Structural insight into the mechanism of streptozotocin inhibition of O-GlcNAcase

He, Yuan; Martinez-Fleites, C.; Bubb, Abigail K.; Gloster, T.M.; Davies, G.J.

doi:10.1016/j.carres.2008.12.007

Cited by 20 publications

(14 citation statements)

References 25 publications

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“…Streptozitocin is a cytotoxic glucose analogue that is selectively absorbed by insulin producing β-cells through GLUT2 and it induces the death of β-cells by donating nitric oxide, generating reactive oxygen species and disrupting the actions of pancreatic antioxidant enzymes [26]. Pancreatic β-cells, which store and release insulin, are the main regulator of glycogenesis in muscle and liver.…”

Section: Discussionmentioning

confidence: 99%

Standardized extract of Ficus deltoidea stimulates insulin secretion and blocks hepatic glucose production by regulating the expression of glucose-metabolic genes in streptozitocin-induced diabetic rats

Farsi

Ahmad

Hor

et al. 2014

BMC Complement Altern Med

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BackgroundRecently, there has been increasing interest in Ficus deltoidea Jack. (Moraceae) due to its chemical composition and the potential health benefits. The present study was undertaken to investigate the effect of extracts of F. deltoidea leaves on diabetes.MethodsThe petroleum ether, chloroform and methanol extracts of F. deltoidea were prepared and subjected to standardization using preliminary phytochemical and HPLC analysis. Dose selection was made on the basis of acute oral toxicity study (50–5000 mg/kg b. w.) as per OECD guidelines. Diabetes mellitus was induced with streptozotocin and rats found diabetic were orally administered with the extract (250, 500 and 1000 mg/kg) for 14 days. Levels of blood glucose and insulin were measured in control as well as diabetic rats on 0, 7 and 14th day. In addition, glucose metabolism regulating gene expression was assessed using RT-PCR.ResultsHPLC analysis revealed that the methanol extract is enriched with C-glycosylflavones particularly, vitexin and isovitexin. In oral glucose tolerance test, oral administration of the methanol extract increased the glucose tolerance. The methanol extract showed significant (P < 0.01) antidiabetic activity. The extract treatment caused significant reduction (p < 0.01) in elevated fasting blood glucose level in streptozotocin-induced diabetic rats. The streptozotocin-related weight loss in rats was noticeably reversed by the extract treatment. Finally, RT-PCR analysis revealed a novel mechanisms for the anti-diabetic action of methanol extract of F. deltoidea. The extract exerted its effect via an increase of insulin secretion which impeded the hepatic glucose production, via down-regulation of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase genes expression on one hand, and up-regulation of hepatic GK and PPARγ genes expression on the other hand. The extract caused an increased expression of GLUT-4 gene expression in skeletal muscles which leads to normalize the hyperglycemia. The extract also nullified the toxic effects of streptozitocin by blocking its entry into the islet β-cells through reducing the expression of GLUT-2 gene.ConclusionIt can be concluded that, F. deltoidea could potentially inhibits the streptozitocin-induced hyperglycemia in rats. Further the herb can be utilized as useful remedy for alleviation of diabetes complications.

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Section: Discussionmentioning

confidence: 99%

Standardized extract of Ficus deltoidea stimulates insulin secretion and blocks hepatic glucose production by regulating the expression of glucose-metabolic genes in streptozitocin-induced diabetic rats

Farsi

Ahmad

Hor

et al. 2014

BMC Complement Altern Med

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“…STZ is widely used to induce type 1 diabetes in rodent models (30, 42, 43). However, it is known that in some cases STZ can induce AKI.…”

Section: Discussionmentioning

confidence: 99%

Urinary Angiotensinogen as a Novel Early Biomarker of Intrarenal Renin^|^ndash;Angiotensin System Activation in Experimental Type 1 Diabetes

2012

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Urinary excretion of albumin (UAlb) is used clinically as a marker of diabetic nephropathy (DN). Although DN was thought to be a unidirectional process, recent studies demonstrated that a large proportion of patients diagnosed with DN reverted to normoalbuminuria. Moreover, despite the normoalbuminuria, one-third of them exhibited reduced renal function even during the microalbuminuric stage. This study was performed to investigate whether urinary angiotensinogen (UAGT) level may serve as a useful marker of the early stage of experimental type 1 diabetes (T1DM). T1DM was induced by a single intraperitoneal injection of streptozotocin. Control mice were injected with citrate buffer. Two days after streptozotocin injection, half of the mice received continuous insulin treatment. Our data showed that UAlb excretion was increased 6 days after streptozotocin injection compared to controls, whereas UAGT excretion was increased at an earlier time point. These increases were reversed by insulin treatment. The UAGT to UAlb ratio was increased in diabetic mice compared to control mice. Furthermore, the increased AGT expression in the kidneys was observed in diabetic mice. These data suggest that UAGT might be useful as a novel early biomarker of activation of the renin–angiotensin system in experimental type 1 diabetes.

