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Jin Zhang – One of the best experts on this subject based on the ideXlab platform.

  • direct activation of epac by Sulfonylurea is isoform selective
    Chemistry & Biology, 2011
    Co-Authors: Katie J Herbst, Jin Zhang, Carla Coltharp, Mario L Amzel
    Abstract:

    Commonly used as a treatment for Type II diabetes, Sulfonylureas (SUs) stimulate insulin secretion from pancreatic β cells by binding to Sulfonylurea receptors. Recently, SUs have been shown to also activate exchange protein directly activated by cAMP 2 (Epac2), however, little is known about this molecular action. Using biosensor imaging and biochemical analysis, we show that SUs activate Epac2 and the downstream signaling via direct binding to Epac2. We further identify R447 of Epac2 to be critically involved in SU binding. This distinct binding site from cAMP points to a new mode of allosteric activation of Epac2. We also show that SUs selectively activate Epac2 isoform, but not the closely related Epac1, further establishing SUs as a new class of isoform-selective enzyme activators.

Ronald G Duggleby – One of the best experts on this subject based on the ideXlab platform.

  • structure activity relationships for a new family of Sulfonylurea herbicides
    Journal of Computer-aided Molecular Design, 2005
    Co-Authors: Jianguo Wang, Baolei Wang, Lin Jiang, Siew Siew Pang, Yuting Lee, Luke W Guddat, Ronald G Duggleby
    Abstract:

    Acetohydroxyacid synthase (AHAS; EC 2.2.1.6) catalyzes the first common step in branched-chain aminamino acid biosynthesis. The enzyme is inhibited by several chemical classes of compounds and this inhibition is the basis of action of the Sulfonylurea and imidazolinone herbicides. The commercial Sulfonylureas contain a pyrimidine or a triazine ring that is substituted at both meta positions, thus obeying the initial rules proposed by Levitt. Here we assess the activity of 69 monosubstituted Sulfonylurea analogs and related compounds as inhibitors of pure recombinant Arabidopsis thaliana AHAS and show that disubstitution is not absolutely essential as exemplified by our novel herbicide, monosulfuron (2-nitro-N-(4′-methyl-pyrimidin-2′-yl) phenyl-Sulfonylurea), which has a pyrimidine ring with a single meta substituent. A subset of these compounds was tested for herbicidal activity and it was shown that their effect in vivo correlates well with their potency in vitro as AHAS inhibitors. Three-dimensional quantitative structure-activity relationships were developed using comparative molecular field analysis and comparative molecular similarity indices analysis. For the latter, the best result was obtained when steric, electrostatic, hydrophobic and H-bond acceptor factors were taken into consideration. The resulting fields were mapped on to the published crystal structure of the yeast enzyme and it was shown that the steric and hydrophobic fields are in good agreement with Sulfonylurea-AHAS interaction geometry.

  • systematic characterization of mutations in yeast acetohydroxyacid synthase interpretation of herbicide resistance data
    FEBS Journal, 2003
    Co-Authors: Ronald G Duggleby, Siew Siew Pang, Hongqi Yu, Luke W Guddat
    Abstract:

    Acetohydroxyacid synthase (AHAS, EC 4.1.3.18) catalyses the first step in branched-chain aminamino acid biosynthesis and is the target for Sulfonylurea and imidazolinone herbicides, which act as potent and specific inhibitors. Mutants of the enzyme have been identified that are resistant to particular herbicides. However, the selectivity of these mutants towards various Sulfonylureas and imidazolinones has not been determined systematically. Now that the structure of the yeast enzyme is known, both in the absence and presence of a bound herbicide, a detailed understanding of the molecular interactions between the enzyme and its inhibitors becomes possible. Here we construct 10 active mutants of yeast AHAS, purify the enzymes and determine their sensitivity to six Sulfonylureas and three imidazolinones. An additional three active mutants were constructed with a view to increasing imidazolinone sensitivity. These three variants were purified and tested for their sensitivity to the imidazolinones only. Substantial differences are observed in the sensitivity of the 13 mutants to the various inhibitors and these differences are interpreted in terms of the structure of the herbicide-binding site on the enzyme.

Andrew T Hattersley – One of the best experts on this subject based on the ideXlab platform.

