The open enzyme inhibition journal最新文献

{"title":"The Effects of Oxyanions on the Activity of Oxalate Oxidase","authors":"Sandra Winestrand, N. Nilvebrant, L. Jönsson","doi":"10.2174/1874940200902010036","DOIUrl":"https://doi.org/10.2174/1874940200902010036","url":null,"abstract":"Oxalate oxidase catalyzes the conversion of oxalic acid and molecular oxygen to carbon dioxide and hydrogen peroxide. Oxalate-degrading enzymes are of interest for various applications including clinical analysis of the levels of oxalic acid in blood and urine and control of oxalic acid in industrial processes, such as pulp and paper manufacture. In these applications, the presence of oxyanions other than oxalate may affect the enzyme activity. The inhibitory effect of selected oxyanions on oxalate oxidase from barley was investigated. Seven out of fourteen of the compounds studied inhibited oxalate oxidase at a concentration of 1 mM. Perchlorate, chlorate and chlorite were selected for more detailed studies. The results indicate that perchlorate, chlorate and chlorite cause mixed inhibition of oxalate oxidase and that the severity of the inhibition within the series increases with the oxidation state. The apparent KM of the enzyme was 0.28 ± 0.05 mM.","PeriodicalId":89033,"journal":{"name":"The open enzyme inhibition journal","volume":"2 1","pages":"36-40"},"PeriodicalIF":0.0,"publicationDate":"2009-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68096016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism-Based Inhibition of Myeloperoxidase by Hydrogen Peroxide: Enhancement of Inactivation Rate by Organic Donor Substrates","authors":"F. J. Olorunniji, Martin O. Iniaghe, J. Adebayo, S. O. Malomo, S. Adediran","doi":"10.2174/1874940200902010028","DOIUrl":"https://doi.org/10.2174/1874940200902010028","url":null,"abstract":"The effects of two hydrazine derivatives (isoniazid and hydralazine) on the inactivation of myeloperoxidase by H2O2 were investigated. Incubation of 20 nM myeloperoxidase with 0.25 mM H2O2 alone caused a time-dependent irreversible loss of tetramethylbenzidine oxidation activity with a pseudo-first order inactivation rate constant of 0.057 min -1 . The hydrazine derivatives increased the inactivation rate in a concentration-dependent manner. Inactivation of the enzyme by H2O2 with or without the hydrazides showed a saturation kinetics pattern. Steady state kinetics analysis suggests that the hydrazides likely inactivate myeloperoxidase using a similar inactivating species as does H2O2. A bimolecular rate constant, specific inactivation rate enhancement factor (k*enh) is proposed as a formal description of the inactivation rate stimulation by the hydrazides. This parameter potentially avoids confounding the finite inactivation due to H2O2 with that caused by the presence of the hydrazides. The relevance of these findings and the constants derived to the analysis of suicide inactivation of peroxidases by reductant substrates are discussed.","PeriodicalId":89033,"journal":{"name":"The open enzyme inhibition journal","volume":"2 1","pages":"28-35"},"PeriodicalIF":0.0,"publicationDate":"2009-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68096004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition Studies of Cellulolytic Activities Isolated from Planococcus Citri","authors":"Muhammad Fayyaz-ur-Rehman, M. Tariq, Mehwish Aslam, Ghulam Khadija, Aima Iram","doi":"10.2174/1874940200902010008","DOIUrl":"https://doi.org/10.2174/1874940200902010008","url":null,"abstract":"The study was performed to isolate the cellulolytic activities from a mealy bug Planococcus citri and to check their enzyme inhibition against leaf extract of Azdirachta indica and Buxus Sempervirens. Enzyme assay confirmed the presence of endoglucanase activity. Aqueous and non-aqueous fractions showed the maximum inhibition. Proteins containing fraction also reflected inhibition of activity that might lead to identification of some active peptides against cellulolytic activity.","PeriodicalId":89033,"journal":{"name":"The open enzyme inhibition journal","volume":"2 1","pages":"8-11"},"PeriodicalIF":0.0,"publicationDate":"2009-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68095954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncompetitive Phospholipase A2 Inhibition by CHEC Sequences Including Oral Treatment of Experimental Autoimmune Myeloencephalitis","authors":"T. J. Cunningham, J. Greenstein, Lihua Yao","doi":"10.2174/1874940200902010001","DOIUrl":"https://doi.org/10.2174/1874940200902010001","url":null,"abstract":"Catalytic sites of metal dependent phosphatases and phospholipases are characterized by a catalytic histidine (H) and adjacent acidic metal binding residue E (or D). For the secreted phospholipases A2 (sPLA2s), the active sites are stabilized by nearby flanking cystines. CHEC-9 (CHEASAAQC), which