Glycans


Peter D’Adamo ND

(Excerpted from: D’Adamo PJ, Fundamentals of Generative Medicine, 2010-2023. Drum Hill Publishing, Wilton CT)

The term glycan refers to any polysaccharide or oligosaccharide. A true structure-function understanding of the relationship for the glycans can be difficult. Proteins, despite their diverse biological roles, share two basic features that unify the study of their properties: first, each protein is synthesized as an identical copy by translation of mRNA; second, the resulting protein gains its specific activity from the precisely folded three-dimensional structure. In contrast, glycans can be assembled without any sort of template through a series of individually catalyzed reactions. The resulting products, because many different proteins are modified with a relatively common set of glycans structures and different copies of a single polypeptide backbone, can be embellished and modified with scores of differing glycans.

Glycans may resist classification into a set of “simple rules” for some very good reasons; one being that the functions of the protein and glycan portions of the glycoprotein may be independent of each other. In other words, for the same glycoprotein, all copies of a particular protein perform the same role regardless of what particular glycans in that they contain and all copies of a particular glycans perform the same function although they are attached to different proteins. This “fellow traveler” arrangement can be particularly useful when glycans function as “tags” and help direct protein trafficking. Many glycans participate in various “quality-control” checks. The many common glycans serve to hold secretory glycoproteins in various luminal compartments during this QC checking. Since one set of glycans can serve this role for a wide number of proteins, it is assumed that although the proteins will serve a wide variety of functions once outside the cell, the glycans will have no future function when the glycoprotein reaches the outside of the cell.

Conversely, in other instances, glycans may mediate extracellular adhesion (or anti-adhesion) on the surface of the plasma membrane completely independent of the particular protein to which it is attached. This provides a way of producing high densities without requiring a correspondingly high density of one particular type of membrane protein or lipid.

A glycoconjugate is a compound in which one or more monosaccharide or oligosaccharide units (the glycone) are covalently linked to a noncarbohydrate moiety (the aglycone). An oligosaccharide that is not attached to an aglycone possesses the reducing power of the aldehyde or ketone in its terminal monosaccharide component. This end of a sugar chain is therefore often called the reducing terminus or reducing end, terms that tend to be used even when the sugar chain is attached to an aglycone and has thereby lost its reducing power. Correspondingly, the outer end of the chain tends to be called the nonreducing end.

Glycans can be found attached to proteins as in glycoproteins and proteoglycans. These are generally found on the exterior surface of cells attached either to an oxygen molecule (O-linked glycans) or to a nitrogen molecule (N-linked glycans). Glycans can also be attached to lipids forming glycolipids. In addition, glycoconjugates are secreted into biological fluids, such as serum, and they make up the insoluble extracellular matrix that surrounds cells.

Glycoconjugate structures are encoded “indirectly” into the genome. Compared with proteins, there is an extra step in the process. The glycans proteins are not encoded directly into the DNA, but rather arise from transcription and translation of the particular genes needed to produce the glycosyltransferases that in turn control the production of the glycans portion of the glycoconjugates.

N-Glycans

All classes of glycoconjugates have been extensively studied, but the N-linked glycans attached to soluble, secreted proteins are perhaps understood best. This reflects the historical availability of serum glycoproteins for investigation. N-Linked glycans (“N-glycan”) are found attached to the R-group nitrogen (N) of asparagine in the sequence of three consecutive amino acids in a protein that can serve as the attachment site (often called a sequon.) A sequon is either Asparagine-X-Serine or Asparagine-X-Threonine, where X is any amino acid except proline and usually involving an N-acetyl glucosamine (GlcNAc) residue.

Figure 1: Classes of N-glycans. Mannose sugars are green circles.
N-acetyl glucosamine sugars are the blue squares. (3)

N-glycans share a common pentasaccharide core region and can be generally divided into three main classes: the oligomannose type (in which only mannose residues are attached to the core), the complex type (in which “antennae” initiated by N-Acetylglucosaminyltransferases (GlcNAcT’s) are attached to the core), and hybrid type (in which only mannose residues are attached to the Manα1–6 arm of the core and one or two antennae are on the Manα1–3 arm).

