| Structural and Functional Study of D-Glucuronyl C5-epimerase | |
| Qin, Yi4,5; Ke, Jiyuan3; Gu, Xin3; Fang, Jianping2,5; Wang, Wucheng5; Cong, Qifei5; Li, Jie5; Tan, Jinzhi4; Brunzelle, Joseph S.1; Zhang, Chenghai4 | |
| 刊名 | JOURNAL OF BIOLOGICAL CHEMISTRY
 |
| 2015-02-20 | |
| 卷号 | 290期号:8页码:4620-4630 |
| ISSN号 | 0021-9258 |
| DOI | 10.1074/jbc.M114.602201 |
| 文献子类 | Article |
| 英文摘要 | Heparan sulfate (HS) is a glycosaminoglycan present on the cell surface and in the extracellular matrix, which interacts with diverse signal molecules and is essential for many physiological processes including embryonic development, cell growth, inflammation, and blood coagulation. D-Glucuronyl C5-epimerase (Glce) is a crucial enzyme in HS synthesis, converting D-glucuronic acid to L-iduronic acid to increase HS flexibility. This modification of HS is important for protein ligand recognition. We have determined the crystal structures of Glce in apo-form (unliganded) and in complex with heparin hexasaccharide (product of Glce following O-sulfation), both in a stable dimer conformation. A Glce dimer contains two catalytic sites, each at a positively charged cleft in C-terminal alpha-helical domains binding one negatively charged hexasaccharide. Based on the structural and mutagenesis studies, three tyrosine residues, Tyr(468), Tyr(528), and Tyr(546), in the active site were found to be crucial for the enzymatic activity. The complex structure also reveals the mechanism of product inhibition (i.e. 2-O- and 6-O-sulfation of HS keeps the C5 carbon of L-iduronic acid away from the active-site tyrosine residues). Our structural and functional data advance understanding of the key modification in HS biosynthesis. |
| 资助项目 | National Natural Science Foundation of China (NSFC)[31230022] ; National Science Fund for Distinguished Young Scholars[81125025] ; New Drug Creation and Manufacturing Program[2012ZX09301001-003] ; Swedish Research Council[00000000] ; Swedish Cancer Foundation[00000000] ; Michigan Economic Development Corporation[00000000] ; Michigan Technology Tri-Corridor Grant[085P1000817] |
| WOS关键词 | HEPARAN-SULFATE BIOSYNTHESIS ; L-IDURONIC ACID ; CAPSULAR POLYSACCHARIDE ; HEPARIN/HEPARAN SULFATE ; IN-VIVO ; ENZYME ; C-5-EPIMERASE ; MECHANISM ; CELLS ; 2-O-SULFOTRANSFERASE |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| 出版者 | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC |
| WOS记录号 | WOS:000350042000008 |
| 内容类型 | 期刊论文 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276636]  |
| 专题 | 药物靶标结构与功能中心 药理学第三研究室 |
| 通讯作者 | Ke, Jiyuan |
| 作者单位 | 1.Northwestern Univ, Life Sci Collaborat Access Team, Synchrotron Res Ctr, Argonne, IL 60439 USA 2.Uppsala Univ, Dept Med Biochem & Microbiol, SE-75123 Uppsala, Sweden; 3.Van Andel Res Inst, Lab Struct Sci, Ctr Struct Biol & Drug Discovery, Grand Rapids, MI 49503 USA; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, VARI SIMM Ctr,Ctr Struct & Funct Drug Targets, Shanghai 201203, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Glycochemistry & Glycobiol Lab, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Qin, Yi,Ke, Jiyuan,Gu, Xin,et al. Structural and Functional Study of D-Glucuronyl C5-epimerase[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2015,290(8):4620-4630. |
| APA | Qin, Yi.,Ke, Jiyuan.,Gu, Xin.,Fang, Jianping.,Wang, Wucheng.,...&Ding, Kan.(2015).Structural and Functional Study of D-Glucuronyl C5-epimerase.JOURNAL OF BIOLOGICAL CHEMISTRY,290(8),4620-4630. |
| MLA | Qin, Yi,et al."Structural and Functional Study of D-Glucuronyl C5-epimerase".JOURNAL OF BIOLOGICAL CHEMISTRY 290.8(2015):4620-4630. |
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