SIRT1-independent mechanisms of the putative sirtuin enzyme activators SRT1720 and SRT2183

2010 ◽  
Vol 2 (12) ◽  
pp. 1751-1759 ◽  
Author(s):  
Julie L Huber ◽  
Michael W McBurney ◽  
Peter S DiStefano ◽  
Thomas McDonagh
Keyword(s):  
Enzyme Activators

scholarly journals Diadenosine polyphosphate hydrolase from presynaptic plasma membranes of Torpedo electric organ

1997 ◽  
Vol 323 (3) ◽  
pp. 677-684 ◽  
Author(s):  
Jesús MATEO ◽  
Pedro ROTLLAN ◽  
Eulalia MARTI ◽  
Inmaculada GOMEZ DE ARANDA ◽  
Carles SOLSONA ◽  
...  
Keyword(s):  
Plasma Membranes ◽  
Pyridoxal Phosphate ◽  
Electric Organ ◽  
Competitive Inhibitor ◽  
Inhibitory Effect ◽  
Ic50 Value ◽  
Neural Origin ◽  
Disulphonic Acid ◽  
Torpedo Electric Organ ◽  
Enzyme Activators

The diadenosine polyphosphate hydrolase present in presynaptic plasma membranes from the Torpedo electric organ has been characterized using fluorogenic substrates of the form di-(1,N6-ethenoadenosine) 5´,5‴-P1,Pn-polyphosphate. The enzyme hydrolyses diadenosine polyphosphates (Apn A, where n = 3–5), producing AMP and the corresponding adenosine (n-1) 5´-phosphate, Ap(n-1). The Km values of the enzyme were 0.543± 0.015, 0.478±0.043 and 0.520±0.026 μM, and the Vmax values were 633±4, 592±18 and 576±45 pmol/min per mg of protein, for the etheno derivatives of Ap3A (adenosine 5´,5‴-P1,P3-triphosphate), Ap4A (adenosine 5´,5‴-P1,P4 -tetraphosphate) and Ap5A (adenosine 5´,5‴-P1,P5-pentaphosphate) respectively. Ca2+, Mg2+ and Mn2+ are enzyme activators, with EC50 values of 0.86±0.11, 1.35±0.24 and 0.58±0.10 mM respectively. The fluoride ion is an inhibitor with an IC50 value of 1.38±0.19 mM. The ATP analogues adenosine 5´-tetraphosphate and adenosine 5´-[γ-thio]triphosphate are potent competitive inhibitors and adenosine 5´-[α,β-methylene]diphosphate is a less potent competitive inhibitor, the Ki values being 0.29±0.03, 0.43±0.05 and 7.18±0.8 μM respectively. The P2-receptor antagonist pyridoxal phosphate 6-azophenyl-2´,4´-disulphonic acid behaves as a non-competitive inhibitor with a Ki value of 29.7±3.1 μM, and also exhibits a significant inhibitory effect on Torpedo apyrase activity. The effect of pH on the Km and Vmax values, together with inhibition by diethyl pyrocarbonate, strongly suggests the presence of functional histidine residues in Torpedo diadenosine polyphosphate hydrolase. The enzyme from Torpedo shows similarities with that of neural origin from neurochromaffin cells, and significant differences compared with that from endothelial vascular cells.

Deep eutectic solvents can be viable enzyme activators and stabilizers

2014 ◽  
Vol 89 (12) ◽  
pp. 1975-1981 ◽  
Author(s):  
Ze-Lin Huang ◽  
Ben-Pei Wu ◽  
Qing Wen ◽  
Tao-Xiang Yang ◽  
Zhen Yang
Keyword(s):  
Deep Eutectic Solvents ◽  
Enzyme Activators

scholarly journals Mechanism-based enzyme activating compounds

2020 ◽  
Author(s):  
Xiangying Guan ◽  
Alok Upadhyay ◽  
Raj Chakrabarti
Keyword(s):  
Steady State ◽  
Small Molecule ◽  
Active Sites ◽  
Degrees Of Freedom ◽  
Enzymatic Catalysis ◽  
Enzyme Activation ◽  
Allosteric Site ◽  
Age Related ◽  
Small Molecule Modulators ◽  
Enzyme Activators

