Glycobiology

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Defined in the narrowest sense, glycobiology is the study of the structure, biosynthesis, and biology of saccharides (sugar chains or glycans) that are widely distributed in nature. [1] [2] Sugars or saccharides are essential components of all living things and aspects of the various roles they play in biology are researched in various medical, biochemical and biotechnological fields.

Contents

History

According to Oxford English Dictionary the specific term glycobiology was coined in 1988 by Prof. Raymond Dwek to recognize the coming together of the traditional disciplines of carbohydrate chemistry and biochemistry. [3] This coming together was as a result of a much greater understanding of the cellular and molecular biology of glycans. However, as early as the late nineteenth century pioneering efforts were being made by Emil Fisher to establish the structure of some basic sugar molecules. Each year the Society of Glycobiology awards the Rosalind Kornfeld award for lifetime achievement in the field of glycobiology. [4]

Glycoconjugates

Sugars may be linked to other types of biological molecule to form glycoconjugates. The enzymatic process of glycosylation creates sugars/saccharides linked to themselves and to other molecules by the glycosidic bond, thereby producing glycans. Glycoproteins, proteoglycans and glycolipids are the most abundant glycoconjugates found in mammalian cells. They are found predominantly on the outer cell membrane and in secreted fluids. Glycoconjugates have been shown to be important in cell-cell interactions due to the presence on the cell surface of various glycan binding receptors in addition to the glycoconjugates themselves. [5] [6] In addition to their function in protein folding and cellular attachment, the N-linked glycans of a protein can modulate the protein's function, in some cases acting as an on-off switch. [7]

Glycomics

"Glycomics, analogous to genomics and proteomics, is the systematic study of all glycan structures of a given cell type or organism" and is a subset of glycobiology. [8] [9]

Challenges in the study of sugar structures

Part of the variability seen in saccharide structures is because monosaccharide units may be coupled to each other in many different ways, as opposed to the amino acids of proteins or the nucleotides in DNA, which are always coupled together in a standard fashion. [10] The study of glycan structures is also complicated by the lack of a direct template for their biosynthesis, contrary to the case with proteins where their amino acid sequence is determined by their corresponding gene. [11]

Glycans are secondary gene products and therefore are generated by the coordinated action of many enzymes in the subcellular compartments of a cell. Since the structure of a glycan may depend on the expression, activity and accessibility of the different biosynthetic enzymes, it is not possible to use recombinant DNA technology in order to produce large quantities of glycans for structural and functional studies as it is for proteins.

Modern tools and techniques for glycan structure prediction

Advanced analytical instruments and software programs, when used in combination, can unlock the mystery of glycan structures. Current techniques for structural annotation and analysis of glycans include liquid chromatography (LC), capillary electrophoresis (CE), mass spectrometry (MS), nuclear magnetic resonance (NMR) and lectin arrays. [12]

One of the most widely used techniques is mass spectrometry which uses three principal units: the ionizer, analyzer and detector.

Glycan arrays, like that offered by the Consortium for Functional Glycomics and Z Biotech LLC, contain carbohydrate compounds that can be screened with lectins or antibodies to define carbohydrate specificity and identify ligands.

Multiple reaction monitoring (MRM)

MRM is a mass spectrometry-based technique that has recently been used for site-specific glycosylation profiling. Although MRM has been used extensively in metabolomics and proteomics, its high sensitivity and linear response over a wide dynamic range make it especially suited for glycan biomarker research and discovery. MRM is performed on a triple quadrupole (QqQ) instrument, which is set to detect a predetermined precursor ion in the first quadrupole, a fragmented in the collision quadrupole, and a predetermined fragment ion in the third quadrupole. It is a non-scanning technique, wherein each transition is detected individually and the detection of multiple transitions occurs concurrently in duty cycles. [7] This technique is being used to characterize the immune glycome. [7]

Medicine

Drugs already on the market, such as heparin, erythropoietin and a few anti-flu drugs, have proven effective and highlight the importance of glycans as a new class of drug. Additionally, the search for new anti-cancer drugs is opening up new possibilities in glycobiology. [13] Anti-cancer drugs with new and varied action mechanisms together with anti-inflammatory and anti-infection drugs are today undergoing clinical trials. They may alleviate or complete current therapies. Although these glycans are molecules that are difficult to synthesize in a reproducible way, owing to their complex structure, this new field of research is highly encouraging for the future.