A fascinating aspect of N-glycans is their complicated biosynthesis. N-linked glycans are derived from a “core” 14-sugar unit assembled in the cytoplasm and endoplasmic reticulum. Two N-acetyl glucosamine residues are first attached to a lipid (dolichol phosphate) on the external side of the endoplasmic reticulum membrane. Then five mannose residues are added to this structure. The partially finished core glycan is then flipped across the endoplasmic reticulum membrane, so that it is now located within the reticular lumen via an incompletely understood “flippase.” This is followed by the addition of four more mannose residues. Finally, three glucose residues are added to this structure. Following full assembly, the glycan is transferred to a peptide chain, within the reticular lumen. This core structure of N-linked glycans thus consists of 14 residues (3 glucose, 9 mannose, and 2 N-acetylglucosamine).

Figure 2

Figure 2: Processing of an initial high-mannose N-linked glycan to generate complex glycans. First, two GlcNAc’s are added to the Dol-PP anchor in the outer leaflet of ER’s lipid membrane. Further, five mannose saccharides are attached to the structure. This precursor located in cytosol, is now flipped by a yet not fully elucidated mechanism to the inner leaflet. For the rest of the synthesis process, this glycan structure is situated inside the ER lumen. Here, four more mannoses as well as three glucoses are added to create the mature N-glycan precursor. Genes encoding transferases that are responsible for these reactions are designated ALG (asparagine-linked glycosylation). The mature precursor is then detached from its dolichol anchor and transferred to a target polypeptide sequence co-translationally by the large enzyme complex, OST (modified from Varki et al., 2009). B) N-glycan branching. After being transferred to a protein, the N-glycan goes through glucose and mannose trimming, the former being involved in polypeptide folding quality control. The resulting Man5GlcNAc2 structure may be branched – a process mediated by the MGAT family of GlcNAc-transferases. Up to four branches can be added by MGAT1, 2, 4, and 5 respectively and further elongated (orange arrows). Of these, MGAT5 appears to be the most interesting in carcinogenesis; the branch it initiates is preferentially elongated by polylactosamine. In addition to the four previously mentioned branches, a so-called bisecting β-3 branch may be added by MGAT3. This bisecting GlcNAc terminates all further branching, including that mediated by MGAT5. Thus, activity of MGAT3 might inhibit polylactosamine synthesis. The two key reactions, performed by MGAT3 and MGAT5, are highlighted in red. The MGAT transferases require UDP-GlcNAc, which is imported through a transporter (SLC35A3). Genes encoding relevant transferases are displayed in black italic font. C) Core fucosylation. This is one of the possible modifications made to N-glycans’ core structure. Modified from Potapenko IO, Haakensen VD, Lüders T, Helland A, Bukholm I, Sørlie T, Kristensen VN, Lingjaerde OC, Børresen-Dale AL. Glycan gene expression signatures in normal and malignant breast tissue; possible role in diagnosis and progression. Mol Oncol. 2010 Apr; 4(2):98-118.

Once transferred to the peptide chain, N-linked glycans generally undergo extensive processing reactions, whereby the three glucose residues are removed, as well as several mannose residues, depending on the N-linked glycan in question. The first process involves the removal of some of the remaining sugar residues by processing exoglycosidases (glucosidase I and glucosidase II). The removal of the glucose residues is dependent on proper protein folding. The remaining structure is subject to the actions of a series of mannosidases that remove some or all of the four remaining mannose residues. These processing reactions occur in the Golgi apparatus. Modification reactions may involve the addition of a phosphate or acetyl group onto the sugars, or the addition of new sugars, such as neuraminic acid. Processing and modification of N-linked glycans within the Golgi does not follow a linear pathway. As a result, many different variations of N-linked glycan structure are possible, depending on enzyme activity in the Golgi.

