Heparinoid

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Heparinoids are glycosaminoglycans which are chemically and pharmacologically related to heparin. [1] They include oligosaccharides and sulfated polysaccharides of plant, animal, or synthetic origin. [2] Multiple scientific studies have been conducted on heparinoids. [3] [4]

Contents

Heparinoids, like heparin, act by interacting with heparin binding proteins, generally through ionic interactions or hydrogen bonding. Some examples of heparin binding proteins include antithrombin III. It is thought that much protein interaction with heparin is not direct, and instead heparin binding protein actually interact with glycosaminoglycan (GAG) side chains or mucins bound to the heparin polymer, so it is possible that heparinoids interact with these proteins in a similar way, acquiring GAG side chains in vivo. One counterexample is the protein chymase, which directly binds to heparin. [2]

Sulfated polysaccharides

From animal tissues

Dermatan sulfate is one example of a compound that is classified as a heparinoid. It is a naturally-occurring polysaccharide of O-sulfated N-acetyl-D-galatosamine, L-iduronic acid, and D-glucuronic acid that has been clinically used as an antithrombotic agent. [2]

Chondroitin sulfate shows slightly less biological activity than dermatan sulfate, and is composed of O-sulfated N-acetyl-D-galatosamine and D-glucuronic acid. It is theorized that this change in efficacy is related to the absence of L-induronic acid, which affects the flexibility of the polymer chain. [2]

Acharan sulfate is a heparinoid that is naturally produced by the giant African land snail, Lissachatina fulica . Keratan sulfate is a heparinoid that is a component of cartilage. It is found in the cornea. [2]

Chitin, a component of insect shells and fungal structures, can be de-N-acetylated to form chitosan, which when sulfated has a significant chemical similarity to heparin. In fact, it inhibits thrombin by affecting ATIII.

Lepirudin is a recombinant preparation of the polypeptide anticoagulant secreted by leeches and is used in patients with heparin induced thrombocytopenia.

From plant sources

Fucoidan is a polymer composed of sulfated L-fucose.

Carrageenans are isolated from algae.

Hyaluronan functions as a heparinoid when it is sulfated. Intra-articular injections of hyaluronic acid are used to mitigate pain and treat symptoms of osteoarthritis in the knee, but such injections are correlated with increased risk of serious side effects. [5]

Alginic acid functions as a heparinoid when it is sulfated.

Pentosan from the bark of Fagus sylvatica , when sulfated, acts with one-tenth of the efficacy of heparin.

From microbial sources

K5 polysaccharide from E. coli acts as a heparinoid when it is sulfated.

History

Heparin was first isolated from dog liver by medical student Jay McClean in 1916. Jorpes discovered the structure of the heparin polysaccharide in 1935, identifying that it is a highly sulfated polymer of glycosaminoglycoglycan (GAG) and uronic acid. Around that time, heparin began to be used in the prophylaxis and treatment of post-operative thrombosis. [6]

Production

There is no industrial process for the complete synthesis of heparin; heparin is isolated from animal tissue - generally bovine lung, porcine, and intestinal mucosa. [6] Heparinoids generally are also naturally-occurring polysaccharides, and similarly need to be purified from the plant or animal tissue that produces them.

Regulation

There is no internationally accepted molecular standard for the composition of heparin, as it is a complex polymer of GAG units and uronic acids (including D-glucuronic acid, L-iduronic acid, and D-glucosamine). Position of N-acetyl, N-sulfate, and O-sulfate groups in these uronic acids can vary, as can the branching patterns of the chain. This generates an extraordinary amount of variability between molecules of heparin. [6] Current USP standards for heparin limit levels of contamination with dermatan, chondroitin, and over-sulfated chondroitin sulfate, as well as galactosamine levels in the sample, as determined by HPLC, H-NMR, and Strong Anion Exchange Chromatography. [7] [8]

See also

Related Research Articles

<span class="mw-page-title-main">Heparin</span> Anticoagulant

Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treatment of heart attacks and unstable angina. It is given intravenously or by injection under the skin. Other uses for its anticoagulant properties include inside blood specimen test tubes and kidney dialysis machines.

<span class="mw-page-title-main">Chondroitin sulfate</span> Sulfated glycosaminoglycan (GAG) compound

Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) composed of a chain of alternating sugars. 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. Chondroitin sulfate is an important structural component of cartilage, and provides much of its resistance to compression. Along with glucosamine, chondroitin sulfate has become a widely used dietary supplement for treatment of osteoarthritis, although large clinical trials failed to demonstrate any symptomatic benefit of chondroitin.

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

Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge. The Ser residue is generally in the sequence -Ser-Gly-X-Gly-, although not every protein with this sequence has an attached glycosaminoglycan. The chains are long, linear carbohydrate polymers that are negatively charged under physiological conditions due to the occurrence of sulfate and uronic acid groups. Proteoglycans occur in connective tissue.

<span class="mw-page-title-main">Glycosaminoglycan</span> Polysaccharides found in animal tissue

Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units. The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case of the sulfated glycosaminoglycan keratan, where, in place of the uronic sugar there is a galactose unit. GAGs are found in vertebrates, invertebrates and bacteria. Because GAGs are highly polar molecules and attract water; the body uses them as lubricants or shock absorbers.

<span class="mw-page-title-main">Glucuronic acid</span> Sugar acid

Glucuronic acid is a uronic acid that was first isolated from urine. It is found in many gums such as gum arabic, xanthan, and kombucha tea and is important for the metabolism of microorganisms, plants and animals.

<span class="mw-page-title-main">Idose</span> Chemical compound

Idose is a hexose, a six carbon monosaccharide. It has an aldehyde group and is an aldose. It is not found in nature, but its uronic acid, iduronic acid, is important. It is a component of dermatan sulfate and heparan sulfate, which are glycosaminoglycans. The first and third hydroxyls point the opposite way from the second and fourth. It is made by aldol condensation of D- and L-glyceraldehyde. L-Idose is a C-5 epimer of D-glucose.