Skin

Glycobiology, in which recent developments have been made possible by the latest technological advances, helps provide a more specific and precise understanding of skin aging. It has now been clearly established that glycans are major constituents of the skin and play a decisive role in skin homeostasis.

Vital to the proper functioning of skin, glycans undergo both qualitative and quantitative changes in the course of aging. [15] The functions of communication and metabolism are impaired and the skin's architecture is degraded.

See also

Related Research Articles

Glycomics is the comprehensive study of glycomes, including genetic, physiologic, pathologic, and other aspects. Glycomics "is the systematic study of all glycan structures of a given cell type or organism" and is a subset of glycobiology. The term glycomics is derived from the chemical prefix for sweetness or a sugar, "glyco-", and was formed to follow the omics naming convention established by genomics and proteomics.

<span class="mw-page-title-main">Glycoprotein</span> Protein with oligosaccharide modifications

Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. Secreted extracellular proteins are often glycosylated.

<span class="mw-page-title-main">Glycome</span> Complete set of all sugars, free or bound, in an organism.

A glycome is the entire complement or complete set of all sugars, whether free or chemically bound in more complex molecules, of an organism. An alternative definition is the entirety of carbohydrates in a cell. The glycome may in fact be one of the most complex entities in nature. "Glycomics, analogous to genomics and proteomics, is the systematic study of all glycan structures of a given cell type or organism" and is a subset of glycobiology.

<span class="mw-page-title-main">Consortium for Functional Glycomics</span> Glycomics research initiative

The Consortium for Functional Glycomics (CFG) is a large research initiative funded in 2001 by a glue grant from the National Institute of General Medical Sciences (NIGMS) to “define paradigms by which protein-carbohydrate interactions mediate cell communication”. To achieve this goal, the CFG studies the functions of:

<span class="mw-page-title-main">Lectin</span> Carbohydrate-binding protein

Lectins are carbohydrate-binding proteins that are highly specific for sugar groups that are part of other molecules, so cause agglutination of particular cells or precipitation of glycoconjugates and polysaccharides. Lectins have a role in recognition at the cellular and molecular level and play numerous roles in biological recognition phenomena involving cells, carbohydrates, and proteins. Lectins also mediate attachment and binding of bacteria, viruses, and fungi to their intended targets.

Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule in order to form a glycoconjugate. In biology, glycosylation usually refers to an enzyme-catalysed reaction, whereas glycation may refer to a non-enzymatic reaction.

An oligosaccharide is a saccharide polymer containing a small number of monosaccharides. Oligosaccharides can have many functions including cell recognition and cell adhesion.

<span class="mw-page-title-main">Glycolipid</span> Class of chemical compounds

Glycolipids are lipids with a carbohydrate attached by a glycosidic (covalent) bond. Their role is to maintain the stability of the cell membrane and to facilitate cellular recognition, which is crucial to the immune response and in the connections that allow cells to connect to one another to form tissues. Glycolipids are found on the surface of all eukaryotic cell membranes, where they extend from the phospholipid bilayer into the extracellular environment.

The terms glycans and polysaccharides are defined by IUPAC as synonyms meaning "compounds consisting of a large number of monosaccharides linked glycosidically". However, in practice the term glycan may also be used to refer to the carbohydrate portion of a glycoconjugate, such as a glycoprotein, glycolipid, or a proteoglycan, even if the carbohydrate is only an oligosaccharide. Glycans usually consist solely of O-glycosidic linkages of monosaccharides. For example, cellulose is a glycan composed of β-1,4-linked D-glucose, and chitin is a glycan composed of β-1,4-linked N-acetyl-D-glucosamine. Glycans can be homo- or heteropolymers of monosaccharide residues, and can be linear or branched.

In molecular biology and biochemistry, glycoconjugates are the classification family for carbohydrates – referred to as glycans – which are covalently linked with chemical species such as proteins, peptides, lipids, and other compounds. Glycoconjugates are formed in processes termed glycosylation.

Siglecs(Sialic acid-binding immunoglobulin-type lectins) are cell surface proteins that bind sialic acid. They are found primarily on the surface of immune cells and are a subset of the I-type lectins. There are 14 different mammalian Siglecs, providing an array of different functions based on cell surface receptor-ligand interactions.