displays this organization, is a sPLA2 inhibitor that is an effective treatment for models of traumatic and autoimmune neurodegenerative disorders. We screened modifi- cations of this sequence and found that elimination of the two central alanines followed by cyclization results in another potent sPLA2 inhibitor, CHEC-7 (CHEASQC). CHEC-7, like CHEC-9, had uncompetitive kinetic properties making it ideal for in vivo applications. Subcutaneous injections of CHEC-7 into restrained rats inhibited the transient rise in plasma sPLA2 activity suggesting that this peptide was also effective in vivo. Oral delivery of the peptide attenuated the LPS- induced increases in sPLA2 activity. Thin layer chromatography and mass spectroscopy of representative LPS-treated rats suggested that the peptide also reduced levels of lysophosphatidylcholine, a hydrolytic product of the enzyme reaction. In order to test the efficacy of CHEC-7 for neuroimmune therapies, rats were immunized with spinal cord homogenates to induce experimental autoimmune encephalomyelitis (EAE), followed by daily treatment with oral (1.5 mg/kg) or subcuta- neous (0.1, 0.5, and1.5mg/kg) CHEC-7 and CHEC-9 (n=10 for each different condition). The rats were scored for severity of disease applying a standard EAE scale. Control rats all developed disease over the 23-day course of the experiments. Both CHEC-9 and CHEC-7 produced highly significant reductions in disease severity including via oral delivery. The performance of oral CHEC-7 was notable in that this treatment completely prevented disease in half the rats. The results suggested that continued study of modifications of CHEC sequences would provide stable therapeutic peptides for a variety of inflammatory and autoimmune disorders.","PeriodicalId":89033,"journal":{"name":"The open enzyme inhibition journal","volume":"2 1","pages":"1-7"},"PeriodicalIF":0.0,"publicationDate":"2009-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68095904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kinetic Study of Human Full-Length Wild-Type JAK2 and V617F Mutant Proteins","authors":"D. Erdmann, B. Allard, J. Bohn, A. Pover, A. Floersheimer, Patrizia Fontana, M. Gerspacher, J. Hau, F. Hofmann, T. Radimerski, Roman Wille, C. Zimmermann, P. Chène","doi":"10.2174/1874940200801010080","DOIUrl":"https://doi.org/10.2174/1874940200801010080","url":null,"abstract":"The Janus kinase 2 (JAK2) is a drug target in particular because a missense mutation in this gene (V617F) has been identified in various human diseases. We report here the first kinetic study of the human full-length wild type and V617F JAK2 proteins and of their isolated kinase domain. The kinetic parameters of both full-length proteins are similar revealing that the mutation does not affect JAK2 catalytic activity suggesting that it has a more complex role in the regu- lation of JAK2 activity. Our study also shows that the domains located outside the kinase domain have little influence on JAK2 catalytical activity.","PeriodicalId":89033,"journal":{"name":"The open enzyme inhibition journal","volume":"1 1","pages":"80-84"},"PeriodicalIF":0.0,"publicationDate":"2009-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68095845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Porcine Liver Carboxylesterase Requires Polyisoprenylation for High Affinity Binding to Cysteinyl Substrates.","authors":"Nazarius S Lamango, Randolph Duverna, Wang Zhang, Seth Y Ablordeppey","doi":"10.2174/1874940200902010012","DOIUrl":"10.2174/1874940200902010012","url":null,"abstract":"<p><p>The polyisoprenylation pathway enzymes have been the focus of numerous studies to better understand the roles of polyisoprenylated proteins in eukaryotic cells and to identify novel targets against diseases such as cancer. The final step of the pathway is a reversible reaction catalyzed by isoprenyl carboxylmethyl transferase (icmt) whose products are then hydrolyzed by polyisoprenylated methylated protein methyl esterase (PMPMEase). Unlike the other pathway enzymes, the esterase has received little attention. We recently purified PMPMEase from porcine liver using an S-polyisoprenylated cysteine methyl ester substrate-dependent screening assay. However, no data is available showing its relative interaction with structurally diverse substrates. As such, its role as the putative endogenous PMPMEase has not been demonstrated. A series of substrates with S-alkyl substituents ranging from 2 to 20 carbons, including the two moieties found in polyisoprenylated proteins, were synthesized. Enzyme kinetics analysis revealed a 33-fold increase in affinity (K(M) values) from ethyl- (C-2, 505+/-63 microM), prenyl- (C-5, 294+/-25 microM), trans-geranyl- (C-10, 87+/-12 microM), trans, trans-farnesyl- (C-15, 29+/-2.2 microM) to all trans-geranylgeranyl- (C-20-, 15+/-2.7 microM) based analogs. Comparative molecular field analysis of the data yielded a cross-validated q(2) of 0.863+/-0.365 and a final R(2) of 0.995. Since the substrates with the S-trans, trans-farnesyl and S-all trans-geranylgeranyl moieties that occur in proteins show the highest affinity towards PMPMEase and are not hydrolyzed by the cholinesterases, the results suggest that polyisoprenylated proteins are the endogenous substrates of this esterase. The results suggest design strategies for high affinity and selective inhibitors of PMPMEase.