Pub Date : 2001-01-01DOI: 10.1080/14756360109162383
A. Scozzafava, I. Şaramet, M. Banciu, C. Supuran
A small series of 2-[4-(4-substituted-phenylsulfonyl)-phenyl]-4-chloromethylthiazoles has been used as a scaffold for the preparation of carbonic anhydrase (CA) inhibitors and activators. For obtaining CA inhibitors, zinc-binding functions of the sulfamide and sulfamate type have been introduced into the molecules of these compounds, by reaction of the chloromethyl derivatives with sodium sulfamide/sodium sulfamate. For obtaining CA activators, the primary amino function has been introduced in these molecules by means of the Gabriel syntheses. The new sulfamide/sulfamates were effective CA II and CA IV inhibitors, but showed no inhibitory activity against isozyme I. The new amines on the other hand were much more effective CA I, II and IV activators compared to histamine, the lead compound used for their synthesis.
小系列的2-[4-(4-取代苯基磺酰)-苯基]-4-氯甲基噻唑被用作碳酸酐酶(CA)抑制剂和活化剂的支架制备。为了获得CA抑制剂，氯甲基衍生物与磺胺/氨基磺酸钠反应，将磺胺和氨基磺酸类型的锌结合功能引入到这些化合物的分子中。为了得到CA激活剂，通过Gabriel合成在这些分子中引入了一级氨基功能。新胺类化合物是有效的CA II和CA IV抑制剂，但对同工酶I没有抑制活性。另一方面，与组胺相比，新胺类化合物是更有效的CA I, II和IV激活剂。
{"title":"Carbonic Anhydrase Activity Modulators: Synthesis of Inhibitors and Activators Incorporating 2-substituted-thiazol-4-yl-methyl Scaffolds","authors":"A. Scozzafava, I. Şaramet, M. Banciu, C. Supuran","doi":"10.1080/14756360109162383","DOIUrl":"https://doi.org/10.1080/14756360109162383","url":null,"abstract":"A small series of 2-[4-(4-substituted-phenylsulfonyl)-phenyl]-4-chloromethylthiazoles has been used as a scaffold for the preparation of carbonic anhydrase (CA) inhibitors and activators. For obtaining CA inhibitors, zinc-binding functions of the sulfamide and sulfamate type have been introduced into the molecules of these compounds, by reaction of the chloromethyl derivatives with sodium sulfamide/sodium sulfamate. For obtaining CA activators, the primary amino function has been introduced in these molecules by means of the Gabriel syntheses. The new sulfamide/sulfamates were effective CA II and CA IV inhibitors, but showed no inhibitory activity against isozyme I. The new amines on the other hand were much more effective CA I, II and IV activators compared to histamine, the lead compound used for their synthesis.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"14 1","pages":"351 - 358"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86103290","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}
Pub Date : 2001-01-01DOI: 10.1080/14756360109162375
J. Risley, D. Huang, J. J. Kaylor, J. J. Malik, Yuan-qing Xia
Glycosylasparaginase catalyzes the hydrolysis of the N-glycosylic bond between asparagine and N-acetylglucosamine in the catabolism of N-linked glycoproteins. Previously only three competitive inhibitors, one noncompetitive inhibitor, and one irreversible inhibitor of glycosylasparaginase activity had been reported. Using human glycosylasparaginase from human amniotic fluid, L-aspartic acid and four of its analogues, where the a-amino group was substituted with a chloro, bromo, methyl or hydrogen, were competitive inhibitors having K, values between 0.6–7.7 mM. These results provide supporting evidence for a proposed intramolecular autoproteolytic activation reaction. A proposed phosphono transition state mimic and a sulfo transition state mimic were competitive inhibitors with Ki values 0.9 mM and 1.4 mM, respectively. These results support a mechanism for the enzyme-catalyzed reaction involving formation of a tetra-hedral high-energy intermediate. Three analogues of the natural substrate were noncompetitive inhibitors with Ki values between 0.56–0.75 mM, indicating the presence of a second binding site that may recognize (substituted)acetamido groups.