In vertebrate N-glycans, the main core modification is the addition of fucose in an α1,6-linkage to the N-acetylglucosamine adjacent to asparagine in the core. The most important “capping” or “decorating” reactions involve the addition of sialic acid, fucose, galactose, N-acetylgalactosamine, and sulfate to the branches described in the preceding paragraph. Capping sugars are most commonly α-linked and therefore protrude away from the β-linked ribbon-like poly-N-acetyllactosamine branches, thus facilitating the presentation of terminal sugars to lectins and antibodies.

N-linked glycans are extremely important in proper protein folding in eukaryotic cells. Chaperone proteins in the endoplasmic reticulum, such as the lectin Calnexin and Calreticulin bind to the three glucose residues present on the core N-linked glycan. These chaperone proteins then serve to aid in the folding of the protein to which the glycan is attached. Following proper folding, the three glucose residues are removed, and the glycan moves on to further processing reactions. If the protein fails to fold properly, the three glucose residues are reattached, allowing the protein to re-associate with the chaperones. The different glycoforms are recognized by specialized lectins. The folding sensor UGGT acts as an unusual molecular chaperone and covalently modifies the Man9 N-glycan of a misfolded protein by adding a glucose moiety and converts it to Glc1Man9 that rebinds the lectin Calnexin. (6) This cycle may repeat several times until a protein reaches its proper conformation. N-linked glycans play an important role in cell-cell interactions.

N-linked glycans also contribute to protein folding by steric effects. For example, cysteine residues in the peptide may be temporarily blocked from forming disulfide bonds with other cysteine residues, due to the size of a nearby glycan. The presence of an N-linked glycan therefore allows the cell to control what cysteine residues will form disulfide bonds. If a protein repeatedly fails to fold properly, it is excreted from the endoplasmic reticulum and degraded by cytoplasmic proteases. Perhaps not altogether surprisingly (considering their role in the maintenance of protein structure) N-glycans are substantially decreased in Alzheimer’s disease patients but not in controls.(4) Inhibition of the epidermal growth factor receptor is a well-recognized avenue of therapeutic approach to a variety of cancers. Blocking N-glycan precursor biosynthesis appears to be a novel therapeutic strategy for targeting EGFR and RTK signaling in both gliomas and other malignant tumors.(5)

The complex N-glycans that fail to be synthesized in knockout mice are important in retaining growth factor and cytokine receptors at the cell surface, probably through interactions with glycan-binding proteins such as galectins or cytokines such as transforming growth factor β. Cell-surface receptors and a glucose transporter lacking branches of a complex N-glycan have a shorter residence time on the cell surface, and their signaling is attenuated. Deletion of genes encoding sialyltransferases, fucosyltransferases, or branching N-Acetylglucosaminyltransferases has generally produced viable mice with defects in immunity or neuronal cell migration, emphysema of the lung, or inflammation.

Abnormal N-linked glycans are a hallmark of disrupted cellular external architecture due to inflammation, cancer, or infection.(8) They are recognized by the NCR3 receptor on Natural Killer cells as a sign that the cell in question is compromised. N-glycans carried on CD45 modulate galectin-1 binding, CD45 signaling, and T cell death.(7) N-glycans may carry the sugar determinants recognized by selectins that mediate cell–cell interactions important for leukocyte extravasation from the blood stream and regulate lymphocyte homing to lymph nodes. N-Glycans are more highly branched when cells become cancerous, and this change facilitates cancer progression. Thus, certain glycosyltransferases may be appropriate targets for the design of cancer therapeutics.

O-Glycans

Whereas the N-linked glycans are bound to the nitrogen atom of asparagine side chains, the O-linked glycans are bound to the oxygen atom of serine or threonine side chains. In eukaryotes, O-linked glycans are assembled one sugar at a time on a serine or threonine residue of a peptide chain in the Golgi apparatus. Unlike with N-linked glycans, there is no yet known “consensus sequence;” although, the placement of a proline residue at either -1 or +3 relative to the serine or threonine is favorable for O-linked glycosylation.