  • effective treatment with oral Sulfonylureas in patients with diabetes due to Sulfonylurea receptor 1 sur1 mutations
    Diabetes Care, 2008
    Co-Authors: Meena Rafiq, Sarah E Flanagan, Annmarie Patch, Beverley M Shields, Sian Ellard, Andrew T Hattersley
    Abstract:

    OBJECTIVE — Neonatal diabetes can result from mutations in the Kir6.2 or Sulfonylurea receptor 1 (SUR1) subunits of the ATP-sensitive K channel. Transfer from insulin to oral Sulfonylureas in patients with neonatal diabetes due to Kir6.2 mutations is well described, but less is known about changing therapy in patients with SUR1 mutations. We aimed to describe the response to Sulfonylurea therapy in patients with SUR1 mutations and to compare it with Kir6.2 mutations. RESEARCH DESIGN AND METHODS — We followed 27 patients with SUR1 mutations for at least 2 months after attempted transfer to Sulfonylureas. Information was collected on clinical features, treatment before and after transfer, and the transfer protocol used. We compared successful and unsuccessful transfer patients, glycemic control before and after transfer, and treatment requirements in patients with SUR1 and Kir6.2 mutations. RESULTS — Twenty-three patients (85%) successfully transferred onto Sulfonylureas without significant side effects or increased hypoglycemia and did not need insulin injections. In these patients, median A1C fell from 7.2% (interquartile range 6.6 – 8.2%) on insulin to 5.5% (5.3– 6.2%) on Sulfonylureas (P 0.01). When compared with Kir6.2 patients, SUR1 patients

  • improved motor development and good long term glycaemic control with Sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay early onset generalised epilepsy and neonatal diabetes associated with the v59m mutation in
    Diabetologia, 2006
    Co-Authors: Annabelle S Slingerland, Andrew T Hattersley, R Nuboer, Mijna Haddersalgra, G J Bruining
    Abstract:

    Aims/hypothesis Activating mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the KATP channels in pancreatic beta cells are a common cause of neonatal diabetes. One-third of patients also have developmental delay, which probably results from mutated KATP channels in muscle, nerve and brain. Sulfonylureas, which bind to the Sulfonylurea receptor 1 subunit of the KATP channel, can replace insulin injections in patients with KCNJ11 mutations. The aim of this study was to investigate the long-term outcome and impact on neurological features of Sulfonylurea treatment.

Dae Hyun Kim – One of the best experts on this subject based on the ideXlab platform.

  • evaluation of risk of bullous pemphigoid with initiation of dipeptidyl peptidase 4 inhibitor vs second generation Sulfonylurea
    JAMA Dermatology, 2020
    Co-Authors: Hemin Lee, Dae Hyun Kim, Hye Jin Chung, Ajinkya Pawar, Elisabetta Patorno
    Abstract:

    Importance Despite several recent reports on the elevated risk of bullous pemphigoid in patients with type 2 diabetes treated with dipeptidyl peptidase–4 (DPP-4) inhibitors, evidence on the absolute risk and comparative safety against other antidiabetics is limited. Objective To characterize the incidence rate of bullous pemphigoid associated with DPP-4 inhibitor use compared with second-generation Sulfonylureas. Design, Setting, and Participants This cohort study used data from 2 large commercial insurance claims databases (Optum Clinformatics Data Mart from October 17, 2006, to December 31, 2018, and IBM MarketScan Research Database from October 17, 2006, to December 31, 2017) and Medicare data from January 1, 2006, to December 31, 2016. Patients with type 2 diabetes who initiated treatment with DPP-4 inhibitors or second-generation Sulfonylurea were included. Main Outcomes and Measures The primary outcome of the study was bullous pemphigoid, identified using diagnosis codes. After 1:1 propensity score matching, the incidence rates of bullous pemphigoid and the hazard ratios (HRs) with 95% CIs comparing patients who initiated DPP-4 inhibitor and second-generation Sulfonylurea therapy were estimated. Subgroup analyses by age, sex, race, and individual DPP-4 agents were performed. The results from each database were pooled using inverse-variance fixed-effects meta-analysis. Results A total of 1 664 880 patients who initiated DPP-4 inhibitors (51.0% female; mean [SD] age, 63.9 [9.7] years) and Sulfonylurea (50.4% female; mean [SD] age, 63.9 [9.9] years) were included. The incidence rate of bullous pemphigoid per 1000 person-years was 0.42 in the DPP-4 inhibitor group vs 0.31 in the Sulfonylurea group (HR, 1.42; 95% CI, 1.17-1.72). Higher rates per 1000 person-years for DPP-4 inhibitor vs Sulfonylurea groups were seen in those who were 65 years or older (0.79 vs 0.49; HR, 1.62; 95% CI, 1.32-1.99), white (0.93 vs 0.54; HR, 1.70; 95% CI, 1.30-2.24), and treated with linagliptin (1.20 vs 0.55; HR, 1.68; 95% CI, 1.16-2.43). Conclusions and Relevance This study found that patients who initiated DPP-4 inhibitor therapy had higher risk of bullous pemphigoid than those who initiated second-generation Sulfonylurea therapy. Clinicians should be aware of this rare adverse effect of DPP-4 inhibitors in subgroups of patients who are older, white, and linagliptin users.