{"title":"Glycosylasparaginase Inhibition Studies: Competitive Inhibitors, Transition State Mimics, Noncompetitive Inhibitors","authors":"J. Risley, D. Huang, J. J. Kaylor, J. J. Malik, Yuan-qing Xia","doi":"10.1080/14756360109162375","DOIUrl":"https://doi.org/10.1080/14756360109162375","url":null,"abstract":"Glycosylasparaginase catalyzes the hydrolysis of the N-glycosylic bond between asparagine and N-acetylglucosamine in the catabolism of N-linked glycoproteins. Previously only three competitive inhibitors, one noncompetitive inhibitor, and one irreversible inhibitor of glycosylasparaginase activity had been reported. Using human glycosylasparaginase from human amniotic fluid, L-aspartic acid and four of its analogues, where the a-amino group was substituted with a chloro, bromo, methyl or hydrogen, were competitive inhibitors having K, values between 0.6–7.7 mM. These results provide supporting evidence for a proposed intramolecular autoproteolytic activation reaction. A proposed phosphono transition state mimic and a sulfo transition state mimic were competitive inhibitors with Ki values 0.9 mM and 1.4 mM, respectively. These results support a mechanism for the enzyme-catalyzed reaction involving formation of a tetra-hedral high-energy intermediate. Three analogues of the natural substrate were noncompetitive inhibitors with Ki values between 0.56–0.75 mM, indicating the presence of a second binding site that may recognize (substituted)acetamido groups.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"40 1","pages":"269 - 274"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77548947","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}
M. ul-Hassan, A. Scozzafava, Z. Chohan, C. Supuran
Metal complexes of aromatic/heterocyclic sulfonamides act as stronger inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) as compared to the uncomplexed sulfonamides from which they are derived. Here we report the synthesis and inhibition studies against the physiologically relevant isozymes CA I, CA II and CA IV, of a series of metal complexes (Co(II), Ni(II) and Cu(II) derivatives) of a Schiff-base ligand, obtained from sulfanilamide and salicylaldehyde. The best activity was observed for the Cu(II) and Co(II) complexes, against CA II and CA IV, for which inhibition constants in the range of 15-39 and 72-108 nM, respectively, were seen. The enhanced efficacy in inhibiting the enzyme may be due to a dual mechanism of action of the metal complexes, which interact with CA both by means of the sulfonamide moieties as well as the metal ions present in their molecule.
芳香族/杂环磺胺类金属配合物对锌酶碳酸酐酶(CA, EC 4.2.1.1)的抑制作用强于其衍生的未配合的磺胺类化合物。本文报道了从磺胺和水杨醛中获得的一系列希夫碱配体金属配合物(Co(II)， Ni(II)和Cu(II)衍生物)的合成和对生理相关同工酶CA I, CA II和CA IV的抑制研究。Cu(II)和Co(II)配合物对CA II和CA IV的抑制作用最强，抑制常数分别为15 ~ 39 nM和72 ~ 108 nM。抑制酶的效果增强可能是由于金属配合物的双重作用机制，它们既通过磺胺部分又通过其分子中的金属离子与CA相互作用。
{"title":"Carbonic Anhydrase Inhibitors: Metal Complexes of a Sulfanilamide Derived Schiff base and their Interaction with Isozymes I, II and IV","authors":"M. ul-Hassan, A. Scozzafava, Z. Chohan, C. Supuran","doi":"10.1080/14756360127571","DOIUrl":"https://doi.org/10.1080/14756360127571","url":null,"abstract":"Metal complexes of aromatic/heterocyclic sulfonamides act as stronger inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) as compared to the uncomplexed sulfonamides from which they are derived. Here we report the synthesis and inhibition studies against the physiologically relevant isozymes CA I, CA II and CA IV, of a series of metal complexes (Co(II), Ni(II) and Cu(II) derivatives) of a Schiff-base ligand, obtained from sulfanilamide and salicylaldehyde. The best activity was observed for the Cu(II) and Co(II) complexes, against CA II and CA IV, for which inhibition constants in the range of 15-39 and 72-108 nM, respectively, were seen. The enhanced efficacy in inhibiting the enzyme may be due to a dual mechanism of action of the metal complexes, which interact with CA both by means of the sulfonamide moieties as well as the metal ions present in their molecule.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"7 1","pages":"499 - 505"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76280975","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}
Plant invertases play important roles in sucrose metabolism. Cell wall invertase was reported to participate in phloem loading and unloading. Soluble invertases would be involved in hexose level regulation in mature tissues and in stored sucrose utilization within vacuoles. Invertase inhibitory proteins were described as one of the possible mechanisms for invertase activity regulation in some plant species; nevertheless, these proteins were found only in sink tissues, suggesting that this mechanism would not be relevant in the sucrose turnover of leaves. This report describes the purification of invertase from Pteris deflexa fronds and the occurrence of an invertase inhibitory protein in this fern organ, as well as its purification and invertase-inhibitor interactions. The Mr of the invertase and of its inhibitory protein were 90,000 and 18,000, respectively. SDS-PAGE in the presence of 2-mercaptoetanol gave two subunits for the enzyme (Mr=66,000 and 30,000) and only one for the inhibitor. The inhibitor protein is a glycoprotein (12% w/w of neutral sugars) that did not show agglutinating activity like some others, and also showed a high heat stability at pH 5.0. The optimum pH of invertase activity is 5.0, while invertase inhibitory protein caused maximal inhibition at the same pH value. Invertase-inhibitor complex formation occurs in an immediate manner and a protease activity was discarded. The inhibition is non-competitive (Ki=1.5 × 10 −6 M) without interactions among the binding sites. The complex is slightly dissociable and sucrose was able to partially reduce the inhibitory effect. Up to the present, invertase inhibitory proteins have been found solely in heterotrophic tissues. In this work we demonstrate that this protein is also present in an autotrophic tissue of a lower vascular plant.