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“…The unique open-close mechanism of the active site would enable OfHex1 not only to carry out catalysis but also to facilitate substrate binding or release of product. Although no such conformational change has been found in other known GH20 enzymes (14 -23), conformational change has been observed in GH84 ␤-N-acetyl-D-glucosaminidase (CpGH84) after binding with inhibitor due to a 180°rotation by the catalytic aspartate (Asp 298 ) (34,35). Before the binding of substrate, the side chain of the catalytic Glu 368 of OfHex1 is connected to Thr 427 via two hydrogen bonds, whereas Asp 298 of CpGH84 is stabilized by an intramolecular hydrogen bond (34, 35).…”

Section: Temporal and Spatial Transcriptional Patterns Of Ofhex1-mentioning

confidence: 99%

Structural Determinants of an Insect β-N-Acetyl-d-hexosaminidase Specialized as a Chitinolytic Enzyme

Liu

Zhang

Liu

et al. 2011

Journal of Biological Chemistry

119

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␤-N-Acetyl-D-hexosaminidase has been postulated to have a specialized function. However, the structural basis of this specialization is not yet established. OfHex1, the enzyme from the Asian corn borer Ostrinia furnacalis (one of the most destructive pests) has previously been reported to function merely in chitin degradation. Here the vital role of OfHex1 during the pupation of O. furnacalis was revealed by RNA interference, and the crystal structures of OfHex1 and OfHex1 complexed with TMG-chitotriomycin were determined at 2.1 Å . The mechanism of selective inhibition by TMG-chitotriomycin was related to the existence of the ؉1 subsite at the active pocket of OfHex1 and a key residue, Trp 490 , at this site. Mutation of Trp 490 to Ala led to a 2,277-fold decrease in sensitivity toward TMG-chitotriomycin as well as an 18-fold decrease in binding affinity for the substrate (GlcNAc) 2 . Although the overall topology of the catalytic domain of OfHex1 shows a high similarity with the human and bacterial enzymes, OfHex1 is distinguished from these enzymes by large conformational changes linked to an "open-close" mechanism at the entrance of the active site, which is characterized by the "lid" residue, Trp 448 . Mutation of Trp 448 to Ala or Phe resulted in a more than 1,000-fold loss in enzyme activity, due mainly to the effect on k cat . The current work has increased our understanding of the structure-function relationship of OfHex1, shedding light on the structural basis that accounts for the specialized function of ␤-N-acetyl-D-hexosaminidase as well as making the development of species-specific pesticides a likely reality.␤-N-Acetyl-D-hexosaminidase (EC 3.2.1.52), a member of the family 20 glycosyl hydrolyases (GH20), 4 is an enzyme that participates in the breakdown of glycosidic bonds of glycans, glycoproteins, and glycolipids (1). It has been postulated to have specialized physiological functions, including post-translational modification of N-glycans, degradation of glycoconjugates, and egg-sperm recognition (1). The structural basis for these specialized functions is still unclear.It is interesting to note that insects have evolved to have more than one ␤-N-acetyl-D-hexosaminidase, as revealed by genomic analysis of various insects, including Coleoptera, Diptera, Hymenoptera, Lepidoptera, Phthiraptera, and Hemiptera. The activities of insect ␤-N-acetyl-D-hexosaminidases are not restricted to chitin degradation but are also associated with post-translational modification of N-glycans, degradation of glycoconjugates, and egg-sperm recognition, suggesting that these enzymes have rather versatile physiological functions in the growth and development of insects (2). Some of these physiological functions may overlap with those of the same enzymes found in higher organisms. Mammal lysosomal ␤-N-acetyl-D-hexosaminidases are mainly responsible for glycoconjugate degradation in lysosome (3). Likewise, ␤-N-acetyl-D-hexosaminidases from the insects Bombyx mori (4) and Spodoptera frugiperda (5) have broad substrate spe...

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Structural insight into the mechanism of streptozotocin inhibition of O-GlcNAcase

Cited by 20 publications

References 25 publications

Standardized extract of Ficus deltoidea stimulates insulin secretion and blocks hepatic glucose production by regulating the expression of glucose-metabolic genes in streptozitocin-induced diabetic rats

Standardized extract of Ficus deltoidea stimulates insulin secretion and blocks hepatic glucose production by regulating the expression of glucose-metabolic genes in streptozitocin-induced diabetic rats

Urinary Angiotensinogen as a Novel Early Biomarker of Intrarenal Renin^|^ndash;Angiotensin System Activation in Experimental Type 1 Diabetes

Structural Determinants of an Insect β-N-Acetyl-d-hexosaminidase Specialized as a Chitinolytic Enzyme

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