Industry Information

Picoglycan sulfate is an aminoglycan sulfate

  Pathway Summary from MetaCyc:

  Dermatan sulfate is a sulfated glycosaminoglycan composed of alternating units of sulfated N-acetyl-α-D-galactosamine and α-L-idopyranuronate (and some β-D-glucuronate) residues. The N-acetyl-α-D-galactosamine residues are substituted to varying degrees with sulfate linked to 4- and/or 6-hydroxyl positions, forming N-acetyl-β-D-galactosamine 4-sulfate, N-acetyl-D-galactosamine 6-O-sulfate or N-acetyl-D-galactosamine 4,6-bissulfate, and the uronic acid residues may be substituted with sulfate at the 2-hydroxyl position forming 2-O-sulfo-β-D-glucuronate or α-L-iduronate 2-O-sulfate. The uronic acid residues may also be substituted with sulfate at the 3-hydroxyl positions, although this substitution is quite rare. The dermatan chains vary in size up to a hundred or more disaccharide repeating units. They are usually found attached to assorted core proteins as part of a proteoglycan complex. Dermatan sulfate is a major component of connective tissue matrix (such as skin and cartilage), but is 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 dermatan chains are 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 inglycosaminoglycan-protein linkage region biosynthesis.

  The linkage region may be extended into mutiple kinds of glycosaminoglycans. However, the addition of an N-acetyl-α-D-galactosamine residue prevents the formation ofheparin or 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 CSGALNACT1 and CSGALNACT2 genes [Uyama02, Kitagawa03,Uyama03].

  Once the linkage region has been formed and committed, the polymerzation of the chondroitin/dermatan chain proceeds by the alternate addition of β-D-glucuronate and N-acetyl-α-D-galactosamine from activated precursors to the non-reducing end of the elongating chain. The addition of both residues is catalyzed by the bifunctional chondroitin sulfate synthases. Humans possess three isoforms of this bifunctional enzyme ( CHSY1, CHPF and CHSY3), plus an additional enzyme that can catalyze only the addition of β-D-glucuronate ( CHPF2) [Kitagawa01, Yada03, Gotoh02]. 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 [Izumikawa07, Izumikawa08].

  Up to this point in the pathway dermatan and chondroitin share the same biosynthesis pathway and enzymes. The difference in their synthetic routes begin only at the later stages of synthesis. A key reaction in the conversion of the chondroitin/dermatan precursor chain to a dermatan sulfate chain is the conversion of β-D-glucuronateresidues to α-L-idopyranuronate residues. This reaction is catalyzed by the enzyme dermatan-sulfate epimerase, encoded by the DSE gene [Maccarana06].

  The rest of the modifications consist of sulfation reactions. The enzyme dermatan 4-sulfotransferase 1, encoded by the CHST14 gene, is a sulfotransferase that appears to be specific for sulfating the C4 position of N-acetyl-α-D-galactosamine linked to α-L-idopyranuronate residues, and is thus dermatan-specific. Although a similar enzyme specific for 6-sulfation of dermatan has not been found, it has been suggested that such an enzyme exists, as the enzymes that sulfate chondroitin at the 6 position of N-acetyl-α-D-galactosamine do not have high activity when that residue is linked to α-L-idopyranuronate [Tsutsumi98].

  On the other hand, the enzyme that catalyzes the 6-sulfation of N-acetyl-α-D-galactosamine residues that are already sulfated at the C4 position is the same one that catalyzes the reaction with a [chondroitin-sulfate] containing 4-O-sulfo-N-acetylgalactosamine, encoded by CHST15 [Ohtake01]. Similarly, the enzyme that catalyzes the sulfation of the C2 position of a [dermatan] containing α-L-iduronate is the enzyme that catalyzes a similar reaction with a [chondroitin] containing β-D-glucuronateresidues, uronyl 2-sulfotransferase ( UST) [Kobayashi99].

  The very first reaction in this pathway, the addition of a xylose molecule to a serine residue of the core protein, is performed at the endoplasmic reticulum. The rest of the pathway occurs at the Golgi apparatus.