Pathway: chondroitin and dermatan biosynthesis

General Background |FRAME: Chondroitin-sulfates "Chondroitin sulfate| and |FRAME: Dermatan-Sulfate dermatan sulfate| are related sulfated |FRAME: Glycosaminoglycans "glycosaminoglycans"|. |FRAME: Chondroitin-sulfates "Chondroitin sulfate"| is composed of alternating units of sulfated |FRAME:CPD-12557 N-acetyl-β-D-galactosamine| and |FRAME: CPD-12521 β-D-glucuronate| residues, while in |FRAME: Dermatan-Sulfate dermatan sulfate| the |FRAME: CPD-12521 β-D-glucuronate| residues have largely been converted to |FRAME: CPD-12515 α-L-iduronate|. The |FRAME: CPD-12557 N-acetyl-β-D-galactosamine| residues are substituted to varying degrees with sulfate linked to 4- and/or 6-hydroxyl positions, forming |FRAME: CPD-12516 N-acetyl-β-D-galactosamine 4-sulfate|, |FRAME: CPD-12565 β-N-acetyl-D-glucosamine 6-sulfate| or |FRAME: CPD-12526 N-acetyl-D-galactosamine 4,6-bissulfate|, and to a lesser extent the uronic acid residues may be substituted with sulfate at the 2-hydroxyl position forming |FRAME: CPD-12527 2-O-sulfo-β-D-glucuronate| or |FRAME:CPD-12518 2-O-sulfo-α-L-iduronate|. The uronic acid residues may also be substituted with sulfate at the 3-hydroxyl positions, although this substitution is quite rare. The chondroitin/dermatan chains vary in size up to a hundred or more disaccharide repeating units. Both are usually found attached to assorted core proteins as part of a proteoglycan complex. They are major components of connective tissue matrix (such as skin and cartilage), but are also found on cell surface and basement membranes and in intracellular granules of certain cells. Functions in matrix locations are mainly structural, while functions in membranes are mainly as receptors. The chondroitin/dermatan chains are actually synthesized in situ on the protein chain. They are attached to the core protein via a specific tetrasaccharide known as the "glycoaminoglycan-protein linkage region", which is formed by sequential stepwise additions of the sugar residues to specific core proteins. The synthesis of the linkage region is described in |FRAME: PWY-6557 glycoaminoglycan-protein linkage region biosynthesis|. About This Pathway The linkage region may be extended into mutiple kinds of glycosaminoglycans. However, the addition of an |FRAME: CPD-12557 N-acetyl-β-D-galactosamine| residue prevents the formation of |FRAME: HEPARIN heparin| or |FRAME: Heparan-Sulfate heparan sulfate| and commits the molecule to become chondroitin or dermatan. This reaction is catalyzed by the enzyme chondroitin sulfate N-acetylgalactosaminyltransferase. Humans have two isoforms of this enzyme, encoded by the |FRAME: HS07428 CSGALNACT1| and |FRAME:HS10013 CSGALNACT2| genes |CITS: [11788602][12716890][12433924]|. Once the linkage region has been formed and committed, the polymerzation of the chondroitin/dermatan chain proceeds by the alternate addition of |FRAME: CPD-12521 β-D-glucuronate| and |FRAME: CPD-12557 N-acetyl-β-D-galactosamine| from activated precursors to the non-reducing end of the elongating chain. The addition of both residues is catalyzed by the biofunctional chondroitin sulfate synthases. Humans possess three isoforms of this bifunctional enzyme (|FRAME: HS13400 CHSY1|, |FRAME: HS13103 CHPF| and |FRAME: HS11959 CHSY3|), plus an additional enzyme that can catalyze only the addition of |FRAME: CPD-12521 β-D-glucuronate| (|FRAME: HS12080 CHPF2|) |CITS:[11514575][12907687][12145278]|. It has been suggested that chondroitin polymerization is achieved by multiple combinations of the different enzymes and that each combination may play a unique role in the biosynthesis of chondroitin or dermatan sulfate |CITS:[17253960][18316376]|. Further modifications of |FRAME: Chondroitin-sulfates chondroitin sulfate| and |FRAME: Dermatan-Sulfate dermatan sulfate| are described in the pathways |FRAME: PWY-6567 chondroitin sulfate biosynthesis (late stages)| and |FRAME: PWY-6568 dermatan sulfate biosynthesis (late stages)|, respectively.