<span class="mw-page-title-main">Galectin</span> Protein family binding to β-galactoside sugars

Galectins are a class of proteins that bind specifically to β-galactoside sugars, such as N-acetyllactosamine, which can be bound to proteins by either N-linked or O-linked glycosylation. They are also termed S-type lectins due to their dependency on disulphide bonds for stability and carbohydrate binding. There have been about 15 galectins discovered in mammals, encoded by the LGALS genes, which are numbered in a consecutive manner. Only galectin-1, -2, -3, -4, -7, -7B, -8, -9, -9B, 9C, -10, -12, -13, -14, and -16 have been identified in humans. Galectin-5 and -6 are found in rodents, whereas galectin-11 and -15 are uniquely found in sheep and goats. Members of the galectin family have also been discovered in other mammals, birds, amphibians, fish, nematodes, sponges, and some fungi. Unlike the majority of lectins they are not membrane bound, but soluble proteins with both intra- and extracellular functions. They have distinct but overlapping distributions but found primarily in the cytosol, nucleus, extracellular matrix or in circulation. Although many galectins must be secreted, they do not have a typical signal peptide required for classical secretion. The mechanism and reason for this non-classical secretion pathway is unknown.

Richard D. Cummings is an American biochemist who is the S. Daniel Abraham Professor of Surgery at Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts. He also the chief of the division of surgical sciences within the department of surgery. He is the director of the Harvard Medical School Center for Glycoscience, director of the National Center for Functional Glycomics, and also founder of the Glycomics Core at BIDMC. As of 2018 Cummings is also the scientific director of the Feihi Nutrition Laboratory at BIDMC. Before moving to BIDMC/HMS, Cummings was the William Patterson Timmie Professor and chair of the department of biochemistry at Emory University School of Medicine in Atlanta, Georgia from 2006 to 2015. At Emory, Cummings was a founder in 2007 of the Emory Glycomics Center.

Glycoinformatics is a field of bioinformatics that pertains to the study of carbohydrates involved in protein post-translational modification. It broadly includes database, software, and algorithm development for the study of carbohydrate structures, glycoconjugates, enzymatic carbohydrate synthesis and degradation, as well as carbohydrate interactions. Conventional usage of the term does not currently include the treatment of carbohydrates from the better-known nutritive aspect.

Glycopeptides are peptides that contain carbohydrate moieties (glycans) covalently attached to the side chains of the amino acid residues that constitute the peptide.

<i>N</i>-linked glycosylation Attachment of an oligosaccharide to a nitrogen atom

N-linked glycosylation, is the attachment of an oligosaccharide, a carbohydrate consisting of several sugar molecules, sometimes also referred to as glycan, to a nitrogen atom, in a process called N-glycosylation, studied in biochemistry. The resulting protein is called an N-linked glycan, or simply an N-glycan.

Translational glycobiology or applied glycobiology is the branch of glycobiology and glycochemistry that focuses on developing new pharmaceuticals through glycomics and glycoengineering. Although research in this field presents many difficulties, translational glycobiology presents applications with therapeutic glycoconjugates, with treating various bone diseases, and developing therapeutic cancer vaccines and other targeted therapies. Some mechanisms of action include using the glycan for drug targeting, engineering protein glycosylation for better efficacy, and glycans as drugs themselves.

<span class="mw-page-title-main">Carbohydrate Structure Database</span>

Carbohydrate Structure Database (CSDB) is a free curated database and service platform in glycoinformatics, launched in 2005 by a group of Russian scientists from N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences. CSDB stores published structural, taxonomical, bibliographic and NMR-spectroscopic data on natural carbohydrates and carbohydrate-related molecules.

<span class="mw-page-title-main">Glycan-protein interactions</span> Class of biological intermolecular interactions

Glycan-Protein interactions represent a class of biomolecular interactions that occur between free or protein-bound glycans and their cognate binding partners. Intramolecular glycan-protein (protein-glycan) interactions occur between glycans and proteins that they are covalently attached to. Together with protein-protein interactions, they form a mechanistic basis for many essential cell processes, especially for cell-cell interactions and host-cell interactions. For instance, SARS-CoV-2, the causative agent of COVID-19, employs its extensively glycosylated spike (S) protein to bind to the ACE2 receptor, allowing it to enter host cells. The spike protein is a trimeric structure, with each subunit containing 22 N-glycosylation sites, making it an attractive target for vaccine search.

Nicki Packer FRSC is an Australian college professor and researcher. She currently serves as a distinguished professor of glycoproteomics in the School of Natural Sciences at Macquarie University and principal research leader at Griffith University's Institute for Glycomics. Packer is a Fellow of the Royal Society of Chemistry and in 2021 received the Distinguished Achievement in Proteomic Sciences Award from the Human Proteome Organization. Her research focuses on biological functional of glycoconjugates by linking glycomics with proteomics and bioinformatics.

