Inhibitor effect
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Inhibitor Effects on Enzyme Kinetics and Cellular Responses
Generalized Equations for Inhibitor Analysis in Michaelis-Menten Kinetics
The study of enzyme inhibition, particularly within the framework of Michaelis-Menten kinetics, has led to the development of generalized equations that describe the combined effects of multiple inhibitors. These equations do not require knowledge of kinetic constants for substrates or inhibitors, making them broadly applicable. For mutually exclusive reversible inhibitors, the fractional velocity in the presence of both inhibitors can be described without needing specific kinetic constants1. This approach extends to higher-order systems with multiple binding sites, providing a robust method for analyzing complex inhibition scenarios1.
Methods for Studying Combined Inhibitor Effects
Several methods have been proposed to study the concurrent effects of two linear inhibitors on a single enzyme, including the fractional product of Webb, the Yonetani-Theorell plot, and the method of Chou and Talalay. However, these methods often rely on assumptions about the inhibitors' mechanisms of action, which can lead to misleading results if the assumptions are incorrect. An alternative representation that does not require knowledge of inhibition constants has been suggested, allowing for more accurate experimental data retrieval2. Isobolographic analysis is particularly useful for determining the effectiveness of inhibitor combinations without detailed mechanistic information2.
Interactive Effects of DNA Repair Inhibitors
Inhibitors of DNA-dependent protein kinase (DNA-PK) and poly(ADP-ribose) polymerase (PARP) have been shown to interactively affect cellular responses to DNA damage. For instance, the combination of wortmannin (a DNA-PK inhibitor) and NU1025 (a PARP inhibitor) significantly potentiates the cytotoxicity of ionizing radiation and temozolomide in Chinese hamster ovary cells. This combination also increases DNA double-strand break levels, suggesting a potential therapeutic application for combined DNA repair inhibitors3.
Inhibitory After-Effects in Motor Inhibition Tasks
Inhibitory processes can leave measurable after-effects in various tasks, including the stop signal task. These after-effects manifest as longer reaction times in subsequent trials where previously ignored stimuli become targets. This phenomenon, known as negative priming, indicates that residual inhibition must be overcome before a relevant response can be produced. The study of these inhibitory after-effects provides insights into the persistence and specificity of inhibition in cognitive and motor tasks4.
Short-Term and Long-Term Effects of ACE Inhibition in Heart Failure
Angiotensin converting enzyme (ACE) inhibitors have distinct short-term and long-term effects on patients with chronic heart failure. Short-term ACE inhibition improves hemodynamic output during rest and exercise but does not significantly alter peripheral blood flow or oxygen consumption. In contrast, long-term ACE inhibition enhances exercise cardiac output, leg blood flow, and systemic oxygen uptake, suggesting that the long-term benefits are partly due to improved peripheral vascular function and oxygen utilization5.
Inhibition of Endopeptidase and Its Renal and Endocrine Effects
The inhibition of neutral metalloendopeptidase EC 3.4.24.11 by UK 79300 in humans results in increased plasma concentrations of atrial natriuretic factor and decreased plasma renin activity and aldosterone levels. This leads to enhanced sodium excretion and other biological effects similar to those observed with low-dose atrial natriuretic factor infusions. These findings suggest potential therapeutic applications for endopeptidase inhibitors in conditions like hypertension and heart failure6.
Synergistic Effects of Dual Inhibitor Systems on Amyloid β-Protein Aggregation
A dual-inhibitor system combining (-)-epigallocatechin-3-gallate (EGCG) and negatively charged hydrophobic nanoparticles (NP10) has shown synergistic effects in inhibiting amyloid β-protein aggregation, a key factor in Alzheimer's disease. This system is more effective at low concentrations than either inhibitor alone, with NP10 primarily inhibiting primary nucleation and EGCG suppressing fibril elongation. The synergistic interaction enhances the overall inhibitory effect, offering a promising approach for developing potent inhibitor systems against amyloid neurotoxicity8.
Conclusion
The study of inhibitor effects on enzyme kinetics and cellular responses reveals complex interactions that can be harnessed for therapeutic purposes. Generalized equations and alternative analytical methods provide robust tools for understanding these interactions, while specific inhibitor combinations show promise in enhancing treatment efficacy for various conditions, including DNA damage repair and amyloid aggregation. Understanding these mechanisms is crucial for developing effective therapeutic strategies.
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Most relevant research papers on this topic
Generalized equations for the analysis of inhibitions of Michaelis-Menten and higher-order kinetic systems with two or more mutually exclusive and nonexclusive inhibitors.
This paper presents generalized equations for analyzing inhibitory effects in enzyme systems with two or more mutually exclusive and nonexclusive inhibitors, enabling simple graphical representations of inhibitory effects.
Highly CitedAnalysis of the combined effect of two linear inhibitors on a single enzyme.
Combining two linear inhibitors on a single enzyme can be more effective than their individual use, but understanding their mechanism of action is crucial for accurate results.
Interactive effects of inhibitors of poly(ADP-ribose) polymerase and DNA-dependent protein kinase on cellular responses to DNA damage.
Combining DNA repair inhibitors wortmannin and NU1025 may have therapeutic potential by enhancing cell survival and DNA damage response after exposure to ionizing radiation or temozolomide.
In Vitro StudyHighly CitedInhibitory after‐effects in the stop signal paradigm
Inhibitory after-effects are present in the stop signal task, regardless of successful inhibition of reactions, and are greater when both trials involve the same primary task properties.
Non-RCTHighly CitedContrasting peripheral short-term and long-term effects of converting enzyme inhibition in patients with congestive heart failure. A double-blind, placebo-controlled trial.
Long-term ACE inhibition improves blood flow to skeletal muscle during exercise, potentially due to peripheral mechanisms such as vessel dilation and improved oxygen utilization.
RCTHighly CitedInhibition of endopeptidase EC 24.11 in humans. Renal and endocrine effects.
UK 79300, an orally active inhibitor of endopeptidase EC 24.11, enhances atrial natriuretic factor levels and suppresses renin activity and aldosterone, potentially benefiting hypertension or heart failure.
RCTHighly CitedA simple generalized equation for the analysis of multiple inhibitions of Michaelis-Menten kinetic systems.
Multiple inhibitors in Michaelis-Menten kinetic systems can cause synergism or antagonism, depending on the deviation from the equation.
Highly CitedSynergistic effects of negatively charged hydrophobic nanoparticles and (-)-epigallocatechin-3-gallate on inhibiting amyloid β-protein aggregation.
The dual-inhibitor system containing EGCG and negatively charged nanoparticles (NP10) at low concentrations effectively inhibits amyloid -protein aggregation, offering new insights into developing potent inhibitor systems against amyloid neurotoxicity.
In Vitro StudyEffect of inhibitors on the substrate-dependent quenching of 9-aminoacridine fluorescence in inside-out membrane vesicles of Escherichia coli.
Inhibitors like 2-heptyl-4-hydroxyquinoline N-oxide and piericidin A can both inhibit the respiratory chain and act as uncoupling agents, resulting in a maximum pH difference of 3.3-3.7 units.
In Vitro StudyInhibitory Effect of α-Glucosidase Inhibitors Varies According to Its Origin
The inhibitory effect of -glucosidase inhibitors varies greatly depending on its origin, with green and oolong teas showing no inhibitory activity against rat AGH but inhibiting yeast AGH.
In Vitro StudyHighly Cited