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Biosynthesis of natural and hyperelongated chondroitin sulfate glycosaminoglycans: new insights into an elusive process.

Little PJ, Ballinger ML, Burch ML, Osman N - Open Biochem J (2008)

Bottom Line: The mechanism by which the CS/DS GAG chains are polymerized is unknown.Recent work has identified several monosaccharide transferases which when co-expressed yield GAG polymers and the length of the polymers depends upon the pair of enzymes coexpressed.The further extension of these chains is regulated by signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: Diabetes and Cell Biology Laboratory, Vascular and Hypertension Division, BakerIDI Heart and Diabetes Institute, Melbourne, VIC, Australia 3004 and.

ABSTRACT
Proteoglycans are important components of the extracellular matrix of all tissues. Proteoglycans are comprised of a core protein and one or more covalently attached glycosaminoglycan (GAG) chains. The major chondroitin sulfate (CS) and dermatan sulfate (DS) proteoglycans are aggrecan, versican, biglycan and decorin. Cells synthesize GAGs of natural or basal lengths and the GAG chains are subject to considerable growth factor, hormonal and metabolic regulation to yield longer GAG chains with altered structure and function. The mechanism by which the CS/DS GAG chains are polymerized is unknown. Recent work has identified several monosaccharide transferases which when co-expressed yield GAG polymers and the length of the polymers depends upon the pair of enzymes coexpressed. The further extension of these chains is regulated by signaling pathways. Inhibition of these latter pathways may be a therapeutic target to prevent the elongation which is associated with increased binding of atherogenic lipids and the disease process of atherosclerosis.

No MeSH data available.


Related in: MedlinePlus

Schema of the biochemical processes leading to the synthesis of natural chondroitin sulfate glycosaminoglycan (GAG) chains and the hyperelongation of GAG chains elicited by multiple cell signaling pathways resulting from the action of growth factor such as PDGF and TGFβ. ChSy chondroitin synthase; ChPF chondroitin polymerizing factor. The scheme to the left shows the normal biosynthesis of a proteoglycan core protein which is new protein and therefore cycloheximide sensitive but is also subject, based on individual and specific core proteins, to up regulation by growth factors. Various combinations, at least pairs of polymerases (see Table 1) add monosaccharides to the preformed tetrasaccharide linkage region on a serine residue on the core protein to produce the “natural” length glycosaminoglycan (GAG) chain. To the right of the scheme it is indicated that growth factors can intervene to result in the production of longer, so called hyperelon-gated GAG chains and although this is cycloheximide sensitive (see text) and acutely requires new protein synthesis the site at which the new protein synthesis occurs, either in the signaling pathway or in the actual transporters and enzymes that synthesis GAGs is unknown. The GAG elongation in response to growth factors is of the order of 20 per cent but this is sufficient to half the affinity of binding of the GAG chain to LDL.
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Figure 2: Schema of the biochemical processes leading to the synthesis of natural chondroitin sulfate glycosaminoglycan (GAG) chains and the hyperelongation of GAG chains elicited by multiple cell signaling pathways resulting from the action of growth factor such as PDGF and TGFβ. ChSy chondroitin synthase; ChPF chondroitin polymerizing factor. The scheme to the left shows the normal biosynthesis of a proteoglycan core protein which is new protein and therefore cycloheximide sensitive but is also subject, based on individual and specific core proteins, to up regulation by growth factors. Various combinations, at least pairs of polymerases (see Table 1) add monosaccharides to the preformed tetrasaccharide linkage region on a serine residue on the core protein to produce the “natural” length glycosaminoglycan (GAG) chain. To the right of the scheme it is indicated that growth factors can intervene to result in the production of longer, so called hyperelon-gated GAG chains and although this is cycloheximide sensitive (see text) and acutely requires new protein synthesis the site at which the new protein synthesis occurs, either in the signaling pathway or in the actual transporters and enzymes that synthesis GAGs is unknown. The GAG elongation in response to growth factors is of the order of 20 per cent but this is sufficient to half the affinity of binding of the GAG chain to LDL.

Mentions: Thus, there appears to be a clear difference between natural GAG synthesis and GAG hyperelongation and a schema is shown in Fig. (2). The fact that GAG hyperelongation has very specific signaling pathways that involve de novo protein synthesis further validates GAG hyperelongation as a potential therapeutic target [14, 16, 17].


