Two dermatan sulfate epimerases form iduronic acid domains in dermatan sulfate.
A second dermatan sulfate epimerase (DS-epi2) was identified as a homolog of the first epimerase (DS-epi1), which was previously described by our group. DS-epi2 is 1,222 amino acids long and has an approximately 700-amino acid N-terminal epimerase domain that is highly conserved between the two enzymes. In addition, the C-terminal portion is predicted to be an O-sulfotransferase domain. In this study we found that DS-epi2 has epimerase activity, which involves conversion of d-glucuronic acid to l-iduronic acid (EC 5.1.3.19), but no O-sulfotransferase activity was detected. In dermatan sulfate, iduronic acid residues are either clustered together in blocks or alternating with glucuronic acid, forming hybrid structures. By using a short interfering RNA approach, we found that DS-epi2 and DS-epi1 are both involved in the biosynthesis of the iduronic acid blocks in fibroblasts and that DS-epi2 can also synthesize the hybrid structures. Both iduronic acid-containing domains have been shown to bind to several growth factors, many of which have biological roles in brain development. DS-epi2 has been genetically linked to bipolar disorder, which suggests that the dermatan sulfate domains generated by a defective enzyme may be involved in the etiology of the disease.
Pacheco
Benny
B
Department of Experimental Medical Science, Biomedical Center D12, Lund University, Tornavägen 10, SE-221 84 Lund, Sweden.
Malmström
Anders
A
Maccarana
Marco
M
D000595:Amino Acid Sequence; D002460:Cell Line; D002478:Cells, Cultured; D003871:Dermatan Sulfate / Q000737:chemistry*; D005347:Fibroblasts / Q000378:metabolism; D020723:Glucuronic Acid / Q000737:chemistry; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007067:Iduronic Acid / Q000737:chemistry*; D008969:Molecular Sequence Data; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D019998:Racemases and Epimerases / Q000378:metabolism*; D015238:Sulfotransferases / Q000378:metabolism
D034741:RNA, Small Interfering; D003871:Dermatan Sulfate; D007067:Iduronic Acid; D020723:Glucuronic Acid; D015238:Sulfotransferases; D019998:Racemases and Epimerases