{"title":"An Invertase Inhibitory Protein From Pteris deflexa Link Fronds","authors":"J. Sayago, M. A. Vattuone, A. Sampietro, M. Isla","doi":"10.1080/14756360127573","DOIUrl":"https://doi.org/10.1080/14756360127573","url":null,"abstract":"Plant invertases play important roles in sucrose metabolism. Cell wall invertase was reported to participate in phloem loading and unloading. Soluble invertases would be involved in hexose level regulation in mature tissues and in stored sucrose utilization within vacuoles. Invertase inhibitory proteins were described as one of the possible mechanisms for invertase activity regulation in some plant species; nevertheless, these proteins were found only in sink tissues, suggesting that this mechanism would not be relevant in the sucrose turnover of leaves. This report describes the purification of invertase from Pteris deflexa fronds and the occurrence of an invertase inhibitory protein in this fern organ, as well as its purification and invertase-inhibitor interactions. The Mr of the invertase and of its inhibitory protein were 90,000 and 18,000, respectively. SDS-PAGE in the presence of 2-mercaptoetanol gave two subunits for the enzyme (Mr=66,000 and 30,000) and only one for the inhibitor. The inhibitor protein is a glycoprotein (12% w/w of neutral sugars) that did not show agglutinating activity like some others, and also showed a high heat stability at pH 5.0. The optimum pH of invertase activity is 5.0, while invertase inhibitory protein caused maximal inhibition at the same pH value. Invertase-inhibitor complex formation occurs in an immediate manner and a protease activity was discarded. The inhibition is non-competitive (Ki=1.5 × 10 −6 M) without interactions among the binding sites. The complex is slightly dissociable and sucrose was able to partially reduce the inhibitory effect. Up to the present, invertase inhibitory proteins have been found solely in heterotrophic tissues. In this work we demonstrate that this protein is also present in an autotrophic tissue of a lower vascular plant.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"43 1","pages":"517 - 525"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85804011","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}
Pub Date : 2001-01-01DOI: 10.1080/14756360109162380
D. Lewis, M. Dickins
The results of quantitative structure-activity relationship (QSAR) studies on series of F450 inhibitors are reported. Cytochrome F450 families CYP1, CYP2 and CYP51 have been investigated for QSAR analysis, including those of CYP2 subfamilies: CYP2A, CYP2B, CYP2C, CYP2D and CYP2E. The accumulated evidence indicates different structural descriptors being involved, depending on the P450 enzyme concerned, although compound lipophilicity in the form of either logP or logD7.4 appears to represent a common factor in some cases. This is thought to represent desolvation of the P450 active site, although quadratic expressions in lipophilicity tend to suggest that membrane transport is important, especially for CYP2B and CYP2E isoforms. In general, there is close agreement (R = 0.95–0.99) between experimental pKi values and those calculated via QSAR analysis.