Biosynthesis of natural and hyperelongated chondroitin sulfate glycosaminoglycans: new insights into an elusive process.

Little PJ, Ballinger ML, Burch ML, Osman N - Open Biochem J (2008)

Schema of the biochemical processes leading to the synthesis of natural chondroitin sulfate glycosaminoglycan (GAG) chains and the hyperelongation of GAG chains elicited by multiple cell signaling pathways resulting from the action of growth factor such as PDGF and TGFβ. ChSy chondroitin synthase; ChPF chondroitin polymerizing factor. The scheme to the left shows the normal biosynthesis of a proteoglycan core protein which is new protein and therefore cycloheximide sensitive but is also subject, based on individual and specific core proteins, to up regulation by growth factors. Various combinations, at least pairs of polymerases (see Table 1) add monosaccharides to the preformed tetrasaccharide linkage region on a serine residue on the core protein to produce the “natural” length glycosaminoglycan (GAG) chain. To the right of the scheme it is indicated that growth factors can intervene to result in the production of longer, so called hyperelon-gated GAG chains and although this is cycloheximide sensitive (see text) and acutely requires new protein synthesis the site at which the new protein synthesis occurs, either in the signaling pathway or in the actual transporters and enzymes that synthesis GAGs is unknown. The GAG elongation in response to growth factors is of the order of 20 per cent but this is sufficient to half the affinity of binding of the GAG chain to LDL.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2627520&req=5

Figure 2: Schema of the biochemical processes leading to the synthesis of natural chondroitin sulfate glycosaminoglycan (GAG) chains and the hyperelongation of GAG chains elicited by multiple cell signaling pathways resulting from the action of growth factor such as PDGF and TGFβ. ChSy chondroitin synthase; ChPF chondroitin polymerizing factor. The scheme to the left shows the normal biosynthesis of a proteoglycan core protein which is new protein and therefore cycloheximide sensitive but is also subject, based on individual and specific core proteins, to up regulation by growth factors. Various combinations, at least pairs of polymerases (see Table 1) add monosaccharides to the preformed tetrasaccharide linkage region on a serine residue on the core protein to produce the “natural” length glycosaminoglycan (GAG) chain. To the right of the scheme it is indicated that growth factors can intervene to result in the production of longer, so called hyperelon-gated GAG chains and although this is cycloheximide sensitive (see text) and acutely requires new protein synthesis the site at which the new protein synthesis occurs, either in the signaling pathway or in the actual transporters and enzymes that synthesis GAGs is unknown. The GAG elongation in response to growth factors is of the order of 20 per cent but this is sufficient to half the affinity of binding of the GAG chain to LDL.
Mentions: Thus, there appears to be a clear difference between natural GAG synthesis and GAG hyperelongation and a schema is shown in Fig. (2). The fact that GAG hyperelongation has very specific signaling pathways that involve de novo protein synthesis further validates GAG hyperelongation as a potential therapeutic target [14, 16, 17].

Bottom Line: The mechanism by which the CS/DS GAG chains are polymerized is unknown.Recent work has identified several monosaccharide transferases which when co-expressed yield GAG polymers and the length of the polymers depends upon the pair of enzymes coexpressed.The further extension of these chains is regulated by signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: Diabetes and Cell Biology Laboratory, Vascular and Hypertension Division, BakerIDI Heart and Diabetes Institute, Melbourne, VIC, Australia 3004 and.

ABSTRACT
Proteoglycans are important components of the extracellular matrix of all tissues. Proteoglycans are comprised of a core protein and one or more covalently attached glycosaminoglycan (GAG) chains. The major chondroitin sulfate (CS) and dermatan sulfate (DS) proteoglycans are aggrecan, versican, biglycan and decorin. Cells synthesize GAGs of natural or basal lengths and the GAG chains are subject to considerable growth factor, hormonal and metabolic regulation to yield longer GAG chains with altered structure and function. The mechanism by which the CS/DS GAG chains are polymerized is unknown. Recent work has identified several monosaccharide transferases which when co-expressed yield GAG polymers and the length of the polymers depends upon the pair of enzymes coexpressed. The further extension of these chains is regulated by signaling pathways. Inhibition of these latter pathways may be a therapeutic target to prevent the elongation which is associated with increased binding of atherogenic lipids and the disease process of atherosclerosis.

No MeSH data available.


Related in: MedlinePlus