Structural and Functional Study of d-Glucuronyl C5-epimerase

Qin, Yi; Ke, Jiyuan; Gu, Xin; Fang, Jianping; Wang, Wucheng; Cong, Qifei; Li, Jie; Tan, Jingjing; Brunzelle, J.S.; Zhang, Chenghai; Jiang, Yi; Melcher, Karsten; Li, Jin Ping; Xu, H. Eric; Ding, Kan

doi:10.1074/jbc.m114.602201

Cited by 37 publications

(33 citation statements)

References 37 publications

(43 reference statements)

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“…The disaccharide in HS, a minor component of heparin (-4 (Maruyama et al, 1998 Pharmacology of Heparin and Related Drugs crystal structure of this enzyme (the sequence from Danio rero) in complex with a heparin oligosaccharide was recently solved (4PXQ.pdb) and compared with the unbound enzyme (4PW2.pdb) (Qin et al, 2015). The sequence GlcNAc-IdoA is therefore not found in mammalian HS or heparin.…”

Section: A Biosynthesismentioning

confidence: 99%

“…The sequence GlcNAc-IdoA is therefore not found in mammalian HS or heparin. Closely associated with the epimerase is the IdoA-2-O-sulfotransferase (2-OST) (Qin et al, 2015), which as its name implies adds sulfate to the 2-position of the newly formed IdoA residue to give IdoA2S; rarely, it can also add 2-O-sulfate to b-DGlcA. 2-O-sulfated GlcA was found in nuclear HS as long ago as 1986 (Fedarko and Conrad, 1986) and has also been seen in highly sulfated heparin sequences (Yamada et al, 1995).…”

Section: A Biosynthesismentioning

confidence: 99%

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Pharmacology of Heparin and Related Drugs

et al. 2015

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Section: A Biosynthesismentioning

confidence: 99%

Section: A Biosynthesismentioning

confidence: 99%

Pharmacology of Heparin and Related Drugs

et al. 2015

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“…The region that binds most strongly in the EG matches the crystallographic positions of the heparin hexasaccharide, and covers the amino acid residues most important for enzymatic activity. 49 However, the low energy Table S1) according to Equation 11. (C) EG based probability density of heparin disaccharide drawn around 20% HDR (solid green) and 30% HDR (translucent green).…”

Section: Sonic Hedgehog and Heparinmentioning

confidence: 99%

Locating Large, Flexible Ligands on Proteins

Grad

Gigante

Wilms

et al. 2018

J. Chem. Inf. Model.

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Many biologically important ligands of proteins are large, flexible, and in many cases charged molecules that bind to extended regions on the protein surface. It is infeasible or expensive to locate such ligands on proteins with standard methods such as docking or molecular dynamics (MD) simulation. The alternative approach proposed here is scanning of a spatial and angular grid around the protein with smaller fragments of the large ligand. Energy values for complete grids can be computed efficiently with a well-known fast Fourier transform-accelerated algorithm and a physically meaningful interaction model. We show that the approach can readily incorporate flexibility of the protein and ligand. The energy grids (EGs) resulting from the ligand fragment scans can be transformed into probability distributions and then directly compared to probability distributions estimated from MD simulations and experimental structural data. We test the approach on a diverse set of complexes between proteins and large, flexible ligands, including a complex of sonic hedgehog protein and heparin, three heparin sulfate substrates or nonsubstrates of an epimerase, a multibranched supramolecular ligand that stabilizes a protein-peptide complex, a flexible zwitterionic ligand that binds to a surface basin of a Kringle domain, and binding of ATP to a flexible site of an ion channel. In all cases, the EG approach gives results that are in good agreement with experimental data or MD simulations.

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“…This selectivity requires the NST pre-treatment before C5-epimerase and 2OST [82]. C5-epimerase only converts GlcA residues between two GlcNS residues [82,83] to IdoA and works best in conjunction with 2OST, which locks the normally reversible reaction into the IdoA epimer with the introduction of a 2- O -sulfo group [84]. Complete introduction of 6- O -sulfo groups relies on two of the three 6OST isoforms, 6OST-1 and 6OST-3, which transfer sulfo groups to GlcNS residues next to GlcA and IdoA2S residues, respectively [50].…”

Section: Bioengineering Ulmwh Lmwh and Heparinmentioning

confidence: 99%

Bioengineered heparins and heparan sulfates

Suflita

Linhardt

2016

Advanced Drug Delivery Reviews

107

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Heparin and heparan sulfates are closely related linear anionic polysaccharides, called glycosaminoglycans, which exhibit a number of important biological and pharmacological activities. These polysaccharides, having complex structures and polydispersity, are biosynthesized in the Golgi of animal cells. While heparan sulfate is a widely distributed membrane and extracellular glycosaminoglycan, heparin is found primarily intracellularly in the granules of mast cells. While heparin has historically received most of the scientific attention for its anticoagulant activity, interest has steadily grown in the multi-faceted role heparan sulfate plays in normal and pathophysiology. The chemical synthesis of these glycosaminoglycans is largely precluded by their structural complexity. Today, we depend on livestock animal tissues for the isolation and the annual commercial production of hundred ton quantities of heparin used in the manufacture of anticoagulant drugs and medical device coatings. The variability of animal-sourced heparin and heparan sulfates, their inherent impurities, the limited availability of source tissues, the poor control of these source materials and their manufacturing processes, suggest a need for new approaches for their production. Over the past decade there have been major efforts in the biotechnological production of these glycosaminoglycans, driven by both therapeutic applications and as probes to study their natural functions. This review focuses on the complex biology of these glycosaminoglycans in human health and disease, and the use of recombinant technology in the chemoenzymatic synthesis and metabolic engineering of heparin and heparan sulfates.

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Structural and Functional Study of d-Glucuronyl C5-epimerase

Cited by 37 publications

References 37 publications

Pharmacology of Heparin and Related Drugs

Pharmacology of Heparin and Related Drugs

Locating Large, Flexible Ligands on Proteins

Bioengineered heparins and heparan sulfates

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