scholarly journals The kinetics of inhibition of erythrocyte cholinesterase by monomethylcarbamates

1966 ◽  
Vol 98 (2) ◽  
pp. 501-505 ◽  
Author(s):  
E Reiner ◽  
V Simeon-Rudolf
Keyword(s):  
Kinetics Of ◽  
Kinetics Of Inhibition

The Kinetics of Inhibition of the Action of Thrombin by the Fibrinopeptides Formed during the Clotting of Fibrinogen

1966 ◽  
Vol 16 (01/02) ◽  
pp. 277-295 ◽  
Author(s):  
A Silver ◽  
M Murray
Keyword(s):  
Amino Acids ◽  
Competitive Inhibition ◽  
Amorphous Material ◽  
Peptide Bond ◽  
Initial Reaction ◽  
Reaction Products ◽  
Coagulation Mechanism ◽  
Kinetics Of ◽  
Kinetics Of Inhibition ◽  
Burk Plot

SummaryVarious investigators have separated the coagulation products formed when fibrinogen is clotted with thrombin and identified fibrinopeptides A and B. Two other peaks are observed in the chromatogram of the products of coagulation, but these have mostly been dismissed by other workers. They have been identified by us as amino acids, smaller peptides and amorphous material (37). We have re-chromatographed these peaks and identified several amino acids. In a closed system of fibrinogen and thrombin, the only reaction products should be fibrin and peptide A and peptide B. This reasoning has come about because thrombin has been reported to be specific for the glycyl-arginyl peptide bond. It is suggested that thrombin also breaks other peptide linkages and the Peptide A and Peptide B are attacked by thrombin to yield proteolytic products. Thrombin is therefore probably not specific for the glycyl-arginyl bond but will react on other linkages as well.If the aforementioned is correct then the fibrinopeptides A and B would cause an inhibition with the coagulation mechanism itself. We have shown that an inhibition does occur. We suggest that there is an autoinhibition to the clotting mechanism that might be a control mechanism in the human body.The experiment was designed for coagulation to occur under controlled conditions of temperature and time. Purified reactants were used. We assembled an apparatus to record visually the speed of the initial reaction, the rate of the reaction, and the density of the final clot formed after a specific time.The figures we derived made available to us data whereby we could calculate and plot the information to show the mechanism and suggest that such an inhibition does exist and also further suggest that it might be competitive.In order to prove true competitive inhibition it is necessary to fulfill the criteria of the Lineweaver-Burk plot. This has been done. We have also satisfied other criteria of Dixon (29) and Bergman (31) that suggest true competitive inhibition.

Kinetics of inhibition of purified bovine neutrophil matrix metalloproteinase 9 by low–molecular-weight inhibitors

2009 ◽  
Vol 70 (5) ◽  
pp. 633-639 ◽  
Author(s):  
Gregory A. Bannikov ◽  
Jeffrey Lakritz ◽  
Christopher Premanandan ◽  
John S. Mattoon ◽  
Eric J. Abrahamsen
Keyword(s):  
Molecular Weight ◽  
Matrix Metalloproteinase ◽  
Matrix Metalloproteinase 9 ◽  
Low Molecular Weight ◽  
Kinetics Of ◽  
Metalloproteinase 9 ◽  
Kinetics Of Inhibition ◽  
Bovine Neutrophil

For a PDK1 inhibitor, the substrate matters

2010 ◽  
Vol 433 (2) ◽  
pp. e1-e2 ◽  
Author(s):  
Zachary A. Knight
Keyword(s):  
Cell Growth ◽  
Protein Kinases ◽  
Cell Signalling ◽  
Central Component ◽  
Specific Inhibition ◽  
Biochemical Journal ◽  
Regulate Cell Growth ◽  
Kinetics Of ◽  
Kinetics Of Inhibition ◽  
Phosphoinositide Dependent Kinase

More than 20 protein kinases are directly activated by 3-phosphoinositide-dependent kinase 1 (PDK1), which is a central component of the pathways that regulate cell growth, proliferation and survival. Despite the importance of PDK1 in cell signalling, highly selective PDK1 inhibitors have not been described. In this issue of the Biochemical Journal, Dario Alessi's group and their collaborators at GlaxoSmithKline report GSK2334470, a potent and selective PDK1 inhibitor. They show that this compound blocks the phosphorylation of known PDK1 substrates, but surprisingly find that the potency and kinetics of inhibition vary for different PDK1 targets. This substrate-specific inhibition has implications for the development of PDK1 inhibitors as drugs.