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.

Ground substance is an amorphous gel-like substance in the extracellular space of animals that contains all components of the extracellular matrix (ECM) except for fibrous materials such as collagen and elastin. Ground substance is active in the development, movement, and proliferation of tissues, as well as their metabolism. Additionally, cells use it for support, water storage, binding, and a medium for intercellular exchange. Ground substance provides lubrication for collagen fibers.

<span class="mw-page-title-main">Dermatan sulfate</span> Glycosaminoglycan found in animals

Dermatan sulfate is a glycosaminoglycan found mostly in skin, but also in blood vessels, heart valves, tendons, and lungs.

<span class="mw-page-title-main">Heparan sulfate</span> Macromolecule

Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. In this form, HS binds to a variety of protein ligands, including Wnt, and regulates a wide range of biological activities, including developmental processes, angiogenesis, blood coagulation, abolishing detachment activity by GrB, and tumour metastasis. HS has also been shown to serve as cellular receptor for a number of viruses, including the respiratory syncytial virus. One study suggests that cellular heparan sulfate has a role in SARS-CoV-2 Infection, particularly when the virus attaches with ACE2.

<span class="mw-page-title-main">Heparin cofactor II</span> Protein-coding gene in the species Homo sapiens

Heparin cofactor II (HCII), a protein encoded by the SERPIND1 gene, is a coagulation factor that inhibits IIa, and is a cofactor for heparin and dermatan sulfate.

<span class="mw-page-title-main">Iduronic acid</span> Chemical compound

l-Iduronic acid is the major uronic acid component of the glycosaminoglycans (GAGs) dermatan sulfate, and heparin. It is also present in heparan sulfate, although here in a minor amount relative to its carbon-5 epimer glucuronic acid.

The enzyme chondroitin B lyase catalyzes the following process:

The enzyme chondroitin-sulfate-ABC endolyase catalyzes the following process:

In enzymology, a glucuronate-2-sulfatase is an enzyme that catalyzes the chemical reaction of cleaving off the 2-sulfate groups of the 2-O-sulfo-D-glucuronate residues of chondroitin sulfate, heparin and heparitin sulfate.

A xyloside is a type of glycoside derived from the sugar xylose.

Dermatan 4-sulfotransferase is an enzyme with systematic name 3'-phospho-5'-adenylyl sulfate:(dermatan)-N-acetyl-D-galactosamine 4-sulfotransferase. This enzyme catalyses the following chemical reaction

Unsaturated chondroitin disaccharide hydrolase (EC 3.2.1.180, UGL, unsaturated glucuronyl hydrolase) is an enzyme with systematic name beta-D-4-deoxy-Delta4-GlcAp-(1->3)-beta-D-GalNAc6S hydrolase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Stains-all</span> Dye

Stains-all is a carbocyanine dye, which stains anionic proteins, nucleic acids, anionic polysaccharides and other anionic molecules.

Ulvan lyase is an enzyme found within the cell-wall of the marine organism Ulvales, and some marine bacterium. A lyase is a class of enzyme that catalyzes the breakdown of chemical bonds through an elimination reaction mechanism, rather than a substitution reaction mechanism. Ulvan lyase belongs to the polysaccharide lyase family, a type of enzyme that primarily functions to cleave glycosidic linkages in polysaccharides.

References

  1. Heparinoids at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  2. 1 2 3 4 5 Gunay NS, Linhardt RJ (1999). "Heparinoids: structure, biological activities and therapeutic applications". Planta Medica. 65 (4): 301–6. doi: 10.1055/s-1999-13990 . PMID   10364832.
  3. Vecchio, Cesare; Frisinghelli, Anna (2008). "Topically Applied Heparins for the Treatment of Vascular Disorders: A Comprehensive Review". Clinical Drug Investigation. 28 (10): 603–614. doi:10.2165/00044011-200828100-00001. PMID   18783299. S2CID   31783368.
  4. Mehta PP, Sagar S, Kakkar VV (1975). "Treatment of superficial thrombophlebitis: a randomized, bouble-blind trial of heparinoid cream". British Medical Journal. 3 (5984): 614–6. doi:10.1136/bmj.3.5984.614. JSTOR   20406780. PMC   1674425 . PMID   51664.
  5. Rutjes, Anne W.S.; Jüni, Peter; Da Costa, Bruno R.; Trelle, Sven; Nüesch, Eveline; Reichenbach, Stephan (2012). "Viscosupplementation for Osteoarthritis of the Knee". Annals of Internal Medicine. 157 (3): 180–91. doi:10.7326/0003-4819-157-3-201208070-00473. PMID   22868835. S2CID   5660398.
  6. 1 2 3 Linhardt, Robert J.; Toida, Toshihiko (1997). "Heparin oligosaccharides: New analogues development and applications" (PDF). In Witczak, Zbigniew J.; Nieforth, Karl A. (eds.). Carbohydrates in Drug Design. pp. 277–308. ISBN   0-8247-9982-8.
  7. {{U.S. Pharmacopeia Heparin Stage Two Monograph Revisions Open Microphone Web Meeting March 3, 2009 Powerpoint Presentation. Morris, Tina S.; Szajeck, Anita; Wahab, Samir; Ambrose, Michael; Jameison, Fabian A.; <http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/key-issues/2009-03-09-HeparinMeeting.pdf> }}
  8. USP Safety Data Sheet: Heparin Sodium with Oversulfated Chondroitin Sulfate. http://static.usp.org/pdf/EN/referenceStandards/msds/1304050.pdf Accessed on 11/30/2015.