Relationships between inhibition constants, inhibitor concentrations for 50% inhibition and types of inhibition: new ways of analysing data

2001 ◽  
Vol 357 (1) ◽  
pp. 263-268 ◽  
Author(s):  
Antoni CORTÉS ◽  
Marta CASCANTE ◽  
María Luz CÁRDENAS ◽  
Athel CORNISH-BOWDEN
Keyword(s):  
Lactate Dehydrogenase ◽  
Malate Dehydrogenase ◽  
Competitive Inhibitor ◽  
Inhibitor Concentration ◽  
Catalysed Reaction ◽  
Pharmacological Studies ◽  
The Common ◽  
Uncompetitive Inhibitor ◽  
Cytosolic Malate Dehydrogenase ◽  
Theory And Experiment

The concentration of an inhibitor that decreases the rate of an enzyme-catalysed reaction by 50%, symbolized i0.5, is often used in pharmacological studies to characterize inhibitors. It can be estimated from the common inhibition plots used in biochemistry by means of the fact that the extrapolated inhibitor concentration at which the rate becomes infinite is equal to −i0.5. This method is, in principle, more accurate than comparing the rates at various different inhibitor concentrations, and inferring the value of i0.5 by interpolation. Its reciprocal, 1/i0.5, is linearly dependent on v0/V, the uninhibited rate divided by the limiting rate, and the extrapolated value of v0/V at which 1/i0.5 is zero allows the type of inhibition to be characterized: this value is 1 if the inhibition is strictly competitive; greater than 1 if the inhibition is mixed with a predominantly competitive component; infinite (i.e. 1/i0.5 does not vary with v0/V) if the inhibition is pure non-competitive (i.e. mixed with competitive and uncompetitive components equal); negative if the inhibition is mixed with a predominantly uncompetitive component; and zero if it is strictly uncompetitive. The type of analysis proposed has been tested experimentally by examining inhibition of lactate dehydrogenase by oxalate (an uncompetitive inhibitor with respect to pyruvate) and oxamate (a competitive inhibitor with respect to pyruvate), and of cytosolic malate dehydrogenase by hydroxymalonate (a mixed inhibitor with respect to oxaloacetate). In all cases there is excellent agreement between theory and experiment.

scholarly journals Four Weeks of Aerobic Training Affects Cardiac Tissue Matrix Metalloproteinase, Lactate Dehydrogenase and Malate Dehydrogenase Enzymes Activities, and Hepatorenal Biomarkers in Experimental Hyperhomocysteinemia in Rats

2021 ◽  
Vol 22 (13) ◽  
pp. 6792
Author(s):  
Dusan Todorovic ◽  
Marija Stojanovic ◽  
Ana Medic ◽  
Kristina Gopcevic ◽  
Slavica Mutavdzin ◽  
...  
Keyword(s):  
Physical Activity ◽  
Lactate Dehydrogenase ◽  
Malate Dehydrogenase ◽  
Subcutaneous Injection ◽  
Cardiac Tissue ◽  
Albino Rats ◽  
Wistar Albino Rats ◽  
And Control ◽  
Tissue Matrix ◽  
Increased Activity

The aim of this study was to investigate the effect of the application of homocysteine as well as its effect under the condition of aerobic physical activity on the activities of matrix metalloproteinases (MMP), lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) in cardiac tissue and on hepato-renal biochemical parameters in sera of rats. Male Wistar albino rats were divided into four groups (n = 10, per group): C: 0.9% NaCl 0.2 mL/day subcutaneous injection (s.c.); H: homocysteine 0.45 µmol/g b.w./day s.c.; CPA saline (0.9% NaCl 0.2 mL/day s.c.) and a program of physical activity on a treadmill; and HPA homocysteine (0.45 µmol/g b.w./day s.c.) and a program of physical activity on a treadmill. Subcutaneous injection of substances was applied 2 times a day at intervals of 8 h during the first two weeks of experimental protocol. Hcy level in serum was significantly higher in the HPA group compared to the CPA group (p < 0.05). Levels of glucose, proteins, albumin, and hepatorenal biomarkers were higher in active groups compared with the sedentary group. It was demonstrated that the increased activities of LDH (mainly caused by higher activity of isoform LDH2) and mMDH were found under the condition of homocysteine-treated rats plus aerobic physical activity. Independent application of homocysteine did not lead to these changes. Physical activity leads to activation of MMP-2 isoform and to increased activity of MMP-9 isoform in both homocysteine-treated and control rats.

scholarly journals Contribution of engineered electrostatic interactions to the stability of cytosolic malate dehydrogenase

2001 ◽  
Vol 14 (11) ◽  
pp. 911-917 ◽  
Author(s):  
Francesca Trejo ◽  
Josep Ll. Gelpí ◽  
Albert Ferrer ◽  
Albert Boronat ◽  
Montserrat Busquets ◽  
...  
Keyword(s):  
Malate Dehydrogenase ◽  
Electrostatic Interactions ◽  
The Stability ◽  
Cytosolic Malate Dehydrogenase

scholarly journals Interaction of difluoro-oxaloacetate with aspartate transaminase