Siew Siew Pang – One of the best experts on this subject based on the ideXlab platform.

  • structure activity relationships for a new family of Sulfonylurea herbicides
    Journal of Computer-aided Molecular Design, 2005
    Co-Authors: Jianguo Wang, Baolei Wang, Lin Jiang, Siew Siew Pang, Yuting Lee, Luke W Guddat, Ronald G Duggleby
    Abstract:

    Acetohydroxyacid synthase (AHAS; EC 2.2.1.6) catalyzes the first common step in branched-chain amino acid biosynthesis. The enzyme is inhibited by several chemical classes of compounds and this inhibition is the basis of action of the Sulfonylurea and imidazolinone herbicides. The commercial Sulfonylureas contain a pyrimidine or a triazine ring that is substituted at both meta positions, thus obeying the initial rules proposed by Levitt. Here we assess the activity of 69 monosubstituted Sulfonylurea analogs and related compounds as inhibitors of pure recombinant Arabidopsis thaliana AHAS and show that disubstitution is not absolutely essential as exemplified by our novel herbicide, monosulfuron (2-nitro-N-(4′-methyl-pyrimidin-2′-yl) phenyl-Sulfonylurea), which has a pyrimidine ring with a single meta substituent. A subset of these compounds was tested for herbicidal activity and it was shown that their effect in vivo correlates well with their potency in vitro as AHAS inhibitors. Three-dimensional quantitative structure-activity relationships were developed using comparative molecular field analysis and comparative molecular similarity indices analysis. For the latter, the best result was obtained when steric, electrostatic, hydrophobic and H-bond acceptor factors were taken into consideration. The resulting fields were mapped on to the published crystal structure of the yeast enzyme and it was shown that the steric and hydrophobic fields are in good agreement with Sulfonylurea-AHAS interaction geometry.

  • systematic characterization of mutations in yeast acetohydroxyacid synthase interpretation of herbicide resistance data
    FEBS Journal, 2003
    Co-Authors: Ronald G Duggleby, Siew Siew Pang, Hongqi Yu, Luke W Guddat
    Abstract:

    Acetohydroxyacid synthase (AHAS, EC 4.1.3.18) catalyses the first step in branched-chain amino acid biosynthesis and is the target for Sulfonylurea and imidazolinone herbicides, which act as potent and specific inhibitors. Mutants of the enzyme have been identified that are resistant to particular herbicides. However, the selectivity of these mutants towards various Sulfonylureas and imidazolinones has not been determined systematically. Now that the structure of the yeast enzyme is known, both in the absence and presence of a bound herbicide, a detailed understanding of the molecular interactions between the enzyme and its inhibitors becomes possible. Here we construct 10 active mutants of yeast AHAS, purify the enzymes and determine their sensitivity to six Sulfonylureas and three imidazolinones. An additional three active mutants were constructed with a view to increasing imidazolinone sensitivity. These three variants were purified and tested for their sensitivity to the imidazolinones only. Substantial differences are observed in the sensitivity of the 13 mutants to the various inhibitors and these differences are interpreted in terms of the structure of the herbicide-binding site on the enzyme.