scholarly journals Naturally Occurring Enzyme Inhibitors: A Smart Way to Fight against Micro- Inflammation in Human Gut

2016 ◽  
Vol 3 (1) ◽  
Author(s):  
Rabail Razi ◽  
Zainab Mir
Keyword(s):  
Enzyme Inhibitors ◽  
Human Gut ◽  
Naturally Occurring

scholarly journals Interruption of tumor-associated platelet consumption with platelet enzyme inhibitors

Blood ◽  
1982 ◽  
Vol 59 (6) ◽  
pp. 1252-1258 ◽  
Author(s):  
SJ Slichter ◽  
PL Weiden ◽  
MR O'Donnell ◽  
R Storb
Keyword(s):  
Synergistic Effect ◽  
Enzyme Inhibitors ◽  
Enzyme Inhibitor ◽  
Phosphodiesterase Inhibitor ◽  
Metastatic Tumor ◽  
Mechanisms Of Action ◽  
Cyclooxygenase Inhibitor ◽  
Normal Platelet ◽  
Naturally Occurring ◽  
Platelet Survival

Abstract Twenty dogs with naturally occurring metastatic tumors were treated with anticoagulants (Warfarin) or platelet enzyme inhibitor drugs (dipyridamole, dipyridamole plus aspirin, RA233, sulfinpyrazone, or a combination of RA233 and sulfinpyrazone) to determine if tumor-related reductions in platelet survival and concentration could be reversed. Anticoagulation was ineffective, while platelet enzyme inhibitors were able to produce improvements in platelet survival. Of the 18 dogs with metastatic tumor treated with platelet enzyme inhibitors, only 5 (28%) showed a reduction in platelet survival during the first week of observation on therapy compared to their baseline survivals. This is significantly different than the decreases in platelet survivals observed in 8 of 10 untreated dogs (80%) with metastatic tumor observed for the same interval. Furthermore, 8 of the 18 treated dogs (44%) had platelet survivals within 2 standard deviations of normal, compared to only 1 of 10 untreated dogs. Of the 8 dogs with normal platelet survivals, 6 were treated with a combination of a phosphodiesterase inhibitor (RA233 or dipyridamole) and a cyclooxygenase inhibitor (sulfinpyrazone or aspirin). The combination of RA233 and sulfinpyrazone was the best drug program tested and resulted in normal platelet survivals in 63% and improved platelet counts in 75% of the animals treated. Thus, platelet enzyme inhibitors with different mechanisms of action may have a synergistic effect in reversing the abnormal platelet hemostasis found in a variety of spontaneously occurring canine neoplasms.

scholarly journals Comprehensive Mining and Characterization of CRISPR-Cas Systems in Bifidobacterium

2020 ◽  
Vol 8 (5) ◽  
pp. 720 ◽  
Author(s):  
Meichen Pan ◽  
Matthew A. Nethery ◽  
Claudio Hidalgo-Cantabrana ◽  
Rodolphe Barrangou
Keyword(s):  
Genome Engineering ◽  
Rare Variants ◽  
Adaptive Immune System ◽  
Effector Proteins ◽  
Type I ◽  
Human Gut ◽  
Adaptive Immune ◽  
Naturally Occurring ◽  
History Of

The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas (CRISPR-associated cas) systems constitute the adaptive immune system in prokaryotes, which provides resistance against bacteriophages and invasive genetic elements. The landscape of applications in bacteria and eukaryotes relies on a few Cas effector proteins that have been characterized in detail. However, there is a lack of comprehensive studies on naturally occurring CRISPR-Cas systems in beneficial bacteria, such as human gut commensal Bifidobacterium species. In this study, we mined 954 publicly available Bifidobacterium genomes and identified CRIPSR-Cas systems in 57% of these strains. A total of five CRISPR-Cas subtypes were identified as follows: Type I-E, I-C, I-G, II-A, and II-C. Among the subtypes, Type I-C was the most abundant (23%). We further characterized the CRISPR RNA (crRNA), tracrRNA, and PAM sequences to provide a molecular basis for the development of new genome editing tools for a variety of applications. Moreover, we investigated the evolutionary history of certain Bifidobacterium strains through visualization of acquired spacer sequences and demonstrated how these hypervariable CRISPR regions can be used as genotyping markers. This extensive characterization will enable the repurposing of endogenous CRISPR-Cas systems in Bifidobacteria for genome engineering, transcriptional regulation, genotyping, and screening of rare variants.

