Inhibition Effects of Phenolic Compounds on Human Serum Paraoxonase-1 Enzyme

Yıl 2019, Cilt: 9 Sayı: 2, 1013 - 1022, 01.06.2019

Cüneyt Türkeş

https://doi.org/10.21597/jist.491054

Cited By: 27

Öz

Metabolic processes in living organisms are closely related to the catalytic activity of enzymes. Inhibition or induction of enzymes leads to toxicities and metabolic interactions. This study

aims to contribute to the growing drug design field by studying PON1-phenolic compound interactions. For this purpose, the paraoxonase-1 enzyme was purified from fresh human serum by

using rapid and different chromatographic techniques. Additionally, it was investigated the inhibitory effects of some phenolic substances on the PON1 and was found that the purified enzyme had the

molecular weight of 43 kDa and the specific activity of 3945.15 EU mg-1. These compounds showed potent inhibition against PON1, especially homovanillic acid exhibited a significant inhibition profile

against PON1 with an IC50 value of 13.84±0.08 mM. Ki constants were 6.10±0.26 mM for homovanillic acid and 16.96±0.76 mM for phloridzin dihydrate. Homovanillic acid had competitive

inhibition while the phloridzin dihydrate inhibited the PON1 as non-competitive. Also, molecular docking computations were performed by using the Glide XP mode. Glide energy of the homovanillic

acid determined to be -23.95 kcal mol-1.

Anahtar Kelimeler

Paraoxonase, HDL, chromatography, inhibition, phenolic compound, molecular docking

Destekleyen Kurum

Research Fund of Erzincan Binali Yıldırım University

Proje Numarası

FBA-2017-501

Teşekkür

The author thanks Samet Karataş and Muhammed Kerem Türkeş for his kind help suggestions during the preparation of the manuscript. This work was supported by the Research Fund of Erzincan Binali Yıldırım University (project number FBA-2017-501). The author is grateful to Erzincan Binali Yıldırım University for financial support.

Fenolik Bileşiklerin İnsan Serum Paraoksonaz-1 Enzimi Üzerindeki İnhibisyon Etkileri

Öz

Canlı organizmalardaki metabolik süreçler, enzimlerin katalitik aktivitesi ile yakından ilişkilidir. Enzimlerin inhibisyonu veya indüksiyonu toksisiteye ve metabolik etkileşimlere yol açar.

Bu çalışma, PON1-fenolik madde etkileşimlerini inceleyerek büyüyen ilaç tasarım alanına katkıda bulunmayı amaçlamaktadır. Bu amaçla, paraoksonaz-1 enzimi, hızlı ve farklı kromatografik teknikler

kullanılarak taze insan serumundan saflaştırılmıştır. Ek olarak, bazı fenolik bileşiklerin PON1 üzerindeki inhibisyon etkileri araştırılmış ve saflaştırılan enzimin 3945.15 EU mg-1 protein spesifik

aktiviteye ve 43 kDa molekül ağırlığına sahip olduğu bulunmuştur. Bu bileşikler PON1’e karşı güçlü inhibisyon gösterdiler, özellikle homovanilik asit 13.84±0.08 mM’lık bir IC50 değeri ile PON1’e karşı

önemli bir inhibisyon profili sergiledi. Ki sabitleri homovanillik asit için 6.10±0.26 mM ve phloridzin dihidrat için 16.96±0.76 mM idi. Homovanilik asit yarışmalı inhibisyona sahipken, phloridzin dihidrat

PON1’i yarışmasız olarak inhibe etmiştir. Ayrıca, moleküler yerleştirme hesaplamaları Glide XP modu kullanılarak gerçekleştirilmiştir. Homovanilik asitin glide enerjisi -23.95 kcal mol-1 olarak belirlenmiştir.

