Glycosaminoglycans and Glycoproteins .

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Diagram of glycosaminoglycans. Glycosaminoglycan (GAGs) are substantial edifices of adversely charged heteropolysaccharide chains. They are by and large connected with a little measure of protein, framing proteoglycans, which normally comprise of > 95% CHO.Note: this is in examination to the glycoproteins, which comprise principally of protein with a little measure of CHOGlycosaminoglycans have the uncommon abi
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Glycosaminoglycans and Glycoproteins UNIT II: Intermediary Metabolism

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Overview of glycosaminoglycans Glycosaminoglycan (GAGs) are substantial buildings of adversely charged heteropolysaccharide chains. They are by and large connected with a little measure of protein, framing proteoglycans , which commonly comprise of > 95% CHO. Take note of: this is in contrast with the glycoproteins , which comprise basically of protein with a little measure of CHO Glycosaminoglycans have the unique capacity to tie a lot of water, accordingly delivering the gel-like lattice that structures the premise of the body\'s ground substance The thick, greasing up properties of mucous discharges likewise result from the nearness of GAGs, which prompted to the first naming of these cpds as mucopolysaccharides

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II. Structure of GAGs are since quite a while ago, unbranched, heteropolysaccharide chains by and large made out of a rehashing disacch unit [acidic sugar-amino sugar]n The amino sugar is either D-glucosamine or D-galactosamine, in which the amino gathering is typically acetylated, in this way wiping out its +ve charge. The amino sugar may likewise be sulfated on C-4 or 6 or on a non-acetylated nitrogen The acidic sugar is either D-glucuronic corrosive or its C-5 epimer, L-iduronic corrosive Note: a solitary special case is keratan sulfate, in which galactose as opposed to an acidic sugar is available These acidic sugars contain carboxyl gatherings that are contrarily charged at physiologic pH &, together with the sulfate bunches, give GAGs their emphatically –ve nature

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Figure 14.1. Rehashing disaccharide unit.

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Figure 14.2. Some monosaccharide units found in glycosaminoglycans.

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A. Relationship between GAG structure and capacity Because of their vast # of –ve charges, these heteropolysacch fastens have a tendency to be reached out in arrangements. They repulse each other and are encompassed by a shell of water atoms. At the point when united, they "slip" past each other, much as two magnets with a similar extremity appear to slip past each other. This produces "elusive" consistency of mucous emissions & synovial liquid When a soln of GAGs is packed, the water is "crushed out" & the GAGs are compelled to possess a littler volume. At the point when the pressure is discharged, the GAGs spring back to their unique, hydrated volume in light of repugnance of their –ve charges. This property adds to the strength of synovial liquid & the vitreous amusingness of the eye.

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Figure 14.3. Versatility of glycosaminoglycans.

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B. Order of GAGs The six noteworthy classes of GAGs are isolated by monomeric creation, sort of glycosidic linkages, & degree & area of sulfate units. The structure of the GAGs & their circulation in the body delineated in Fig. 4.

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C. Structure of proteoglycans - All of the GAGs, with the exception of hyaluronic cid, are discovered covalently connected to proteins, shaping proteoglycan monomers. 1. Structure of proteoglycan monomer: - A proteoglycan monomer found in ligament comprises of a center protein to which the direct GAG chains are covalently appended These chains which may each be made out of >100 monosacch, reach out from the center protein & stay isolated from each other due to charge shock. The subsequent structure takes after a "jug brush" In ligament proteoglycan, the types of GAGs incorporate chondroitin sulfate & keratan sulfate Note: various proteoglycans have been described & named in view of their structure & practical area. E.g., syndecan is an indispensable memb proteoglycan, versican & aggrecan are the dominating extracellular proteoglycans, & neurocan & cerebrocan are discovered basically in the NS.

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Figure 14.5. "Bottle-brush" model of a ligament proteoglycan monomer.

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2. Linkage between the starch chain & the protein This linkage is most usually through a trihexoside (galactose-galactose-xylose) & a ser buildup, separately. An O-glycosidic bond is framed b/w the xylose & the hydroxyl gathering of the ser.

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3. Proteoglycan totals The proteoglycan monomers connect with an atom of hyaluronic corrosive to frame proteoglycan totals. The affiliation is not covalent, but rather happens fundamentally through ionic collaborations b/w center protein & the hyaluronic corrosive The affiliation is settled by extra little proteins called interface proteins

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Figure 14.7. Proteoglycan total.

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III. Amalgamation of glycosaminoglycans The polysacch chains are lengthened by the successive expansion of rotating acidic & amino sugars, gave by their UDP-subsidiaries The responses are catalyzed by particular transferases The blend of the GAGs is comparable to that of glycogen aside from that the GAGs are created for fare from the cell. The amalgamation happens, along these lines, in the ER & the Golgi, instead of in the cytosol.