{"title":"Quantitative Structure-Activity Relationships (QSARs) Within Series of Inhibitors for Mammalian Cytochromes P450 (CYPs)","authors":"D. Lewis, M. Dickins","doi":"10.1080/14756360109162380","DOIUrl":"https://doi.org/10.1080/14756360109162380","url":null,"abstract":"The results of quantitative structure-activity relationship (QSAR) studies on series of F450 inhibitors are reported. Cytochrome F450 families CYP1, CYP2 and CYP51 have been investigated for QSAR analysis, including those of CYP2 subfamilies: CYP2A, CYP2B, CYP2C, CYP2D and CYP2E. The accumulated evidence indicates different structural descriptors being involved, depending on the P450 enzyme concerned, although compound lipophilicity in the form of either logP or logD7.4 appears to represent a common factor in some cases. This is thought to represent desolvation of the P450 active site, although quadratic expressions in lipophilicity tend to suggest that membrane transport is important, especially for CYP2B and CYP2E isoforms. In general, there is close agreement (R = 0.95–0.99) between experimental pKi values and those calculated via QSAR analysis.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"1 1","pages":"321 - 330"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88777857","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}
Pub Date : 2001-01-01DOI: 10.1080/14756360109162377
L. Salvati, M. Mattu, F. Tiberi, F. Polticelli, P. Ascenzi
Phosphomannose isomerase (PMI; EC. 5.3.1.8) is an essential metalloenzyme in the early steps of the protein glycosylation pathway in both prokaryotes and eukaryotes. The Cysl50 residue (according to Candida albicans PMI numbering) is conserved in the active centre of mammalian and yeast PMI, but not in bacterial species where it is replaced by Asn. Here, the dose- and time-dependent inhibitory effect of the NO-donor S-nitroso-acetyl-penicillamine on the Saccharomyces cerevisiae PMI catalytic activity is reported. The analysis of the X-ray crystal structure of C. albicans PMI and of the molecular model of S. cerevisiae PMI provides a rationale for the low reactivity of Cysl50 towards alkylating and nitrosylating agents.
{"title":"Inhibition of Saccharomyces cerevisiae Phosphomannose Isomerase by the NO-donor S-nitroso-acetyl-penicillamine","authors":"L. Salvati, M. Mattu, F. Tiberi, F. Polticelli, P. Ascenzi","doi":"10.1080/14756360109162377","DOIUrl":"https://doi.org/10.1080/14756360109162377","url":null,"abstract":"Phosphomannose isomerase (PMI; EC. 5.3.1.8) is an essential metalloenzyme in the early steps of the protein glycosylation pathway in both prokaryotes and eukaryotes. The Cysl50 residue (according to Candida albicans PMI numbering) is conserved in the active centre of mammalian and yeast PMI, but not in bacterial species where it is replaced by Asn. Here, the dose- and time-dependent inhibitory effect of the NO-donor S-nitroso-acetyl-penicillamine on the Saccharomyces cerevisiae PMI catalytic activity is reported. The analysis of the X-ray crystal structure of C. albicans PMI and of the molecular model of S. cerevisiae PMI provides a rationale for the low reactivity of Cysl50 towards alkylating and nitrosylating agents.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"44 1","pages":"287 - 292"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86576747","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}
Pub Date : 2001-01-01DOI: 10.1080/14756360109162363
Benjamin D. Malkin, Karen R. Thickman, C. Markworth, D. Wilcox, F. Kull
The activity of potato polyphenol oxidase (tyrosinase) toward DL-3,4-dihydroxyphenylalanine (KM 5.39 mM) was studied using a variety of carboxylate buffers at a common pH and ionic strength. Enzyme activity, greatest in citrate and least in oxalate, correlated with increasing carboxyl concentration and molecular mass. The lower activity in oxalate was attributed to more effective chelation of a copper(II) form of the enzyme by the oxalate dianion. Sodium halide salts inhibited the enzyme. Although there was little difference in inhibition between sodium and potassium salts, the degree and type of inhibition was anion dependent; Kis, values for NaCl and KC1, (competitive inhibitors) were 1.82 and 1.62 mM, whereas Na2SO4 and K2SO4 (mixed inhibitors) had Kis and Kii values in the 250 to 450 mM range.
