhibition. Am. J. Hum. Genet., 68(6), 1419-1427. CrossRef Scholar google search
Reily C., Stewart T.J., Renfrow M.B., Novak J. (2019) Glycosylation in health and disease. Nat. Rev. Nephrol., 15(6), 346-366. CrossRef Scholar google search