Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reversible phosphorylation is the cell's most prevalent form of posttranslational modification, yet its role in the regulation of mitochondrial functions is poorly understood. We have discovered that a member of the dual-specific protein tyrosine phosphatase (DS-PTP) family, PTPMT1 (PTP localized to the Mitochondrion 1) resides nearly exclusively in mitochondria. PTPMT1 is targeted to the mitochondrion by an N-terminal signal sequence and is found anchored to the matrix face of the inner membrane. Knockdown of PTPMT1 expression in the pancreatic insulinoma cell line INS-1 832/13 alters the mitochondrial phosphoprotein profile and markedly enhances both ATP production and insulin secretion. These data define PTPMT1 as a potential drug target for the treatment of type II diabetes and strengthen the notion that mitochondria are an underappreciated site of signaling by reversible phosphorylation.
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PMID:Involvement of a mitochondrial phosphatase in the regulation of ATP production and insulin secretion in pancreatic beta cells. 1606 Nov 74

Zinc ions have an insulin-like (insulinomimetic) effect. A particularly sensitive target of zinc ions is protein tyrosine phosphatase 1B (PTP 1B), a key regulator of the phosphorylation state of the insulin receptor. Modulation of insulin signaling by zinc chelating agents and the recognition of temporal and spatial fluctuations of zinc suggest a physiological role of zinc in insulin signal transduction. Tyrosine phosphatases seem to be regulated jointly by insulin-induced redox (hydrogen peroxide) signaling, which results in their oxidative inactivation, and by their zinc inhibition after oxidative zinc release from other proteins. In diabetes, the significant oxidative stress and associated changes in zinc metabolism modify the cell's response and sensitivity to insulin. Zinc deficiency activates stress pathways and may result in a loss of tyrosine phosphatase control, thereby causing insulin resistance.
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PMID:Protein tyrosine phosphatases as targets of the combined insulinomimetic effects of zinc and oxidants. 1615 25

PTPs (protein tyrosine phosphatases) are fundamental enzymes for cell signalling and have been linked to the pathogenesis of several diseases, including cancer. Hence, PTPs are potential drug targets and inhibitors have been designed as possible therapeutic agents for Type II diabetes and obesity. However, a complete understanding of the detailed catalytic mechanism in PTPs is still lacking. Free-energy profiles, obtained by computer simulations of catalysis by a dual-specificity PTP, are shown in the present study and are used to shed light on the catalytic mechanism. A highly accurate hybrid potential of quantum mechanics/molecular mechanics calibrated specifically for PTP reactions was used. Reactions of alkyl and aryl substrates, with different protonation states and PTP active-site mutations, were simulated. Calculated reaction barriers agree well with experimental rate measurements. Results show the PTP substrate reacts as a bi-anion, with an ionized nucleophile. This protonation state has been a matter of debate in the literature. The inactivity of Cys-->Ser active-site mutants is also not fully understood. It is shown that mutants are inactive because the serine nucleophile is protonated. Results also clarify the interpretation of experimental data, particularly kinetic isotope effects. The simulated mechanisms presented here are better examples of the catalysis carried out by PTPs.
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PMID:Free-energy profiles for catalysis by dual-specificity phosphatases. 1678 17

Protein tyrosine phosphatase 1B (PTP1B) is a key enzyme in the counterregulation of insulin signaling, and its physiological modulation depends on H2O2 and glutathione (GSH). Se via GSH peroxidases (GPxs) and its specific metabolism is involved in the removal of H2O2 and in the regulation of GSH metabolism. Recent results from animal trials and epidemiological studies with humans have shown that a high GPx1 activity or a permanent surplus of Se may promote the development of obesity and diabetes. Our nutrition physiological study with 7 x 7 growing rats was carried out to examine if PTP1B is modulated by Se supplements and, thus, may represent one trigger mediating these undesirable metabolic effects of Se. One group of rats was fed an Se-deficient diet for 8 weeks. The diets of the other six groups contained Se as selenite or selenate according to the recommendations (0.20 mg/kg diet) and at two supranutritional levels (1.00 and 2.00 mg/kg diet). All Se-supplemented animals featured a significantly higher body weight (6-14%) compared to their Se-deficient companions. Expression and activity of GPx1 in the liver of Se supplemented animals was 10- and 70-fold higher compared to Se deficiency. The detailed study of PTP1B regulation using an enzymatic assay and Western Blot analysis with an antibody against protein glutathionylation revealed that PTP1B was significantly up-regulated by both a maximization of GPx1 activity and by increasing dietary Se supply, reducing its inhibition via glutathionylation. Selenate effected a stronger PTP activation compared to selenite. In conclusion, our results suggest that the modulation of PTP1B activity may represent one plausible mechanism by which a long-term intake of Se supplements exceeding the requirements can promote the development of obesity and diabetes and needs further intensive investigation.
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PMID:Regulation of the insulin antagonistic protein tyrosine phosphatase 1B by dietary Se studied in growing rats. 1860 18