Compared to inhibitors, which constitute the vast majority of today’s drugs, enzyme activators have considerable advantages, especially in the context of enzymes that regulate reactive flux through metabolic pathways associated with chronic, age-related diseases and lifespan. Across all families of enzymes, only a dozen or so distinct classes of small molecule activators have been characterized. Enzyme activators that are not based on naturally evolved allosteric mechanisms are much more difficult to design than inhibitors, because enzymatic catalysis has been optimized over billions of years of evolution. Here, we introduce modes of enzyme activation based on the catalytic reaction mechanisms of enzymes for which naturally evolved activators may not exist. We establish biophysical properties of small molecule modulators that are necessary to achieve desired changes in the steady state and non-steady state parameters of these enzymes, including changes in local conformational degrees of freedom conducive to the enhancement of catalytic activity that can be identified through computational modeling of their active sites. We illustrate how the modes of action of several compounds reported to activate enzymes without known allosteric sites may be understood using the framework presented. We also present simulations and new experimental results in support of this framework, including identification of the mechanism of a compound that activates the human SIRT3 enzyme, which does not contain a known allosteric site, under physiologically relevant conditions.

scholarly journals The Appearance of a Leptin Effect on Glucose Absorption in Caco2 Cells Depends on Their Differentiation Level

2015 ◽  
Vol 37 (2) ◽  
pp. 491-500 ◽  
Author(s):  
Ola El-Zein ◽  
Julnar Usta ◽  
Sawsan Ibrahim Kreydiyyeh
Keyword(s):  
Intestinal Transport ◽  
Glucose Transporters ◽  
Inhibitory Effect ◽  
Glucose Absorption ◽  
Leptin Receptors ◽  
Transport Studies ◽  
Hormone Effect ◽  
Lower Chamber ◽  
Enzyme Activators ◽  
Upper Chamber

Backdround/Aims: The aim of this work was to study the effect and mechanism of action of leptin added apically, on glucose absorption, using Caco-2 cells as a model. Methods: Cells were grown on inserts and treated with leptin, at different time points after confluence. Radiolabelled glucose was added to the upper chamber and samples from the lower chamber were collected and assayed for radioactivity. Results: Glucose absorption increased with an increase in the level of differentiation and was associated with an increase in the protein expression level of glucose transporters. Leptin reduced glucose absorption only by day 16 after confluence, the time at which apical leptin receptors started appearing. This inhibitory effect became higher the longer the post confluence period, and was prominent on day 23. The hormone effect was found to be mediated via a decrease in the number of glucose transporters (SGLT1 and GLUT2) and a decrease in the activity of the Na+/K+ ATPase which was assayed by measuring the amount of inorganic phosphate liberated in presence and absence of enzyme activators. Conclusion: It was concluded that by day 23 post confluence, Caco-2 cells are differentiated and are appropriate to use as a model for intestinal transport studies.

Polymeric thiols as enzyme activators of serum creatine phosphokinase

1987 ◽  
Vol 16 (1) ◽  
pp. 145-156 ◽  
Author(s):  
Brent A. Burdick ◽  
Theodore W. Esders ◽  
James R. Schaeffer ◽  
Shirley Lynn
Keyword(s):  
Creatine Phosphokinase ◽  
Serum Creatine Phosphokinase ◽  
Enzyme Activators

scholarly journals Discovery of small-molecule enzyme activators by activity-based protein profiling

2020 ◽  
Vol 16 (9) ◽  
pp. 997-1005 ◽  
Author(s):  
Bernard P. Kok ◽  
Srijana Ghimire ◽  
Woojoo Kim ◽  
Shreyosree Chatterjee ◽  
Tyler Johns ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Profiling ◽  
Enzyme Activators

scholarly journals Peptide-Modulated Activity Enhancement of Acidic Protease Cathepsin E at Neutral pH

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Masayuki Komatsu ◽  
Madhu Biyani ◽  
Sunita Ghimire Gautam ◽  
Koichi Nishigaki
Keyword(s):  
Molecular Evolution ◽  
Cancer Cell ◽  
Cell Apoptosis ◽  
Cancer Drug ◽  
Neutral Ph ◽  
Cathepsin E ◽  
Cancer Cell Apoptosis ◽  
Activity Enhancement ◽  
Enzyme Activators

Enzymes are regulated by their activation and inhibition. Enzyme activators can often be effective tools for scientific and medical purposes, although they are more difficult to obtain than inhibitors. Here, using the paired peptide method, we report on protease-cathepsin-E-activating peptides that are obtained at neutral pH. These selected peptides also underwent molecular evolution, after which their cathepsin E activation capability improved. Thus, the activators we obtained could enhance cathepsin-E-induced cancer cell apoptosis, which indicated their potential as cancer drug precursors.

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