Naturally occurring enzyme inhibitors and their pharmaceutical applications

2011 ◽  
Vol 83 (9) ◽  
pp. 1741-1749 ◽  
Author(s):  
Athar Ata ◽  
Samina Naz ◽  
Evan M. Elias
Keyword(s):  
Enzyme Inhibitors ◽  
Senile Dementia ◽  
Discovery Process ◽  
Drug Discovery Process ◽  
Ache Inhibitors ◽  
Sar Studies ◽  
Naturally Occurring ◽  
Structure Activity ◽  
Antiparasitic Drug

Enzyme inhibitors play a significant role in the drug discovery process. For instance, acetylcholinesterase (AChE) inhibitors have applications in curing Alzheimer’s disease (AD), senile dementia, ataxia, myasthenia gravis, and Parkinson’s disease. Glutathione S-transferase (GST) inhibitors have applications as adjuvants to overcome anticancer and antiparasitic drug resistance problems. Compounds inhibiting the activity of α-glucosidase are used to treat type 2 diabetes mellitus and obesity problems. This article describes the identification of natural products exhibiting AChE, GST, and α-glucosidase inhibitory activities from medicinally important plants. Additionally, structure–activity relationship (SAR) studies of these newly discovered enzyme inhibitors are also discussed.

scholarly journals Interruption of tumor-associated platelet consumption with platelet enzyme inhibitors

Blood ◽  
1982 ◽  
Vol 59 (6) ◽  
pp. 1252-1258
Author(s):  
SJ Slichter ◽  
PL Weiden ◽  
MR O'Donnell ◽  
R Storb
Keyword(s):  
Synergistic Effect ◽  
Enzyme Inhibitors ◽  
Enzyme Inhibitor ◽  
Phosphodiesterase Inhibitor ◽  
Metastatic Tumor ◽  
Mechanisms Of Action ◽  
Cyclooxygenase Inhibitor ◽  
Normal Platelet ◽  
Naturally Occurring ◽  
Platelet Survival

Twenty dogs with naturally occurring metastatic tumors were treated with anticoagulants (Warfarin) or platelet enzyme inhibitor drugs (dipyridamole, dipyridamole plus aspirin, RA233, sulfinpyrazone, or a combination of RA233 and sulfinpyrazone) to determine if tumor-related reductions in platelet survival and concentration could be reversed. Anticoagulation was ineffective, while platelet enzyme inhibitors were able to produce improvements in platelet survival. Of the 18 dogs with metastatic tumor treated with platelet enzyme inhibitors, only 5 (28%) showed a reduction in platelet survival during the first week of observation on therapy compared to their baseline survivals. This is significantly different than the decreases in platelet survivals observed in 8 of 10 untreated dogs (80%) with metastatic tumor observed for the same interval. Furthermore, 8 of the 18 treated dogs (44%) had platelet survivals within 2 standard deviations of normal, compared to only 1 of 10 untreated dogs. Of the 8 dogs with normal platelet survivals, 6 were treated with a combination of a phosphodiesterase inhibitor (RA233 or dipyridamole) and a cyclooxygenase inhibitor (sulfinpyrazone or aspirin). The combination of RA233 and sulfinpyrazone was the best drug program tested and resulted in normal platelet survivals in 63% and improved platelet counts in 75% of the animals treated. Thus, platelet enzyme inhibitors with different mechanisms of action may have a synergistic effect in reversing the abnormal platelet hemostasis found in a variety of spontaneously occurring canine neoplasms.

scholarly journals Naturally occurring cobalamin (B12) analogs can function as cofactors for human methylmalonyl-CoA mutase

2020 ◽  
Author(s):  
Olga M. Sokolovskaya ◽  
Tanja Plessl ◽  
Henry Bailey ◽  
Sabrina Mackinnon ◽  
Matthias R. Baumgartner ◽  
...  
Keyword(s):  
Binding Kinetics ◽  
Human Biology ◽  
Vitamin B ◽  
Human Gut ◽  
Future Directions ◽  
Naturally Occurring ◽  
Human Enzyme ◽  
Related Compounds ◽  
Exclusive Focus

AbstractCobalamin, commonly known as vitamin B12, is an essential micronutrient for humans because of its role as an enzyme cofactor. Cobalamin is one of over a dozen structurally related compounds – cobamides – that are found in food and are produced by microorganisms in the human gut. Very little is known about how different cobamides affect B12-dependent metabolism in human cells. Here, we test in vitro how diverse cobamide cofactors affect the function of methylmalonyl-CoA mutase (MMUT), one of two cobalamin-dependent enzymes in humans. We find that, although cobalamin is the most effective cofactor for MMUT, multiple cobamides support MMUT function with differences in binding affinity (Kd), binding kinetics (kon), and concentration dependence during catalysis (KM, app). Additionally, we find that six disease-associated MMUT variants that cause cobalamin-responsive impairments in enzymatic activity also respond to other cobamides, with the extent of catalytic rescue dependent on the identity of the cobamide. Our studies challenge the exclusive focus on cobalamin in the context of human physiology, indicate that diverse cobamides can support the function of a human enzyme, and suggest future directions that will improve our understanding of the roles of different cobamides in human biology.