</p>","PeriodicalId":89033,"journal":{"name":"The open enzyme inhibition journal","volume":"2 ","pages":"12-27"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906805/pdf/nihms203414.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29153201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sphingolipid Metabolism Inhibitors and Cell Function","authors":"E. Albi, M. V. Magni","doi":"10.2174/1874940200801010072","DOIUrl":"https://doi.org/10.2174/1874940200801010072","url":null,"abstract":"It has been widely shown that ceramide, ceramide phosphate, sphingosine and sphingosine-1-phosphate are molecules involved in cell proliferation, differentiation and apoptosis. The regulation of the enzymes that control their metabolism has an important role for cellular fate. Many studies in the field have shed light on sphingolipid metabolism inhibition and on its role in cell processes such as gene expression, DNA duplication and RNA transcription. The aim of this review is to collect, in a systematic way, the recent advances in the field of sphingolipid metabolism inhibitors, with special emphasis on their effects on cell function. The name sphingolipid was born at the end of the XIX century on the basis of the molecule structure similar to the riddle of the sphinx. These molecules are complex lipids, localized in animal and plant membranes and in some forms of lower life, which contain sphingoid bases and have a very complex metabolism. The sphingolipid biosynthetic pathway initiates with the condensation of the serine with palmitoyl-CoA to form 3- ketodihydrosphingosine or 3-ketosphinganine, a serine pal- mitoyl transferase (SPT) catalyzed reaction. 3-ketodihy- drosphingosine is reduced to dehydrosphingosine or sphin- ganine by a NADPH dependent 3-ketosphinganine reduc- tase. An acylation in the presence of acyl-CoA produces di- hydroceramide by ceramide synthase (CerS). Dihydrocera- mide is then converted to ceramide through the introduction of the double bond trans-4,-5 by dihydroceramide desatu- rase. The ceramide can be transformed to sphingomyelin (SM) by two different ways: the first one involves the reaction with CDP-choline catalyzed by ceramide choline phos- photransferase and the second, described subsequently, con- sists in phosphocholine transfer from lecithin to ceramide by phosphatidylcholine: ceramide phosphocholine transferase or sphingomyelin synthase (SM-synthase). The synthesized SM can be used as source of phosphocholine to form phosphati- dylcholine in the presence of diacylglycerol by reverse- sphingomyelin-synthase (RSM-synthase) freeing ceramide, or can be degraded to ceramide and phosphocholine by acid or neutral sphingomyelinase (aSMase or N-SMase). The new-produced ceramide can be deacylated by acid or neutral ceramidase (AC or NC) to form sphingosine, which can be phosphorylated by a sphingosine kinase 1 (SphK1) or by sphingosine kinase 2 (SphK2) to sphingosine phosphate, can be phosphorylated by ceramide kinase (CerK) or can be","PeriodicalId":89033,"journal":{"name":"The open enzyme inhibition journal","volume":"64 1","pages":"72-79"},"PeriodicalIF":0.0,"publicationDate":"2008-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68095832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical Synthesis, 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitory Activity and Assessment of In Vitro and In Vivo Estrogenic Activities of Estradiol Derivatives","authors":"François Rouillard, J. Lefebvre, M. Fournier, D. Poirier","doi":"10.2174/1874940200801010061","DOIUrl":"https://doi.org/10.2174/1874940200801010061","url":null,"abstract":"hydroxysteroid dehydrogenase type 1 (17�-HSD1) was chosen as a key steroidogenic target enzyme to reduce the formation of estradiol (E2), which is the most potent estrogen. This article completes a previous study by synthesizing and testing 16� -methylene derivatives (Br, Cl and OH) of E2 in order to gen- erate new structure-activity relationships. This study also investigates a series of 2-methoxy (MeO) deriva- tives synthesized as non-estrogenic inhibitors of 17�-HSD1. The 2-MeO-E2 derivatives (16� -CH2Br, 16� - CH2OH and 16� -(CH2)3Br) are all less potent inhibitors (IC50 = 5.91, 3.80 and 5.80 μM) than analogues without the 2-MeO group (IC50 = 1.20, 1.27 and 0.99 μM, respectively) for the reduction of estrone into E2 by 17�-HSD1 overexpressed