デジマ カツフミ   Dejima Katsufumi
  出嶋 克史
   所属   医学部 医学科
   職種   助教
論文種別 原著
言語種別 英語
査読の有無 査読あり
表題 Analysis of Drosophila glucuronyl C5-epimerase: implications for developmental roles of heparan sulfate sulfation compensation and 2-O-sulfated glucuronic acid.
掲載誌名 正式名:The Journal of biological chemistry
略  称:J Biol Chem
ISSNコード:1083-351X(Electronic)0021-9258(Linking)
巻・号・頁 288(48),34384-93頁
著者・共著者 Dejima Katsufumi, Takemura Masahiko, Nakato Eriko, Peterson Jesse, Hayashi Yoshiki, Kinoshita-Toyoda Akiko, Toyoda Hidenao, Nakato Hiroshi
発行年月 2013/11
概要 During the biosynthesis of heparan sulfate (HS), glucuronyl C5-epimerase (Hsepi) catalyzes C5-epimerization of glucuronic acid (GlcA), converting it to iduronic acid (IdoA). Because HS 2-O-sulfotransferase (Hs2st) shows a strong substrate preference for IdoA over GlcA, C5-epimerization is required for normal HS sulfation. However, the physiological significance of C5-epimerization remains elusive. To understand the role of Hsepi in development, we isolated Drosophila Hsepi mutants. Homozygous mutants are viable and fertile with only minor morphological defects, including the formation of an ectopic crossvein in the wing, but they have a short lifespan. We propose that two mechanisms contribute to the mild phenotypes of Hsepi mutants: HS sulfation compensation and possible developmental roles of 2-O-sulfated GlcA (GlcA2S). HS disaccharide analysis showed that loss of Hsepi resulted in a significant impairment of 2-O-sulfation and induced compensatory increases in N- and 6-O-sulfation. Simultaneous block of Hsepi and HS 6-O-sulfotransferase (Hs6st) activity disrupted tracheoblast formation, a well established FGF-dependent process. This result suggests that the increase in 6-O-sulfation in Hsepi mutants is critical for the rescue of FGF signaling. We also found that the ectopic crossvein phenotype can be induced by expression of a mutant form of Hs2st with a strong substrate preference for GlcA-containing units, suggesting that this phenotype is associated with abnormal GlcA 2-O-sulfation. Finally, we show that Hsepi formed a complex with Hs2st and Hs6st in S2 cells, raising the possibility that this complex formation contributes to the close functional relationships between these enzymes.
DOI 10.1074/jbc.M113.499269
文献番号 24133213