Use of inhibitors to study reactions catalyzed by enzymes requiring pyridoxal phosphate as coenzyme

2000 ◽  
Vol 72 (3) ◽  
pp. 373-384 ◽  
Author(s):  
Benjamin Adams ◽  
B. Svante Axelsson ◽  
Kenneth J. M. Beresford ◽  
Nicola J. Church ◽  
Philip A. Spencer ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Active Site ◽  
Aspartate Aminotransferase ◽  
Pyridoxal Phosphate ◽  
Family Formation ◽  
Enzyme Inhibitors ◽  
Acid Oxidase ◽  
Amino Acid Oxidase ◽  
Naturally Occurring

The stereochemistry of a variety of pyridoxal phosphate-mediated enzymic reactions has been studied using enzyme inhibitors that are stereospecifically labeled in the β-position with deuterium. A versatile synthesis has been developed to prepare a wide variety of stereospecifically labeled d- and l-amino acids and inhibitors. Investigation of the "turnover" of β-chloro-d-alanine and d- and l-serine-O-sulfate by d-amino acid aminotransferase and l-aspartate aminotransferase respectively has shown that reaction within the active site of the former enzyme occurs with retention of stereochemistry. Although l-aspartate aminotransferase is an enzyme of the α-family, when it was incubated with β-chloro-l-alanine in the presence of 2-mercaptoethanol, β-substitution occurred. This was shown to involve retention of stereochemistry, an outcome typical of reactions catalyzed by enzymes of the β-family that have little or no homology with enzymes of the α-family. Formation of the "Schnackerz intermediate" has been studied as has the d-amino acid oxidase catalyzed reaction of the naturally occurring inhibitor d-propargylglycine.

Glutathione S-transferase- and acetylcholinesterase-inhibiting natural products from medicinally important plants

2007 ◽  
Vol 79 (12) ◽  
pp. 2269-2276 ◽  
Author(s):  
Athar Ata ◽  
Stephanie A. Van Den Bosch ◽  
Drew J. Harwanik ◽  
Grant E. Pidwinski
Keyword(s):  
Natural Products ◽  
Enzyme Inhibitors ◽  
Glutathione S Transferase ◽  
Ache Inhibitors ◽  
Sar Studies ◽  
Naturally Occurring ◽  
Structure Activity ◽  
Potential Applications ◽  
Drug Discovery Program ◽  
Antiparasitic Agents

Naturally occurring enzyme inhibitors play an important role in a drug discovery program. Glutathione S-transferases (GSTs) play a significant role in the detoxification and metabolism of many xenobiotic and endobiotic compounds. GSTs are considered to be responsible for decreasing the effectiveness of anticancer/antiparasitic agents used for the treatment of cancer and parasitic diseases. The effectiveness of these biomedical agents may be improved by using GST inhibitors as an adjuvant during chemotherapy. Acetylcholinesterase (AChE) inhibitors have potential applications in curing cardiac problems and Alzheimer's disease. This article describes the identification of natural products exhibiting GST and AChE inhibitory activities, from medicinally important plants. Results obtained from the structure-activity relationship (SAR) studies of some of these newly discovered enzyme inhibitors are also discussed.

scholarly journals The Tumor-Selective Cytotoxic Agent β-Lapachone is a Potent Inhibitor of IDO1

2013 ◽  
Vol 6 ◽  
pp. IJTR.S12094 ◽  
Author(s):  
Hollie E. Flick ◽  
Judith M. LaLonde ◽  
William P. Malachowski ◽  
Alexander J. Muller
Keyword(s):  
Active Site ◽  
Inhibitory Activity ◽  
Tumor Response ◽  
Enzyme Inhibitors ◽  
Potent Inhibitor ◽  
Naturally Occurring ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Tumor Selective ◽  
Clinical Candidate

β-lapachone is a naturally occurring 1,2-naphthoquinone-based compound that has been advanced into clinical trials based on its tumor-selective cytotoxic properties. Previously, we focused on the related 1,4-naphthoquinone pharmacophore as a basic core structure for developing a series of potent indoleamine 2,3-dioxygenase 1 (IDO1) enzyme inhibitors. In this study, we identified IDO1 inhibitory activity as a previously unrecognized attribute of the clinical candidate β-lapachone. Enzyme kinetics-based analysis of β-lapachone indicated an uncompetitive mode of inhibition, while computational modeling predicted binding within the IDO1 active site consistent with other naphthoquinone derivatives. Inhibition of IDO1 has previously been shown to breach the pathogenic tolerization that constrains the immune system from being able to mount an effective anti-tumor response. Thus, the finding that β-lapachone has IDO1 inhibitory activity adds a new dimension to its potential utility as an anti-cancer agent distinct from its cytotoxic properties, and suggests that a synergistic benefit can be achieved from its combined cytotoxic and immunologic effects.

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