There has been considerable interest in protein tyrosine phosphatase 1B (PTP1B) as a therapeutic target for diabetes, obesity, as well as cancer. Identifying inhibitory compounds with good bioavailability is a major challenge of drug discovery programs targeted toward PTPs. Most current PTP active site-directed pharmacophores are negatively charged pTyr mimetics which cannot readily enter the cell. This lack of cell permeability limits the utility of such compounds in signaling studies and further therapeutic development. We identify aryl diketoacids as novel pTyr surrogates and show that neutral amide-linked aryl diketoacid dimers also exhibit excellent PTP inhibitory activity. Kinetic studies establish that these aryl diketoacid derivatives act as noncompetitive inhibitors of PTP1B. Crystal structures of ligand-bound PTP1B reveal that both the aryl diketoacid and its dimeric derivative bind PTP1B at the active site, albeit with distinct modes of interaction, in the catalytically inactive, WPD loop open conformation. Furthermore, dimeric aryl diketoacids are cell permeable and enhance insulin signaling in hepatoma cells, suggesting that targeting the inactive conformation may provide a unique opportunity for creating active site-directed PTP1B inhibitors with improved pharmacological properties.
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PMID:Targeting inactive enzyme conformation: aryl diketoacid derivatives as a new class of PTP1B inhibitors. 1901 96

Diabetes mellitus is a systemic disease responsible for morbidity in the western world and is gradually becoming prevalent in developing countries too. The prevalence of diabetes is rapidly increasing in industrialized countries and type 2 diabetes accounts for 90% of the disease. Insulin resistance is a major pathophysiological factor in the development of type 2 diabetes, occurring mainly in muscle, adipose tissues, and liver leading to reduced glucose uptake and utilization and increased glucose production. The prevalence and rising incidence of diabetes emphasized the need to explore new molecular targets and strategies to develop novel antihyperglycemic agents. Protein Tyrosine Phosphatase 1B (PTP 1B) has recently emerged as a promising molecular level legitimate therapeutic target in the effective management of type 2 diabetes. PTP 1B, a cytosolic nonreceptor PTPase, has been implicated as a negative regulator of insulin signal transduction. Therefore, PTP 1B inhibitors would increase insulin sensitivity by blocking the PTP 1B-mediated negative insulin signaling pathway and might be an attractive target for type 2 diabetes mellitus and obesity. With X-ray crystallography and NMR-based fragment screening, the binding interactions of several classes of inhibitors have been elucidated, which could help the design of future PTP 1B inhibitors. The drug discovery research in PTP 1B is a challenging area to work with and many pharmaceutical organizations and academic research laboratories are focusing their research toward the development of potential PTP 1B inhibitors which would prove to be a milestone for the management of diabetes.
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PMID:Protein tyrosine phosphatase 1B inhibitors: a molecular level legitimate approach for the management of diabetes mellitus. 2081 56

Human leukocyte antigen-related (PTP-LAR) is a receptor-like transmembrane phosphatase and a potential target for diabetes, obesity and cancer. In the present study, a sequence of in silico strategies (pharmacophore mapping, a 3D database searching, SADMET screening, and docking and toxicity studies) was performed to identify eight novel nontoxic PTP-LAR inhibitors. Twenty different pharmacophore hypotheses were generated using two methods; the best (hypothesis 2) consisted of three hydrogen-bond acceptor (A), one ring aromatic (R), and one hydrophobic aliphatic (Z) features. This hypothesis was used to screen molecules from several databases, such as Specs, IBS, MiniMaybridge, NCI, and an in-house PTP inhibitor database. In order to overcome the general bioavailability problem associated with phosphatases, the hits obtained were filtered by Lipinski's rule of five and SADMET properties and validated by molecular docking studies using the available crystal structure 1LAR. These docking studies suggested the ligand binding pattern and interactions required for LAR inhibition. The docking analysis also revealed that sulfonylurea derivatives with an isoquinoline or naphthalene scaffold represent potential LAR drugs. The screening protocol was further validated using ligand pharmacophore mapping studies, which showed that the abovementioned interactions are indeed crucial and that the screened molecules can be presumed to possess potent inhibitory activities.
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PMID:Identification of novel, less toxic PTP-LAR inhibitors using in silico strategies: pharmacophore modeling, SADMET-based virtual screening and docking. 2152 50