The most common O-linked glycoproteins are often termed mucins. In mucins, O-glycans are covalently α-linked via an N-acetylgalactosamine (GalNAc) moiety to the -OH of serine or threonine by an O-glycosidic bond, and the structures are named mucin O-glycans or O-GalNAc glycans. Mucin glycoproteins are ubiquitous in mucous secretions on cell surfaces and in body fluids.(9)

Figure 3

There are four common O-GalNAc glycan core structures, designated cores 1 through 4 and an additional four designated cores 5 through 8.(9) Mucin O-glycans can be branched, and many sugars or groups of sugars on mucin O-glycans are antigenic. Important modifications of mucin O-glycans include O-acetylation of sialic acid and O-sulfation of galactose and N-acetylglucosamine. Thus, mucin O-glycans are often very heterogeneous, with hundreds of different chains being present in some mucins. 

Mucins

Mucus is the slimy and viscoelastic secretion that covers the epithelial surface of tubular organs such as tracheobronchial, gastrointestinal, reproductive tracts, and other specialized organs. In the body, specialized epithelial cells known as goblet cells secrete mucus, and these cells are abundant in the epithelium of the gastrointestinal, respiratory, and reproductive tracts, and the secretory epithelial surfaces of the liver, pancreas, gall bladder, kidney, salivary, and lacrimal glands.(14) Mucus secretions adhere to the epithelial surface, where they serve as a protective diffusion barrier against harmful substances and act as a lubricant between the lumen and the cell surface.(15,16) The composition of mucus varies with its location and pathophysiological conditions, but normally mucus is composed of water, inorganic salts, immunoglobulins, secreted proteins, and mucins.(13)

Figure 3. O-linked glycosylation. A) Synthesis of O-linked glycans. Several different core O-glycan structures exist, but some are very rare. The initial synthesis of cores 1 and 2, as well as tumor-associated antigens (T antigens), are illustrated. Each of the cores can be extended and then further modified by, for example, fucosylation. Genes encoding relevant transferases are displayed in black italic font. B) Initiation of O-glycosylation on MUC1. This illustration shows a single VNTR (orange) of MUC1 with its amino acid sequence, and specificities of the well-studied GalNAcT’s. The enzymes involved are sometimes overlapping in specificity, although it should be noted that some transferases require preceding activity of other GalNAcT’s (not shown). Modified from Potapenko IO, Haakensen VD, Lüders T, Helland A, Bukholm I, Sørlie T, Kristensen VN, Lingjaerde OC, Børresen-Dale AL. Glycan gene expression signatures in normal and malignant breast tissue; possible role in diagnosis and progression. Mol Oncol. 2010 Apr; 4(2):98-118.

Mucins are present at many epithelial surfaces of the body, including the gastrointestinal, genitourinary, and respiratory tracts, where they shield the epithelial surfaces against physical and chemical damage and protect against infection by pathogens. Mucin O-glycans begin with an α-linked N-acetylgalactosamine residue linked to serine or threonine. The key characteristic of mucins is their ability to form gels; therefore, they are a key component in most gel-like secretions, serving functions from lubrication to cell signaling, to forming chemical barriers. Mucins are the most abundant macromolecules in mucus and are responsible for its biochemical and biophysical properties due to their nature and extent of glycosylation.(17) The mucins are a closely related family of O-glycoproteins that play an important role in the renewal and differentiation of the epithelium, cell adhesions, immune response, and cell signaling.

Figure 4.  MUC1 structure and relationship to signaling cascades.