scholarly journals Purification and kinetic mechanism of the major glutathione S-transferase from bovine brain

1989 ◽  
Vol 257 (2) ◽  
pp. 541-548 ◽  
Author(s):  
P R Young ◽  
A V Briedis
Keyword(s):  
Decanoic Acid ◽  
Kinetic Mechanism ◽  
Order Rate Constant ◽  
Bovine Brain ◽  
Glutathione S Transferase ◽  
Rate Acceleration ◽  
Hydrophobic Binding ◽  
Kinetics Of ◽  
Kinetics Of Inhibition

The major glutathione S-transferase isoenzyme from bovine brain was isolated and purified approx. 500-fold. The enzyme has a pI of 7.39 +/- 0.02 and consists of two non-identical subunits having apparent Mr values of 22,000 and 24,000. The enzyme is uniformly distributed in brain, and kinetic data at pH 6.5 with 1-chloro-2,4-dinitrobenzene (CDNB) as substrate suggest a random rapid-equilibrium mechanism. The kinetics of inhibition by product, by GSH analogues and by NADH are consistent with the suggested mechanism and require inhibitor binding to several different enzyme forms. Long-chain fatty acids are excellent inhibitors of the enzyme, and values of 1nKi for hexanoic acid, octanoic acid, decanoic acid and lauric acid form a linear series when plotted as a function of alkyl chain length. A free-energy change of -1900 J/mol (-455 cal/mol) per CH2 unit is calculated for the contribution of hydrophobic binding energy to the inhibition constants. The turnover number of the purified enzyme dimer is approx. 3400/min. When compared with the second-order rate constant for the reaction between CDNB and GSH, the enzyme is providing a rate acceleration of about 1000-fold. The role of entropic contributions to this small rate acceleration is discussed.

scholarly journals In vitro antibacterial activity and in vivo efficacy of sulbactam-durlobactam against pathogenic Burkholderia species

2020 ◽  
pp. AAC.01930-20
Author(s):  
Krisztina M. Papp-Wallace ◽  
Adam B. Shapiro ◽  
Scott A. Becka ◽  
Elise T. Zeiser ◽  
John J. LiPuma ◽  
...  
Keyword(s):  
Human Pathogens ◽  
Minimal Inhibitory Concentrations ◽  
Class A ◽  
In Vitro Antibacterial Activity ◽  
Lung Infections ◽  
Kinetics Of ◽  
Kinetics Of Inhibition ◽  
Inhibitor Combination

The Gram-negative bacterial genus Burkholderia includes several hard-to-treat human pathogens: two biothreat species, B. mallei (causing glanders) and B. pseudomallei (causing melioidosis), and the B. cepacia complex (BCC) and B. gladioli, which cause chronic lung infections in persons with cystic fibrosis. All Burkholderia spp. possess an Ambler class A Pen β-lactamase, which confers resistance to β-lactams. The β-lactam-β-lactamase inhibitor combination sulbactam-durlobactam (SUL-DUR) is in clinical development for the treatment of Acinetobacter infections. Herein, we evaluated SUL-DUR for in vitro and in vivo activity against Burkholderia clinical isolates. We measured minimal inhibitory concentrations (MICs) of SUL-DUR against BCC and B. gladioli (N = 150), B. mallei (N = 30) and B. pseudomallei (N = 28); studied the kinetics of inhibition of the PenA1 β-lactamase from B. multivorans and the PenI β-lactamase from B. pseudomallei by durlobactam; tested for blaPenA1 induction by SUL-DUR; and evaluated in vivo efficacy in a mouse model of melioidosis. SUL-DUR inhibited growth of 87.3% of the BCC and B. gladioli strains and 100% of the B. mallei and B. pseudomallei strains at 4/4 μg/mL. Durlobactam potently inhibited PenA1 and PenI with k2/K values of 3.9 x 106 M−1s−1 and 2.6 x 103 M−1s−1 and Ki app of 15 nM and 241 nM, respectively, by forming highly stable covalent complexes. Neither sulbactam, durlobactam, nor SUL-DUR increased production of PenA1. SUL-DUR demonstrated activity in vivo in a murine melioidosis model. Taken together, these data suggest SUL-DUR may be useful as a treatment for Burkholderia infections.

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