The design of biological active compounds from the apoenzyme is still a challenging task. Herein a simple yet efficient technique is reported to generate a receptor based pharmacophore solely using a ligand-free protein crystal structure. Human leukocyte antigen-related phosphatase (PTP-LAR) is an apoenzyme and a receptor like transmembrane phosphatase that has emerged as a drug target for diabetes, obesity and cancer. The prior knowledge of the active residues responsible for the mechanism of action of the protein was used to generate the LUDI interaction map. Then, the complement negative image of the binding site was used to generate the pharmacophore features. A unique strategy was followed to design a pharmacophore query maintaining crucial interactions with all the active residues, essential for the enzyme inhibition. The same query was used to screen several databases consisting of the Specs, IBS, MiniMaybridge, NCI and an in-house PTP inhibitor databases. In order to overcome the common bioavailability problem associated with phosphatases, the hits obtained were filtered by Lipinski's Rule of Five, SADMET properties and validated by docking studies in Glide and GOLD. These docking studies not only suggest the essential ligand binding interactions but also the binding patterns necessary for the LAR inhibition. The ligand pharmacophore mapping studies further validated the screened protocol and supported that the final screened molecules, presumably, showed potent inhibitory activity. Subsequently, these molecules were subjected to Derek toxicity predictions and nine new molecules with different scaffold were obtained as non-toxic PTP-LAR inhibitors. The present prospective strategy is a powerful technique to identify potent inhibitors using the protein 3D structure alone and is a valid alternative to other structure-based and random docking approaches.
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PMID:Simplified receptor based pharmacophore approach to retrieve potent PTP-LAR inhibitors using apoenzyme. 2172 94

Pancreatic stone protein (PSP; reported in 1979), pancreatitis-associated protein (PAP; 1984) and regenerating protein (Reg I; 1988) were discovered independently in the fields of the exocrine (pancreatitis) and endocrine (diabetes) pancreas. Subsequent analysis revealed that PSP and Reg I are identical and PAP belongs to the same protein family. PSP/Reg I and PAP share a selective and specific trypsin cleavage site and result in insoluble fibrils (PTP, PATP). Search for a functional role of PSP had led to the idea that it might serve as an inhibitor in pancreatic stone formation and PSP was renamed lithostathine. Inhibitory effects of lithostathine in stone formation have been questioned. Evidence so far obtained can support a lithogenic role rather than a lithostatic role of PSP. PAP and its isoforms have been investigated mainly regarding responses to inflammation and stress. Reg I and its isoforms have been examined on regeneration, growth and mitogenesis in gastrointestinal neoplastic diseases as well as diabetes. Evidence obtained can be applied in the prediction of prognosis and therapy for inflammatory and neoplastic diseases.
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PMID:Pancreatic stone protein/regenerating protein family in pancreatic and gastrointestinal diseases. 2180 74

Protein tyrosine phosphatase 1B (PTP1B) is a key regulator of the insulin-receptor and leptin-receptor signaling pathways, and it has therefore emerged as a critical antitype-II-diabetes and antiobesity drug target. Toward the goal of generating a covalent modulator of PTP1B activity that can be used for investigating its roles in cell signaling and disease progression, we report that the biarsenical probe FlAsH-EDT(2) can be used to inhibit PTP1B variants that contain cysteine point mutations in a key catalytic loop of the enzyme. The site-specific cysteine mutations have little effect on the catalytic activity of the enzyme in the absence of FlAsH-EDT(2). Upon addition of FlAsH-EDT(2), however, the activity of the engineered PTP1B is strongly inhibited, as assayed with either small-molecule or phosphorylated-peptide PTP substrates. We show that the cysteine-rich PTP1B variants can be targeted with the biarsenical probe in either whole-cell lysates or intact cells. Together, our data provide an example of a biarsenical probe controlling the activity of a protein that does not contain the canonical tetra-cysteine biarsenical-labeling sequence CCXXCC. The targeting of "incomplete" cysteine-rich motifs could provide a general means for controlling protein activity by targeting biarsenical compounds to catalytically important loops in conserved protein domains.
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PMID:Specific inhibition of sensitized protein tyrosine phosphatase 1B (PTP1B) with a biarsenical probe. 2226 76


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