The hallmark of mucins is the presence of repeated peptide stretches called “variable number of tandem repeat” (VNTR) regions that are rich in serine or threonine O-glycan acceptor sites and have an abundance of clustered mucin O-glycans that may comprise 80% of the molecule by weight. The tandem repeats are usually rich in proline residues that appear to facilitate O-GalNAc glycosylation. Mucins may have hundreds of O-GalNAc glycans attached to serine or threonine residues in the VNTR regions. The clustering of O-GalNAc glycans causes mucin glycoproteins to adopt an extended “bottle brush” conformation.(9)

Mucins are very large glycoproteins (well over 106 Daltons) composed of carbohydrate and amino acids in a roughly 3:1 ratio. At least 19 human mucin genes have been distinguished: MUC1, MUC2, MUC3A, MUC3B, MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUC8, MUC12, MUC13, MUC15, MUC16, MUC17, MUC19, and MUC20.

Mucins are classified into three categories: Strictly secreted, gel-forming mucins, mucins either tethered at the cell surface or secreted in the mucus and exclusively secreted non-gel forming mucins.

From a prognosis point of view, their expression and alterations in glycosylation are associated with the development and progression of malignant diseases.(13) Their aberrant expression is well documented in a variety of inflammatory or malignant diseases. Therefore, mucins can be used as valuable markers to distinguish between normal and disease conditions. Indeed, this alteration in glycosylation patterns generates several epitopes in the oligosaccharide side chains that can be used as diagnostic and/or prognostic markers. Many of the mucins are oncofetal antigens and increased mucin production occurs in many adenocarcinomas, including cancer of the pancreas, lung, breast, ovary, colon, etc.

About 20 different mucin genes have been cloned, and they are expressed in a tissue-specific fashion. For example, different mucin genes are expressed in different regions of the gastrointestinal tract, suggesting that they serve specific functions. The expression of mucin genes is regulated by a large number of cytokines and growth factors, differentiation factors, and bacterial products. Mucins hydrate and protect the underlying epithelial cells, but they have also been shown to have roles in fertilization, blastocyst implantation, and the immune response.

Because the O-glycans are hydrophilic and usually negatively charged, they promote binding of water and salts and are major contributors to the viscosity and adhesiveness of mucus, which forms a physical barrier between lumen and epithelium. The removal of microbes and particles trapped in mucus is an important physiological process. However, in diseases such as cystic fibrosis, the abnormally high viscosity of the mucus leads to obstruction and life-threatening tissue malfunction.

O-linked glycans, particularly mucin, have been found to be important in developing normal intestinal microflora. Certain strains of intestinal bacteria specifically bind to mucin, allowing them to colonize the intestine.(18) A novel mucin-degrading bacterium designated Akkermansia muciniphila is a common member of the human intestinal tract and that its colonization starts in early life and develops within a year to a level close to that observed in adults but decreases in the elderly.(19)

T and Tn Antigens

The simplest mucin O-glycan is a single N-acetylgalactosamine residue linked to serine or threonine. Named the Tn antigen, this glycan is often antigenic. The most common O-GalNAc glycan is Galβ1-3GalNAc-, and it is found in many glycoproteins and mucins. It is termed a core 1 O-GalNAc glycan because it forms the core of many longer, more complex structures. It is antigenic and is named the T (Thomsen-Friedenreich) antigen. Gerhard Uhlenbruck (b. 1929) established the chemical structure of the T antigen in 1969 at the University of Cologne. (25) Both Tn and T antigens may be modified by sialic acid to form sialylated-Tn or -T antigens, respectively.

Mucins also trap bacteria via specific receptor sites within the O-glycans of the mucin. Some sugar residues or their modifications can serve as “decoys,” thus masking underlying antigens or receptors. For example, O-acetyl groups on the sialic acid residue of the sialyl-Tn antigen prevent recognition by anti-sialyl-Tn antibodies. Gut bacteria often actively remove this decoy. Bacteria can cleave sulfate with sulfatases or terminal sugars with glycosidases.