Anahtar Kelimeler

Paraoksonaz, HDL, kromatografi, inhibisyon, fenolik madde, moleküler yerleştirme, moleküler yerleştirme

Proje Numarası

FBA-2017-501

Kaynakça

• Akbaba Y, Türkeş C, Polat L, Söyüt H, Şahin E, Menzek A, Göksu S, Beydemir Ş, 2013. Synthesis and Paroxonase Activities of Novel Bromophenols. Journal of enzyme inhibition and medicinal chemistry, 28 (5): 1073-1079.
• Alim Z, Beydemir Ş, 2016. Some Anticancer Agents Act on Human Serum Paraoxonase‐1 to Reduce Its Activity. Chemical biology & drug design, 88 (2): 188-196.
• Alim Z, Kilic D, Koksal Z, Beydemir S, Ozdemir H, 2017. Assessment of the Inhibitory Effects and Molecular Docking of Some Sulfonamides on Human Serum Paraoxonase 1. Journal of biochemical and molecular toxicology, 31 (10): e21950.
• Alım Z, Kılıç D, Demir Y, 2018. Some indazoles reduced the activity of human serum paraoxonase 1, an antioxidant enzyme: in vitro inhibition and molecular modeling studies. Archives of physiology and biochemistry, 1-9.
• Aslan HE, Demir Y, Özaslan MS, Türkan F, Beydemir Ş, Küfrevioğlu ÖI, 2018. The behavior of some chalcones on acetylcholinesterase and carbonic anhydrase activity. Drug and chemical toxicology, 1-7.
• Beydemir Ş, Demir Y, 2017. Antiepileptic Drugs: Impacts on Human Serum Paraoxonase‐1. Journal of biochemical and molecular toxicology, 31 (6): e21889.
• Bradford MM, 1976. A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye Binding. Analytical biochemistry, 72 (1-2): 248-254.
• Cebeci B, Alim Z, Beydemir Ş, 2014. In Vitro Effects of Pesticide Exposure on the Activity of the Paraoxonase-1 Enzyme from Sheep Liver Microsomes. Turkish Journal of Chemistry, 38 (3): 512-520.
• Copeland RA, 2004 Enzymes: A Practical Introduction to Structure, Mechanism, and Data Analysis. John Wiley & Sons
• Copeland RA, 2013 Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists and Pharmacologists. John Wiley & Sons
• Costa LG, Li WF, Richter RJ, Shih DM, Lusis A, Furlong CE, 1999. The Role of Paraoxonase (Pon1) in the Detoxication of Organophosphates and Its Human Polymorphism. Chemico-biological interactions, 119: 429-438.
• Ekinci D, Beydemir Ş, 2009. Evaluation of the Impacts of Antibiotic Drugs on Pon 1; a Major Bioscavenger against Cardiovascular Diseases. European journal of pharmacology, 617 (1-3): 84-89.
• Ekinci D, Beydemir Ş, 2010. Purification of Pon1 from Human Serum and Assessment of Enzyme Kinetics against Metal Toxicity. Biological trace element research, 135 (1-3): 112-120.
• Ekinci D, Şentürk M, Beydemir Ş, İrfan Küfrevioğlu Ö, Supuran CT, 2010. An Alternative Purification Method for Human Serum Paraoxonase 1 and Its Interactions with Sulfonamides. Chemical biology & drug design, 76 (6): 552-558.
• Fraga CG, Galleano M, Verstraeten SV, Oteiza PI, 2010. Basic Biochemical Mechanisms Behind the Health Benefits of Polyphenols. Molecular aspects of medicine, 31 (6): 435-445.
• Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, 2004. Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy. Journal of medicinal chemistry, 47 (7): 1739-1749.
• Furlong CE (2008) Paraoxonases: An Historical Perspective The Paraoxonases: Their Role in Disease Development and Xenobiotic Metabolism. Springer, p 3-31