References

  1. ↑ Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, Mohnen D, Kinoshita T, Packer NH, Prestegard JH, Schnaar RL, Seeberger PH (2022). Essentials of Glycobiology (4th ed.). Cold Spring Harbor Laboratory Press. doi:10.1101/9781621824213 (inactive 31 January 2024). ISBN   978-1-621824-21-3. PMID   35536922.{{cite book}}: CS1 maint: DOI inactive as of January 2024 (link)
  2. ↑ Varki A, Cummings R, Esko J, Freeze H, Hart G, Marth J (1999). Essentials of glycobiology. Cold Spring Harbor Laboratory Press. ISBN   0-87969-560-9.
  3. ↑ Rademacher TW, Parekh RB, Dwek RA (1988). "Glycobiology". Annu. Rev. Biochem. 57 (1): 785–838. doi:10.1146/annurev.bi.57.070188.004033. PMID   3052290.
  4. ↑ "Rosalind Kornfeld Award". www.glycobiology.org. Retrieved 2021-11-05.
  5. ↑ Ma BY, Mikolajczak SA, Yoshida T, Yoshida R, Kelvin DJ, Ochi A (2004). "CD28 T cell costimulatory receptor function is negatively regulated by N-linked carbohydrates". Biochem. Biophys. Res. Commun. 317 (1): 60–7. doi:10.1016/j.bbrc.2004.03.012. PMID   15047148.
  6. ↑ Takahashi M, Tsuda T, Ikeda Y, Honke K, Taniguchi N (2004). "Role of N-glycans in growth factor signaling". Glycoconj. J. 20 (3): 207–12. doi:10.1023/B:GLYC.0000024252.63695.5c. PMID   15090734. S2CID   1110879.
  7. 1 2 3 Maverakis E, Kim K, Shimoda M, Gershwin M, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB (2015). "Glycans in the immune system and The Altered Glycan Theory of Autoimmunity". J Autoimmun. 57 (6): 1–13. doi:10.1016/j.jaut.2014.12.002. PMC   4340844 . PMID   25578468.
  8. ↑ Cold Spring Harbor Laboratory Press Essentials of Glycobiology, Second Edition
  9. ↑ Schnaar, RL (June 2016). "Glycobiology simplified: diverse roles of glycan recognition in inflammation". Journal of Leukocyte Biology. 99 (6): 825–38. doi:10.1189/jlb.3RI0116-021R. PMC   4952015 . PMID   27004978.
  10. ↑ Kreuger, J (2001). "Decoding heparan sulfate" . Retrieved 2008-01-11.{{cite journal}}: Cite journal requires |journal= (help)
  11. ↑ Marth, JD (2008). "A unified vision of the building blocks of life". Nature Cell Biology. 10 (9): 1015–6. doi:10.1038/ncb0908-1015. PMC   2892900 . PMID   18758488.
  12. ↑ Aizpurua-Olaizola, O.; Sastre Toraño, J.; Falcon-Perez, J.M.; Williams, C.; Reichardt, N.; Boons, G.-J. (March 2018). "Mass spectrometry for glycan biomarker discovery". TrAC Trends in Analytical Chemistry. 100: 7–14. doi:10.1016/j.trac.2017.12.015. hdl:1874/364403. ISSN   0165-9936.
  13. ↑ Olden K, Bernard BA, Humphries M, et al. (1985). Function of glycoprotein glycans T.I.B.S. pp. 78–82.
  14. ↑ Faury, G (December 2008). "The alpha-L-Rhamnose recognizing lectin site of human dermal fibroblasts functions as a signal transducer: modulation of Ca2+ fluxes and gene expression". Biochimica et Biophysica Acta. 1780 (12): 1388–94. doi:10.1016/j.bbagen.2008.07.008. PMID   18708125.
  15. ↑ Oh, Jang-Hee; Kim, Yeon Kyung; Jung, Ji-Yong; Shin, Jeong-eun; Chung, Jin Ho (2011). "Changes in glycosaminoglycans and related proteoglycans in intrinsically aged human skin in vivo". Experimental Dermatology. 20 (5): 454–456. doi:10.1111/j.1600-0625.2011.01258.x. ISSN   1600-0625. PMID   21426414. S2CID   34434784.
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