Structural and Biochemical Characterization of Glycoside Hydrolase Family 79 β-Glucuronidase from Acidobacterium capsulatum

Michikawa, M.; Ichinose, Hitomi; Momma, Mitsuru; Biely, Peter; Jongkees, Seino A. K.; Yoshida, Makoto; Kotake, Toshihisa; Tsumuraya, Yoichi; Withers, Stephen G.; Fujimoto, Zui; Kaneko, Satoshi

doi:10.1074/jbc.m112.346288

Cited by 40 publications

(43 citation statements)

References 30 publications

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“…Both 8 kDa and 50 kDa subunits are structurally involved in both domains: the 8 kDa subunit contributes 1 β-sheet to the β-sandwich, and the 1 st β-α-β fold of the (β/α) 8 domain, with the remaining folds contributed by the 50 kDa subunit (Figure 1b). Overall, the domain architecture of HPSE is superficially similar to that of previously characterized bacterial GH79s27,28, with Cα root mean square difference of 2.35 Å over 392 residues (out of 457) and 2.59 Å over 387 residues for AcaGH79 and BpHPSE respectively (Supplementary Figure 2a). …”

Section: Resultssupporting

confidence: 68%

Structural characterization of human heparanase reveals insights into substrate recognition

Viola

Brzozowski

et al. 2015

Nat Struct Mol Biol

145

243

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Heparan Sulfate (HS) is a glycosaminoglycan (GAG) which forms a key component of the extracellular matrix (ECM). Breakdown of HS is carried out by heparanase (HPSE), an endo-β-glucuronidase of the glycoside hydrolase (GH)79 family. Overexpression of HPSE is strongly linked to cancer metastases - reflecting breakdown of extracellular HS and release of stored growth factors. Here we present crystal structures of human HPSE at 1.6-1.9 Å resolution reveal how an endo-acting binding cleft is exposed by proteolytic activation of latent proHPSE. Oligosaccharide complexes map the substrate-binding and sulfate recognition motifs. These data shed light on the structure and interactions for a key enzyme involved in ECM maintenance, and provide a starting point for design of HPSE inhibitors as biochemical tools and anti-cancer therapeutics.

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Section: Resultssupporting

confidence: 68%

Structural characterization of human heparanase reveals insights into substrate recognition

Viola

Brzozowski

et al. 2015

Nat Struct Mol Biol

145

243

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“…The BLAST program was used to search suitable template available in the PDB (34). The crystal structure of beta-glucuronidase (PDB:3VNZ) from Acidobacterium Capsulatum with a resolution of 1.8 Å was obtained, shared 24% sequence identity with human heparanase (35). (ii) Sequence alignment.…”

Section: Homology Modeling Of Human Heparanasementioning

confidence: 99%

Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

Dai

Yan

et al. 2017

Clinical Cancer Research

104

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Purpose: Recent epidemiological and clinical studies have suggested the benefit of aspirin for patients with cancer, which inspired increasing efforts to demonstrate the anticancer ability of aspirin and reveal the molecular mechanisms behind. Nevertheless, the anticancer activity and related mechanisms of aspirin remain largely unknown. This study aimed to confirm this observation, and more importantly, to investigate the potential target contributed to the anticancer of aspirin.Experimental Design: A homogeneous time-resolved fluorescence (HTRF) assay was used to examine the impact of aspirin on heparanase. Streptavidin pull-down, surface plasmon resonance (SPR) assay, and molecular docking were performed to identify heparanase as an aspirin-binding protein. Transwell, rat aortic rings, and chicken chorioallantoic membrane model were used to evaluate the antimetastasis and anti-angiogenesis effects of aspirin, and these phenotypes were tested in a B16F10 metastatic model, MDA-MB-231 metastatic model, and MDA-MB-435 xenograft model.Results: This study identified heparanase, an oncogenic extracellular matrix enzyme involved in cancer metastasis and angiogenesis, as a potential target of aspirin. We had discovered that aspirin directly binds to Glu225 region of heparanase and inhibits the enzymatic activity. Aspirin impeded tumor metastasis, angiogenesis, and growth in heparanase-dependent manner.Conclusions: In summary, this study has illustrated heparanase as a target of aspirin for the first time. It provides insights for a better understanding of the mechanisms of aspirin in anticancer effects, and offers a direction for the development of smallmolecule inhibitors of heparanase.

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“…Members of the GH10 and GH11 [76,77], GH16 [78], GH51 [79,80] and GH79 [81] gene families have previously been associated with AX turnover and representatives were found under QAX2.S-3H1 (GH10; MLOC_75090), QAX2.S-5H1 (GH51; MLOC_56099 and GH79; MLOC_15027), and QAX2.S-5H2 (GH16; MLOC_80451). GH10 enzymes are endo-β-1, 4-xylanases and are involved in the hydrolysis of glycoside linkages of the xylan backbone [82].…”

Section: Significantly Associated Modifying and Hydrolytic Genesmentioning

confidence: 99%

A Genome Wide Association Study of arabinoxylan content in 2-row spring barley grain

et al. 2017

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In barley endosperm arabinoxylan (AX) is the second most abundant cell wall polysaccharide and in wheat it is the most abundant polysaccharide in the starchy endosperm walls of the grain. AX is one of the main contributors to grain dietary fibre content providing several health benefits including cholesterol and glucose lowering effects, and antioxidant activities. Due to its complex structural features, AX might also affect the downstream applications of barley grain in malting and brewing. Using a high pressure liquid chromatography (HPLC) method we quantified AX amounts in mature grain in 128 spring 2-row barley accessions. Amounts ranged from ~ 5.2 μg/g to ~ 9 μg/g. We used this data for a Genome Wide Association Study (GWAS) that revealed three significant quantitative trait loci (QTL) associated with grain AX levels which passed a false discovery threshold (FDR) and are located on two of the seven barley chromosomes. Regions underlying the QTLs were scanned for genes likely to be involved in AX biosynthesis or turnover, and strong candidates, including glycosyltransferases from the GT43 and GT61 families and glycoside hydrolases from the GH10 family, were identified. Phylogenetic trees of selected gene families were built based on protein translations and were used to examine the relationship of the barley candidate genes to those in other species. Our data reaffirms the roles of existing genes thought to contribute to AX content, and identifies novel QTL (and candidate genes associated with them) potentially influencing the AX content of barley grain. One potential outcome of this work is the deployment of highly associated single nucleotide polymorphisms markers in breeding programs to guide the modification of AX abundance in barley grain.

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Structural and Biochemical Characterization of Glycoside Hydrolase Family 79 β-Glucuronidase from Acidobacterium capsulatum

Cited by 40 publications

References 30 publications

Structural characterization of human heparanase reveals insights into substrate recognition

Structural characterization of human heparanase reveals insights into substrate recognition

Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

A Genome Wide Association Study of arabinoxylan content in 2-row spring barley grain

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