Other O-linked Glycans

  • Glycophorins are sialoglycoproteins found on the membrane of a red blood cell. They are membrane-spanning proteins and carry sugar molecules. It is heavily glycosylated (60%). Glycophorins are rich in sialic acid and heavily glycosylated, which gives the red cells a very hydrophilic-charged coat, enabling them to circulate without adhering to other cells or vessel walls. Leukosialin, also called CD43 or sialophorin, is a major sialoglycoprotein expressed widely in various leukocytes including granulocytes, monocytes, macrophages, and T-lymphocytes. (21)
  • Notch transmembrane receptors are important regulators of cell fate determination in numerous cell types. Notch signaling in mammals are covalently modulated with O-fucose on many epidermal growth factor-like (EGF) repeats of the extracellular domain. Removal of O-fucose affects Notch signaling in myelopoiesis and lymphopoiesis, and the O-fucose glycan in the Notch1 ligand-binding domain is required for optimal T-cell development.(20) The recent discovery that O-glucose modification of Notch EGF repeats is also required for Notch function has further expanded the range of glycosylation events capable of modulating Notch signaling.(22) This places glycosylation alongside phosphorylation as a means to modulate protein-protein interactions and their resultant downstream signals.
  • Sialyl LewisX (sialyl LeX) is one of the most important blood group antigens and is displayed on the terminus of glycolipids that are present on the cell surface. SLeX is a tetrasaccharide carbohydrate that is usually attached to O-glycans on the surface of cells. It is known to play a vital role in cell-to-cell recognition processes. The Sialyl LewisX determinant, E-selectin ligand carbohydrate structure, is constitutively expressed on granulocytes and monocytes, and it mediates inflammatory extravasation of these cells.
  • Thrombospondins, a family of anti-angiogenic proteins,are O-linked. Similar to the EGF repeat in Notch signaling, a second type of cysteine-rich motif, known as a thrombospondin type 1 repeat (TSR), is also modified with O-fucose glycans. (5) The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) proteins are a family of metalloproteinases with sequence similarity to the ADAM proteases, which contain the thrombospondin type 1 sequence repeat motifs (TSR’s) common to extracellular matrix proteins. ADAMTS proteins have recently gained attention with the discovery of their role in a variety of diseases, including tissue and blood disorders, cancer, osteoarthritis, Alzheimer’s and the genetic syndromes Weill-Marchesani syndrome (ADAMTS10), thrombotic thrombocytopenic purpura (ADAMTS13), and Ehlers-Danlos syndrome type VIIC (ADAMTS2).(26)

Glycosaminoglycans and Proteoglycans

Another class of cellular glycans is the glycosaminoglycans (GAG’s), the most abundant heteropolysaccharides in the body. These comprise 2-aminosugars linked in an alternating fashion with uronic acids, and include polymers such as heparin, heparan sulfate, chondroitin, keratin, and dermatan. Some glycosaminoglycans are found attached to the cell surface, where they are linked through a single xylosyl residue to a protein. Chondroitin sulfate is a sulfated glycosaminoglycan composed of a chain of alternating sugars (N-acetylgalactosamine and glucuronic acid). It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have over 100 individual sugars, each of which can be sulfated in variable positions and quantities. GAG’s are highly negatively charged molecules, with extended conformation that imparts high viscosity to the solution.

GAG’s are located primarily on the surface of cells or in the extracellular matrix (ECM). Along with the high viscosity of GAG’s comes low compressibility, which makes these molecules ideal for a lubricating fluid in the joints. Chondroitin sulfate is an important structural component of cartilage and provides much of its resistance to compression. At the same time, their rigidity provides structural integrity to cells and provides passageways between cells, allowing for cell migration. The majority of GAG’s in the body are linked to core proteins, forming proteoglycans (also called mucopolysaccharides).(23)

One well-defined function of the GAG heparin is its role in preventing coagulation of the blood. Heparin is abundant in granules of mast cells that line blood vessels. The release of heparin from these granules, in response to injury, and its subsequent entry into the serum leads to an inhibition of blood clotting. Several genetically inherited diseases, for example the lysosomal storage diseases, result from defects in the lysosomal enzymes responsible for the metabolism of complex membrane-associated GAG’s. These specific diseases are termed mucopolysaccharidoses (MPS). The inactivity of specific lysosomal enzymes that normally degrade glycosaminoglycans leads to the accumulation of proteoglycans within cells. This leads to a variety of disease symptoms, depending upon the type of proteoglycan that is not degraded.

