The glycogen-synthase-kinase 3 (GSK-3) is an important target in drug discovery. This enzyme is involved in the signaling pathways of type 2 diabetes, neurological disorders, cancer, and other diseases. Therefore, inhibitors of GSK-3 are promising drug candidates for the treatment of a broad range of diseases. Here we report pannorin (1), alternariol (2), and alternariol-9-methylether (3) to be promising inhibitors of the isoform GSK-3β showing sub-μM IC50 values. The in vitro inhibition is in the range of the known highly active GSK-3β inhibitor TDZD-8. Compounds 1-3 have a highly oxygenated benzocoumarin core structure in common, which suggests that this may be a new structural feature for efficient GSK-3β inhibition.

Hepatic glycogen synthesis is impaired in insulin-dependent diabetic rats and in adrenalectomized starved rats, and although this is known to be due to defective activation of glycogen synthase by glycogen synthase phosphatase, the underlying molecular mechanism has not been delineated. Glycogen synthase phosphatase comprises the catalytic subunit of protein phosphatase 1 (PP1) complexed with the hepatic glycogen-binding subunit, termed GL. In liver extracts of insulin-dependent diabetic and adrenalectomized starved rats, the level of GL was shown by immunoblotting to be substantially reduced compared with that in control extracts, whereas the level of PP1 catalytic subunit was not affected by these treatments. Insulin administration to diabetic rats restored the level of GL and prolonged administration raised it above the control levels, whereas re-feeding partially restored the GL level in adrenalectomized starved rats. The regulation of GL protein levels by insulin and starvation/feeding was ...

Phosphatase Subunit Of The Trehalose-6-P Synthase/phosphatase Complex; Involved In Synthesis Of The Storage Carbohydrate Trehalose; Expression Is Induced By Stress Conditions And Repressed By The Ras-cAMP Pathway; Protein Abundance Increases In Response To DNA Replication Stress

1NCE: The only active mutant of thymidylate synthase D169, a residue far from the site of methyl transfer, demonstrates the exquisite nature of enzyme specificity.

Large subunit of trehalose 6-phosphate synthase/phosphatase complex; Tps1p-Tps2p complex converts uridine-5-diphosphoglucose and glucose 6-phosphate to trehalose; mutant has aneuploidy tolerance; protein abundance increases in response to DNA replication stress; TSL1 has a paralog, TPS3, that arose from the whole genome duplication ...

TY - JOUR. T1 - Purification and phosphorylation of rat liver glycogen synthase.. AU - Jett, M. F.. AU - Soderling, Thomas. PY - 1979/7/25. Y1 - 1979/7/25. UR - http://www.scopus.com/inward/record.url?scp=0018801098&partnerID=8YFLogxK. UR - http://www.scopus.com/inward/citedby.url?scp=0018801098&partnerID=8YFLogxK. M3 - Article. C2 - 221508. AN - SCOPUS:0018801098. VL - 254. SP - 6739. EP - 6745. JO - Journal of Biological Chemistry. JF - Journal of Biological Chemistry. SN - 0021-9258. IS - 14. ER - ...

TY - JOUR. T1 - Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels. AU - Aceto, Giuseppe. AU - Colussi, Claudia. AU - Leone, Lucia. AU - Fusco, Salvatore. AU - Rinaudo, Marco. AU - Scala, Federico. AU - Green, Thomas A.. AU - Laezza, Fernanda. AU - DAscenzo, Marcello. AU - Grassi, Claudio. PY - 2020/4/7. Y1 - 2020/4/7. N2 - Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that glycogen-synthase kinase 3β (GSK3β) plays a key role in memory formation, yet its role in mood regulation remains controversial. Here, we investigated whether GSK3β activity in the nucleus accumbens (NAc) is associated with depression-like behaviors and synaptic plasticity. We performed whole-cell patch-clamp recordings of medium spiny neurons (MSNs) in the NAc and determined the role of GSK3β in spike timing-dependent long-term potentiation (tLTP) in the chronic ...

The dephosphorylation of the modulator subunit is an essential step in the kinase FA-mediated activation of the ATP,Mg-dependent protein phosphatase. Mg2+ is implicated in this autocatalytic dephosphorylation which is not effected by the addition of phosphoinhibitor-1. Dephosphorylation of free modulator by the catalytic subunit is also largely Mg2+-dependent but can be abolished by phosphoinhibitor-1 in concentrations comparable to the amount of modulator used as substrate (micromolar). The phosphorylase phosphatase activity of the catalytic subunit is inhibited by nanomolar concentrations of phosphoinhibitor-1 and is completely independent of divalent cations ...