{"title":"Inhibition of Potato Polyphenol Oxidase by Anions and Activity in Various Carboxylate Buffers (pH 4.8) at Constant Ionic Strength","authors":"Benjamin D. Malkin, Karen R. Thickman, C. Markworth, D. Wilcox, F. Kull","doi":"10.1080/14756360109162363","DOIUrl":"https://doi.org/10.1080/14756360109162363","url":null,"abstract":"The activity of potato polyphenol oxidase (tyrosinase) toward DL-3,4-dihydroxyphenylalanine (KM 5.39 mM) was studied using a variety of carboxylate buffers at a common pH and ionic strength. Enzyme activity, greatest in citrate and least in oxalate, correlated with increasing carboxyl concentration and molecular mass. The lower activity in oxalate was attributed to more effective chelation of a copper(II) form of the enzyme by the oxalate dianion. Sodium halide salts inhibited the enzyme. Although there was little difference in inhibition between sodium and potassium salts, the degree and type of inhibition was anion dependent; Kis, values for NaCl and KC1, (competitive inhibitors) were 1.82 and 1.62 mM, whereas Na2SO4 and K2SO4 (mixed inhibitors) had Kis and Kii values in the 250 to 450 mM range.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"7 1","pages":"135 - 145"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72788925","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}
Pub Date : 2001-01-01DOI: 10.1080/14756360109162365
G. Gadda, A. Banerjee, Gaylon S. Fleming, P. Fitzpatrick
The flavoprotein nitroalkane oxidase from the fungus Fusarium oxysporum catalyzes the oxidative denitrification of primary or secondary nitroalkanes to yield the respective aldehydes or ketones, hydrogen peroxide and nitrite. The enzyme is inactivated in a time-dependent fashion upon treatment with the arginine-directed reagents phenylglyoxal, 2,3-butanedione, and cyclohexanedione. The inactivation shows first order kinetics with all reagents. Valerate, a competitive inhibitor of the enzyme, fully protects the enzyme from inactivation, indicating that modification is active site directed. The most rapid inactivation is seen with phenylglyoxal, with a kinact of 14.3 ± 1.1 M−1 min−1 in phosphate buffer at pH 7.3 and 30 °C. The lack of increase in the enzymatic activity of the phenylglyoxal-inactivated enzyme after removing the unreacted reagent by gel filtration is consistent with inactivation being due to co-valent modification of the enzyme. A possible role for an active site arginine in substrate binding is discussed.
{"title":"Evidence for an Essential Arginine in the Flavoprotein Nitroalkane Oxidase","authors":"G. Gadda, A. Banerjee, Gaylon S. Fleming, P. Fitzpatrick","doi":"10.1080/14756360109162365","DOIUrl":"https://doi.org/10.1080/14756360109162365","url":null,"abstract":"The flavoprotein nitroalkane oxidase from the fungus Fusarium oxysporum catalyzes the oxidative denitrification of primary or secondary nitroalkanes to yield the respective aldehydes or ketones, hydrogen peroxide and nitrite. The enzyme is inactivated in a time-dependent fashion upon treatment with the arginine-directed reagents phenylglyoxal, 2,3-butanedione, and cyclohexanedione. The inactivation shows first order kinetics with all reagents. Valerate, a competitive inhibitor of the enzyme, fully protects the enzyme from inactivation, indicating that modification is active site directed. The most rapid inactivation is seen with phenylglyoxal, with a kinact of 14.3 ± 1.1 M−1 min−1 in phosphate buffer at pH 7.3 and 30 °C. The lack of increase in the enzymatic activity of the phenylglyoxal-inactivated enzyme after removing the unreacted reagent by gel filtration is consistent with inactivation being due to co-valent modification of the enzyme. A possible role for an active site arginine in substrate binding is discussed.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"1 1","pages":"157 - 163"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90886988","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}
Pub Date : 2001-01-01DOI: 10.1080/14756360109162384
C. E. Rodríguez, Haiyan Lu, Alicia R. Martinez, Yingying Hu, A. Brunelle, C. Berkman
A limited series of N-thiophosphonyl-glutamates were found to be inhibitors of the prostate-specific membrane antigen (PSMA) form of glutamate carboxypeptidase II. Comparative inhibitory profiles of an analogous O-thiophosphonyl-2-hydroxygluta-rate revealed that the amido-linkage of the N-thio-phosphonyl-glutamate provides a significant enhancement of inhibitory potency presumably due to significant hydrogen-bonding interactions with acceptor groups in the active-site of PSMA resulting in tighter binding. An analogous N-phosphonyl-glutamate exhibited significantly greater inhibitory potency than the parent N-thiophospho-nyl-glutamate indicating that the sulfur ligand of the N-thiophosphonyl-glutamates is responsible for less favorable active-site interactions than oxygen, potentially due to steric crowding from the longer P-S bond or as a result of active-site metal substitution of Co(II) for Zn(II) arising from assay conditions.