Any protein with one or more covalently attached glycosaminoglycan chains is termed a proteoglycan. Proteoglycans and GAG’s perform numerous vital functions within the body, some of which remain to be studied. Virtually all mammalian cells produce proteoglycans and secrete them into the ECM, insert them into the plasma membrane, or store them in secretory granules.(24)

Proteoglycans are a major component of the animal extracellular matrix, the “filler” substance existing between cells in an organism. Here they form large complexes to other proteoglycans, to hyaluronan, and to fibrous matrix proteins (such as collagen). Evidence also shows they can affect the activity and stability of proteins and signaling molecules within the matrix. The protein component of proteoglycans is synthesized by ribosomes and translocated into the lumen of the rough endoplasmic reticulum. Glycosylation of the proteoglycan occurs in the Golgi apparatus in multiple enzymatic steps.

During development, secreted morphogens such as Wnt protein, Hedgehog (Hh), and bone morphogenic protein (BMP) are emitted from their producing cells in a morphogenetic field, where they specify different cell fates in a direct concentration-dependent manner. Understanding how morphogens form their concentration gradients to pattern tissues has been a central issue in developmental biology. Over the past decade, one of the main findings in this field is the characterization of heparan sulfate proteoglycan (HSPG) as an essential regulator for morphogen gradient formation. HSPG’s can directly influence morphogen gradient formation at various levels, including morphogen movement, signaling, and trafficking. HSPG’s can also interact with other molecules such as lipoprotein, which is required for morphogen movement and distribution.(26)

Figure 6

Figure 6:  Three main classes of cell-surface heparan sulfate proteoglycans. (A) Syndecan core proteins are transmembrane proteins that contain a highly conserved carboxy-terminal cytoplasmic domain. Heparan sulfate (HS) chains attach to serine residues distal from the plasma membrane. Some syndecans also contain chondroitin sulfate (CS) chain(s) that attaches to serine residue(s) near the membrane. (B) The glypican core proteins are disulfide-stabilized globular core proteins that are linked to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor. HS chains link to serine residues adjacent to the plasma membrane. (C) Perlecans are secreted HSPG’s that carry HS chains.

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Published September 23, 2023

About the Author

Peter D’Adamo is a naturopathic physician who is also an author, researcher-educator, Ivesian, amateur horologist, budding software developer and air-cooled enthusiast. He is considered a world expert in glycobiology, principally the ABO (ABH) blood groups and the secretor (FUT2) polymorphisms. In 1996 Dr. D’Adamo wrote the NY Times Bestseller Eat Right For Your Type.

In 1990 Dr. D’Adamo was awarded Physician of the Year by The American Association of Naturopathic Physicians. He is Adjunct Clinical Professor for both the Southwest College of Naturopathic Medicine, Tempe AZ, and the National College of Naturopathic Medicine, Portland OR.

In 2001 Dr. D’Adamo founded the Institute for Human Individuality (IfHI). In 2003 he instigated the first IfHI biannual conference and certification, at which he was the keynote speaker. These conferences, which have attracted the best and brightest minds in nutritional genomics, have continued through 2005, 2007, 2009 and 2011.

Dr. D’Adamo is currently developing several new bioinformatics tools. In professional and academic circles, he is best known for his genomic software Opus23 and SWAMI, a program that devises complex one-of-a-kind diet protocols for individuals. Many of his open source bioinformatics programs can be found on his website www.datapunk.net

Dr. D’Adamo is a distinguished professor of clinical sciences at the University of Bridgeport College of Naturopathic Medicine where he directs the new University of Bridgeport Center of Excellence in Generative Medicine.