in HEK-293 cells. Except for one compound, these E2 derivatives have shown an estrogenic-like effect on estrogen-sensitive T-47D cells at 1 �M. A cytotoxic effect was also obtained at higher concentrations for two compounds tested on T-47D cells. However, no estrogenic-like effect was ob- served in the estrogen-sensitive tissues (uterus and vagina) of the ovariectomized mouse model for 2-MeO- 16� -bromopropyl-E2.","PeriodicalId":89033,"journal":{"name":"The open enzyme inhibition journal","volume":"1 1","pages":"61-71"},"PeriodicalIF":0.0,"publicationDate":"2008-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68095793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reversible Inactivation of Human Dipeptidyl Peptidases 8 and 9 by Oxidation","authors":"Joo-Ung Park, H. Knott, N. A. Nadvi, C. Collyer, X. M. Wang, W. B. Church, M. Gorrell","doi":"10.2174/1874940200801010052","DOIUrl":"https://doi.org/10.2174/1874940200801010052","url":null,"abstract":"Hydrogen peroxide (H2O2) can act as an intracellular messenger by oxidizing sulfhydryl groups in cysteines that can be oxidized at neutral pH. The oxidizing agents H2O2 and pyrroloquinoline quinone and the large thiol reagents N-ethylmaleimide and 4-(hydroxymercuri) benzoate each inhibited dipeptidyl peptidase (DP) activity in the intracellular DPIV-related proteins DP8 and DP9 at pH 7.5. In contrast, these treatments did not alter activity in DPIV and fibroblast activation protein. Peptidase inhibition was completely reversed by 2-mercaptoethanol or reduced glutathione. Alkylation of DP8 by the small thiol reagent iodoacetamide prevented inhibition by H2O2, N-ethylmaleimide or pyrroloquinoline qui- none. Two cysteines were reactive per peptidase monomer. We exploited these properties to highly purify DP8 by thiol affinity chromatography. Homology modelling of DP8 and DP9 was consistent with the proposal that the mechanism in- volves decreased protein flexibility caused by intramolecular disulfide bonding. These novel data show that DP8 and DP9 are reversibly inactivated by oxidants at neutral pH and suggest that DP8 and DP9 are H2O2 sensing proteins.","PeriodicalId":89033,"journal":{"name":"The open enzyme inhibition journal","volume":"1 1","pages":"52-60"},"PeriodicalIF":0.0,"publicationDate":"2008-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68095782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PICOT: A Trx- and Grx-Like Protein in Search of a Function","authors":"Ariel Ohayon, G. Dong, Sagit Cohen, M. Galperin, A. Givoni, K. Moyal, N. Isakov","doi":"10.2174/1874940200801010048","DOIUrl":"https://doi.org/10.2174/1874940200801010048","url":null,"abstract":"The PKC-interacting cousin of thioredoxin (PICOT) protein was discovered based on its ability to bind PKC in human T lymphocytes. Overexpression of PICOT was found to impose negative regulatory ef- fects on PKC-dependent functions. This included the inhibition of PKC-dependent activation of c-Jun N- terminal kinase (JNK) and the activator protein 1 (AP-1) and nuclear factor kappa B (NF-B) transcription factors. PICOT is a modular protein consisting of a single thioredoxin (Trx)-like homology domain (HD) and two highly homologous PICOT-HDs. The overall structure of each of the three domains resembles the ca- nonical thioredoxin fold, which is common in enzymes that catalyze disulfide bond formation. Nevertheless, the three PICOT domains lack essential catalytic cysteine residues and their mode of activity is therefore un- clear. PICOT is involved in the regulation of heart muscle function. Its overexpression in the heart of trans- genic mice increased the ventricular function and cardiomyocyte contractility, and inhibited the overall car- diac hypertrophy induced by pressure overload. The effects of PICOT on the cardiac tissue are likely to be mediated via the muscle LIM protein (MLP), which was shown to interact with PICOT in cardiomyocytes, and colocalize with PICOT at the Z-disc of the sarcomer. PICOT interaction with MLP interfered with bind- ing of the latter protein to the Ca 2+ -dependent Ser/Thr phosphatase, calcineurin, causing the displacement of calcineurin from the Z-disc. As a result, PICOT inhibited the calcineurin-mediated dephosphorylation and nuclear translocation of nuclear factor of activated T cells (NF-AT), and the transcriptional activation of NF- AT regulated genes. Whether the effects of PICOT are dependent on PKC, and whether it can mediate cata- lytic activity and/or operate as an adaptor protein are only few of the open questions related to the biological mechanism of action of PICOT.","PeriodicalId":89033,"journal":{"name":"The open enzyme inhibition journal","volume":"1 1","pages":"48-51"},"PeriodicalIF":0.0,"publicationDate":"2008-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68095736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}