• Furlong CE, Richter RJ, Seidel SL, Costa LG, Motulsky AG, 1989. Spectrophotometric Assays for the Enzymatic Hydrolysis of the Active Metabolites of Chlorpyrifos and Parathion by Plasma Paraoxonase/Arylesterase. Analytical biochemistry, 180 (2): 242-247.
• Greenwood JR, Calkins D, Sullivan AP, Shelley JC, 2010. Towards the Comprehensive, Rapid, and Accurate Prediction of the Favorable Tautomeric States of Drug-Like Molecules in Aqueous Solution. Journal of computer-aided molecular design, 24 (6-7): 591-604.
• Gutiérrez-Grijalva EP, Ambriz-Pére DL, Leyva-López N, Castillo-López RI, Heredia JB, 2016. Dietary Phenolic Compounds, Health Benefits and Bioaccessibility. Archivos latinoamericanos de nutricion, 66 (2).
• Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL, 2004. Glide: A New Approach for Rapid, Accurate Docking and Scoring. 2. Enrichment Factors in Database Screening. Journal of medicinal chemistry, 47 (7): 1750-1759.
• Hassett C, Richter RJ, Humbert R, Chapline C, Crabb JW, Omiecinski CJ, Furlong CE, 1991. Characterization of Cdna Clones Encoding Rabbit and Human Serum Paraoxonase: The Mature Protein Retains Its Signal Sequence. Biochemistry, 30 (42): 10141-10149.
• Klaassen CD, Watkins JB, 1996 Casarett and Doull's Toxicology: The Basic Science of Poisons, vol 5. McGraw-Hill New York
• Kontush A, Chapman MJ, 2006. Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis. Pharmacological reviews, 58 (3): 342-374.
• Kuzu M, Kandemir FM, Yildirim S, Kucukler S, Caglayan C, Turk E, 2018. Morin attenuates doxorubicin-induced heart and brain damage by reducing oxidative stress, inflammation and apoptosis. Biomedicine & Pharmacotherapy, 106: 443-453.
• Laemmli UK, 1970. Cleavage of Structural Proteins During the Assembly of the Head of Bacteriophage T4. nature, 227 (5259): 680.
• Lineweaver H, Burk D, 1934. The Determination of Enzyme Dissociation Constants. Journal of the American chemical society, 56 (3): 658-666.
• Mackness MI, Arrol S, Abbott C, Durrington PN, 1993. Protection of Low-Density Lipoprotein against Oxidative Modification by High-Density Lipoprotein Associated Paraoxonase. Atherosclerosis, 104 (1-2): 129-135.
• Mackness MI, Durrington PN, 1995. Hdl, Its Enzymes and Its Potential to Influence Lipid Peroxidation. Atherosclerosis, 115 (2): 243-253.
• Manach C, Williamson G, Morand C, Scalbert A, Rémésy C, 2005. Bioavailability and Bioefficacy of Polyphenols in Humans. I. Review of 97 Bioavailability Studies–. The American journal of clinical nutrition, 81 (1): 230S-242S.
• Manco G, Porzio E, Suzumoto Y, 2018. Enzymatic detoxification: a sustainable means of degrading toxic organophosphate pesticides and chemical warfare nerve agents. Journal of Chemical Technology & Biotechnology, 93: 2064-2082.
• Masumoto S, Akimoto Y, Oike H, Kobori M, 2009. Dietary Phloridzin Reduces Blood Glucose Levels and Reverses Sglt1 Expression in the Small Intestine in Streptozotocin-Induced Diabetic Mice. Journal of agricultural and Food Chemistry, 57 (11): 4651-4656.
• Middleton E, Kandaswami C, Theoharides TC, 2000. The Effects of Plant Flavonoids on Mammalian Cells: Implications for Inflammation, Heart Disease, and Cancer. Pharmacological reviews, 52 (4): 673-751.