The first committed step in the formation of diterpenoids leading to gibberellin (GA) biosynthesis is the conversion of geranylgeranyl diphosphate (GGDP) to ent-kaurene. ent-Kaurene synthase A (KSA) catalyzes the conversion of GGDP to copalyl diphosphate (CDP), which is subsequently converted to ent …

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Alzheimers disease (AD) is neurological disorder characterized by extracellular beta amyloid plaques and intracellular neurofibrillary tangles formed by hyper-phosphorylated Tau protein. Since type 2 diabetes mellitus (T2DM) is a risk factor of AD development, in the first part of the thesis, a potential relationship between hyper-phosphorylation of Tau protein and central insulin resistance was followed in hippocampi of two models of obesity-induced pre-diabetes, fa/fa rats, and mice with monosodium glutamate (MSG) induced obesity. In both 8-month-old fa/fa rats and 6-month- old MSG mice a decreased phosphorylation of insulin signaling cascade resulted in an increased activation of main Tau kinase glycogen-synthase kinase-3Beta (GSK-3β) and an increased Tau phosphorylation at epitopes Ser396 and Thr231. This phenomenon was less developed in 2-month-old animals. The second part of the thesis was focused on a potential neuroprotective anorexigenic neuropeptide, prolactin-releasing peptide ...

SWISS-MODEL Repository entry for Q04KA7 (TRUB_STRP2), tRNA pseudouridine synthase B. Streptococcus pneumoniae serotype 2 (strain D39 / NCTC 7466)

SWISS-MODEL Repository entry for Q72ER4 (TRUB_DESVH), tRNA pseudouridine synthase B. Desulfovibrio vulgaris (strain Hildenborough / ATCC 29579 / DSM 644 / NCIMB8303)

Lithium is an anti-psychotic that has been shown to prevent the hyperphosphorylation of tau protein through the inhibition of glycogen-synthase kinase 3-beta (GSK3β). We recently developed a mouse model that progresses from amyloid pathology to tau pathology and neurodegeneration due to the genetic deletion of NOS2 in an APP transgenic mouse; the APPSwDI/NOS2−/− mouse. Because this mouse develops tau pathology, amyloid pathology and neuronal loss we were interested in the effect anti-tau therapy would have on amyloid pathology, learning and memory. We administered lithium in the diets of APPSwDI/NOS2−/− mice for a period of eight months, followed by water maze testing at 12 months of age, immediately prior to sacrifice. We found that lithium significantly lowered hyperphosphorylated tau levels as measured by Western blot and immunocytochemistry. However, we found no apparent neuroprotection, no effect on spatial memory deficits and an increase in histological amyloid deposition. Aβ levels

G6P -, UDP TRE6P tsl1 subunit of trehalose-6-phosphate synthase\/phosphatase complex\; homologous to TPS3 gene product YMR261C 2.4.1.15 TPS3 trehalose-6-P synthetase, 115 kD regulatory UDPG + G6P -, UDP + TRE6P tps3 subunit of trehalose-6-phosphate synthase\/phosphatase complex YDR074W 3.1.3.12 TPS2 Trehalose-6-phosphate phosphatase TRE6P -, TRE + PI tps2 YPR026W 3.2.1.28 ATH1 Acid trehalase TRE -, 2 GLC ath1 YBR001C 3.2.1.28 NTH2 Neutral trehalase, highly homologous to NthIp TRE -, 2 GLC nth2 YDR001C 3.2.1.28 NTH1 neutral trehalase TRE -, 2 GLC nth1 Glycogen Metabolism (sucorose and sugar metabolism) YEL011W 2.4.1.18 glc3 Branching enzyme, 1,4-glucan-6-(1,4-glucano)- GLYCOGEN + PI -, G1P glc3 transferase YPR160W 2.4.1.1 GPH1 Glycogen phosphorylase GLYCOGEN + PI -, G1P gph1 YFR015C 2.4.1.11 GSY1 Glycogen synthase (UDP-gluocse--starch UDPG -, UDP + GLYCOGEN gsy1 glucosyltransferase) YLR258W 2.4.1.11 GSY2 Glycogen synthase (UDP-gluocse--starch UDPG -, UDP + GLYCOGEN gsy2 glucosyltransferase) ...