1977 ◽  
Vol 161 (2) ◽  
pp. 383-387 ◽  
Author(s):  
P A Briley ◽  
R Eisenthal ◽  
R Harrison ◽  
G D Smith
Keyword(s):  
Steady State ◽  
Competitive Inhibitor ◽  
Aspartate Transaminase ◽  
Steady State Kinetic ◽  
High Concentrations ◽  
State Kinetic ◽  
Uncompetitive Inhibitor

Diffluoro-oxaloacetate behaves as a competitive inhibitor of 2-oxoglutarate and as an uncompetitive inhibitor with respect to aspartate in steady-state kinetic experiments with cytoplasmic aspartate transaminase. In the presence of high concentrations of aspartate transaminase, difluoro-oxaloacetate is slowly transaminated to difluoro-aspartate, suggesting its use as a kinetic probe to study the reactions of the aminic form of the enzyme.

Receptor kinetics pertaining to blockade of nerve-released transmitter at synapses

1988 ◽  
Vol 233 (1273) ◽  
pp. 461-475 ◽  
Keyword(s):  
Channel Blocker ◽  
Competitive Inhibitor ◽  
Tissue Response ◽  
Receptor Density ◽  
Receptor Kinetics ◽  
Tissue Responses ◽  
Competitive Inhibitors ◽  
Transmitter Substance ◽  
Uncompetitive Inhibitor ◽  
Temporal Inhomogeneity

The question is raised as to whether competitive inhibitors should block responses of tissue to nerve-released neurotransmitter to the same extent as they block equivalent responses to exogenous agonist. From a simple dynamic model of synaptic events, which takes into account non-constancy of transmitter concentration in space and time, it is deduced that equal blockade of responses to nerve-released and exogenous transmitter substance will occur if: (i) there are locally many more receptor molecules than transmitter molecules; (ii) the active agonist–receptor complex, A n R, has n = 1 ; and (iii) tissue response is insensitive to spatial or temporal inhomogeneity of AR. In such a case there will also be equal sensitivity of responses to other modes of inhibition: irreversible competitive, uncompetitive, and non-competitive. Equal blockade of responses to equi-effective endogenous and exogenous agonist will also occur if nerve stimulation gives rise to a steady uniform concentration of agonist, so that equilibrium kinetics are applicable. When n > 1 and/or when tissue responses reflect local peak A n R, response to nerve-released transmitter will be relatively insensitive to receptor blockade by a competitive inhibitor. The same is true for irreversible competitive blockade or for modulation of receptor density. However, an uncompetitive inhibitor (e. g. a ‘channel blocker’) may be more effective against nerve-released agonist than against exogenous agonist.

scholarly journals Evidence for the importance of arginine residues in pig kidney alkaline phosphatase

1979 ◽  
Vol 181 (1) ◽  
pp. 137-142 ◽  
Author(s):  
M N Woodroofe ◽  
P J Butterworth
Keyword(s):  
Alkaline Phosphatase ◽  
Active Site ◽  
Competitive Inhibitor ◽  
Arginine Residue ◽  
Pig Kidney ◽  
Close Proximity ◽  
Arginine Residues ◽  
Km Value ◽  
Uncompetitive Inhibitor ◽  
Kidney Alkaline Phosphatase

The arginine-specific reagents 2,3-butanedione and phenylglyoxal inactivate pig kidney alkaline phosphatase. As inactivation proceeds there is a progressive fall in Vmax. of the enzyme, but no demonstrable change in the Km value for substrate. Pi, a competitive inhibitor, and AMP, a substrate of the enzyme, protect alkaline phosphatase against the arginine-specific reagents. These effects are explicable by the assumption that the enzyme contains an essential arginine residue at the active site. Protection is also afforded by the uncompetitive inhibitor NADH through a partially competive action against the reagents. Enzyme that has been exposed to the reagents has a decreased sensitivity to NADH inhibition. It is suggested that an arginine residue is important for NADH binding also, although this residue is distinct from that at the catalytic site. The protection given by NADH against loss of activity is indicative of the close proximity of the active and NADH sites.

scholarly journals Gentamicin Binds to the Megalin Receptor as a Competitive Inhibitor Using the Common Ligand Binding Motif of Complement Type Repeats

2012 ◽  
Vol 288 (6) ◽  
pp. 4424-4435 ◽  
Author(s):  
Robert Dagil ◽  
Charlotte O'Shea ◽  
Anders Nykjær ◽  
Alexandre M. J. J. Bonvin ◽  
Birthe B. Kragelund
Keyword(s):  
Ligand Binding ◽  
Competitive Inhibitor ◽  
Binding Motif ◽  
The Common
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