• Pla A, Rodrigo L, Hernandez AF, Gil F, Lopez O, 2007. Effect of Metal Ions and Calcium on Purified Pon1 and Pon3 from Rat Liver. Chemico-biological interactions, 167 (1): 63-70.
• Renault F, Chabrière E, Andrieu J-P, Dublet B, Masson P, Rochu D, 2006. Tandem Purification of Two Hdl-Associated Partner Proteins in Human Plasma, Paraoxonase (Pon1) and Phosphate Binding Protein (Hpbp) Using Hydroxyapatite Chromatography. Journal of Chromatography B, 836 (1-2): 15-21.
• Robertson JG, 2005. Mechanistic Basis of Enzyme-Targeted Drugs. Biochemistry, 44 (15): 5561-5571.
• Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W, 2013. Protein and Ligand Preparation: Parameters, Protocols, and Influence on Virtual Screening Enrichments. Journal of computer-aided molecular design, 27 (3): 221-234.
• Shelley JC, Cholleti A, Frye LL, Greenwood JR, Timlin MR, Uchimaya M, 2007. Epik: A Software Program for Pk a Prediction and Protonation State Generation for Drug-Like Molecules. Journal of computer-aided molecular design, 21 (12): 681-691.
• Sinan S, Kockar F, Arslan O, 2006. Novel Purification Strategy for Human Pon1 and Inhibition of the Activity by Cephalosporin and Aminoglikozide Derived Antibiotics. Biochimie, 88 (5): 565-574.
• Surh YJ, 1998. Cancer Chemoprevention by Dietary Phytochemicals: A Mechanistic Viewpoint. The Cancer journal, 11 (1): 6-10.
• Teiber JF, Xiao J, Kramer GL, Ogawa S, Ebner C, Wolleb H, Carreira EM, Shih DM, Haley RW, 2018. Identification of Biologically Active δ-lactone Eicosanoids as Paraoxonase Substrates. Biochemical and biophysical research communications, 505 (1): 87-92.
• Tuck KL, Hayball PJ, 2002. Major Phenolic Compounds in Olive Oil: Metabolism and Health Effects. The Journal of nutritional biochemistry, 13 (11): 636-644.
• Türkeş C, Soyut H, Beydemir S, 2013. Inhibition Effects of Gemcitabine Hydrochloride, Acyclovir, and 5-Fluorouracil on Human Serum Paraoxonase-1 (Hpon1): In Vitro. Open J Biochem, 1: 10-15.
• Türkeş C, Söyüt H, Beydemir Ş, 2014. Effect of Calcium Channel Blockers on Paraoxonase-1 (Pon1) Activity and Oxidative Stress. Pharmacological reports, 66 (1): 74-80.
• Türkeş C, Söyüt H, Beydemir Ş, 2015. Human Serum Paraoxonase-1 (Hpon1): In Vitro Inhibition Effects of Moxifloxacin Hydrochloride, Levofloxacin Hemihidrate, Cefepime Hydrochloride, Cefotaxime Sodium and Ceftizoxime Sodium. Journal of enzyme inhibition and medicinal chemistry, 30 (4): 622-628.
• Türkeş C, Söyüt H, Beydemir Ş, 2016. In Vitro Inhibitory Effects of Palonosetron Hydrochloride, Bevacizumab and Cyclophosphamide on Purified Paraoxonase-I (Hpon1) from Human Serum. Environmental toxicology and pharmacology, 42: 252-257.
• -Rodríguez GR, Palafox-Carlos H, Wall-Medrano A, Ayala-Zavala JF, Chen CO, Robles-Sánchez M, Astiazaran-García H, Alvarez-Parrilla E, González-Aguilar GA, 2014. Phenolic Compounds: Their Journey after Intake. Food & function, 5 (2): 189-197.
• Wang Q, Qiu L, Chen X-r, Song K-K, Shi Y, Chen Q-X, 2007. Inhibitory Effects of Phloridzin Dihydrate on the Activity of Mushroom (Agaricus Bisporus) Tyrosinase. Bioorganic & medicinal chemistry, 15 (3): 1568-1571.