{"title":"Inhibition of Glutamate Carboxypeptidase II by Phosphonamidothionate Derivatives of Glutamic Acid","authors":"C. E. Rodríguez, Haiyan Lu, Alicia R. Martinez, Yingying Hu, A. Brunelle, C. Berkman","doi":"10.1080/14756360109162384","DOIUrl":"https://doi.org/10.1080/14756360109162384","url":null,"abstract":"A limited series of N-thiophosphonyl-glutamates were found to be inhibitors of the prostate-specific membrane antigen (PSMA) form of glutamate carboxypeptidase II. Comparative inhibitory profiles of an analogous O-thiophosphonyl-2-hydroxygluta-rate revealed that the amido-linkage of the N-thio-phosphonyl-glutamate provides a significant enhancement of inhibitory potency presumably due to significant hydrogen-bonding interactions with acceptor groups in the active-site of PSMA resulting in tighter binding. An analogous N-phosphonyl-glutamate exhibited significantly greater inhibitory potency than the parent N-thiophospho-nyl-glutamate indicating that the sulfur ligand of the N-thiophosphonyl-glutamates is responsible for less favorable active-site interactions than oxygen, potentially due to steric crowding from the longer P-S bond or as a result of active-site metal substitution of Co(II) for Zn(II) arising from assay conditions.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"38 1","pages":"359 - 365"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90766064","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}
Pub Date : 2001-01-01DOI: 10.1080/14756360109162392
M. Shuaibu, H. Kanbara, T. Yanagi, D. Ameh, J. J. Bonire, A. Nok
Activity and kinetics of phospholipase A2 (PLA2) from Trypanosoma brucei gambiense (Wellcome strain) and Trypanosoma brucei brucei (GUTat 3.1) were examined using two different fluorescent substrates. The activity in the supernatants of sonicated parasites was Ca2+-independent, strongly stimulated by Triton X-100 with optimum activity at 37°C and pH 6.5–8.5. To encourage a possible interaction between the parasite enzyme and organotin compounds, fatty acid derivatives of dibutyltin dichloride were synthesized and evaluated as potential inhibitors of PLA2. The enzyme from the two-trypanosome species differ with respect to kinetic parameters and are noncompetitively inhibited by the organotin compounds. The Michaelis constant (KM) for PLA2 from T. b. brucei is 63.87 and 30.90 μM while for T. b. gambiense it is 119.64 and 32.90 μM for the substrates l,2-bis-(1-pyrenebutanoyl-sn-glycero-3-phosphocholine (PBGPC) and 2-(12-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)dode-canoyl-1-hexadecanoyl-sn-glycero-3-phosphocholine (NBDC12-HPC), respectively.
{"title":"Phospholipase A2 from Trypanosoma brucei gambiense and Trypanosoma brucei brucei: Inhibition by Organotins","authors":"M. Shuaibu, H. Kanbara, T. Yanagi, D. Ameh, J. J. Bonire, A. Nok","doi":"10.1080/14756360109162392","DOIUrl":"https://doi.org/10.1080/14756360109162392","url":null,"abstract":"Activity and kinetics of phospholipase A2 (PLA2) from Trypanosoma brucei gambiense (Wellcome strain) and Trypanosoma brucei brucei (GUTat 3.1) were examined using two different fluorescent substrates. The activity in the supernatants of sonicated parasites was Ca2+-independent, strongly stimulated by Triton X-100 with optimum activity at 37°C and pH 6.5–8.5. To encourage a possible interaction between the parasite enzyme and organotin compounds, fatty acid derivatives of dibutyltin dichloride were synthesized and evaluated as potential inhibitors of PLA2. The enzyme from the two-trypanosome species differ with respect to kinetic parameters and are noncompetitively inhibited by the organotin compounds. The Michaelis constant (KM) for PLA2 from T. b. brucei is 63.87 and 30.90 μM while for T. b. gambiense it is 119.64 and 32.90 μM for the substrates l,2-bis-(1-pyrenebutanoyl-sn-glycero-3-phosphocholine (PBGPC) and 2-(12-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)dode-canoyl-1-hexadecanoyl-sn-glycero-3-phosphocholine (NBDC12-HPC), respectively.","PeriodicalId":15776,"journal":{"name":"Journal of enzyme inhibition","volume":"75 1 1","pages":"433 - 441"},"PeriodicalIF":0.0,"publicationDate":"2001-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74576681","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}
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