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A. Blend of amino sugars Amino sugars are basic segments of GAGs, glycoproteins, glycolipids, & certain oligosaccharides, & are additionally found in a few anti-infection agents. The manufactured pathway of amino sugars is exceptionally dynamic in connective tissues, where as much as 20% of gluc courses through the pathway. 1. N-acetylglucosamine (gluNAc) & N-acetylgalactosamine (galNAc): - The monosacch F-6-P is the antecedent of gluNAc, galNAc, & the sialic acids, including N-acetylneuraminic corrosive (NANA, a nine-carbon, acidic monosacch). In each of these sugars, a hydroxyl gathering of the forerunner is supplanted by an amino gathering gave by the aa, glutamine Note: the amino gatherings are quite often acetylated - The UDP-subsidiaries of gluNAc & galNAc are orchestrated by responses practically equivalent to those depicted for UDP-glucose union. These are enacted types of the monosaccharides that can be utilized to prolong the CHO chain

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2. N-Acetylneuraminic corrosive: NANA is an individual from the group of sialic acids, each of which is acylated at an alternate site. These cpds are typically found as terminal CHO deposits of oligosaccharide side chains of glycoproteins, glycolipids, or, less as often as possible, of GAGs The carbons & nitrogens in NANA originate from N-acetylmannosamine & PEP Note: before NANA can be added to a developing oligosacch, it must be changed over into its dynamic frame by responding with cytidine triphosphate (CTP). The enz N-acetylneuraminate-CMP-pyrophosphorylase expels pyrophosphate from CTP & connects the rest of the CMP to the NANA. This is the main nucleotide sugar in human digestion system in which the bearer nucleotide is a monophosphate

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Figure 14.8. Amalgamation of the amino sugars.

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B. Union of acidic sugars D-glucuronic corrosive, whose structure is that of gluc with an oxidized C-6 (- CH2OH → - COOH), & its C-5 epimer, L-iduronic corrosive, are fundamental parts of GAGs. Glucuronic corrosive is likewise required in detoxification responses of various insoluble cpds, e.g., bilirubin, steroids, & a few medications. In plants & vertebrates (other than guinea pigs & primates, including man), glucuronic corrosive fills in as a forerunner of ascorbic corrosive (vitamin C). The uronic corrosive pathway likewise gives an instrument by which dietary D-xylulose can enter the focal metabolic pathways

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1. Glucuronic corrosive: Glucuronic corrosive can be acquired in little sums from eating regimen. It can likewise be acquired from the intracellular lysosomal corruption of GAGs, or by means of the uronic corrosive pathway. The finished result of glucuronic corrosive digestion system in people is D-xylulose 5-P, which can enter the hexose monophosphate pathway & create the glycolytic intermediates GA-3P & F-6-P The dynamic type of glucuronic corrosive that gives the sugar in GAG combination & other glucuronylating responses is UDP-glucuronic corrosive, which is delivered by oxidation of UDP-glucose 2. L-iduronic corrosive combination: Synthesis of L-iduronic corrosive deposits happens after D-glucuronic corrosive has been consolidated into the CHO chain. Uronosyl 5-epimerase causes epimerization of the D-to L-sugar

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Figure 14.9. Uronic corrosive pathway.

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Figure 14.10. Oxidation of UDP-glucose to UDP-glucuronic corrosive.

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C. Blend of the center protein The center protein is combined on & enters rER. The protein is then glycosylated by memb-bound transferases as it travels through ER. D. Combination of the sugar chain CHO chain arrangement starts by amalgamation of a short linkage district on the center protein on which CHO chain union will be started. The most well-known linkage district is framed by the exchange of xylose from UDP-xylose to the hydroxyl gathering of a ser (or thr) catalyzed by xylosyltransferase . Two galactose atoms are then included, finishing the trihexoside. This is trailed by consecutive expansion of exchanging acidic & amino sugars, & change of some D-glucuronyl to L-iduronyl deposits

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Figure 14.11. Amalgamation of chondroitin sulfate.

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E. Expansion of sulfate gatherings Sulfation of CHO chain happens after the monosacch to be sulfated has been consolidated into the developing CHO chain The wellspring of the sulfate is 3`-phosphoadenosyl-5`-phosphosulfate (PAPS, a particle of AMP with a sulfate aggregate joined to the 5`-phosphate). Sulfotransferases cause the sulfation of the CHO chain at particular locales. Take note of: a deformity in the sulfation procedure brings about one of a few autosomal passive issue that influence the best possible improvement & upkeep of the skeletal framework. This outlines the significance of the sulfation step

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IV. Debasement of glycosaminoglycans GAGs are corrupted in lysosomes, which contain hydrolytic enz\'s that are most dynamic at a pH of ~ 5 [Note: in this way, as a gathering, these are called corrosive hydrolases] The low pH ideal is a defensive instrument that keeps the enz\'s from crushing the phone

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