Abstract
Polyisoprenylated proteins (PPs) methylation by polyisoprenylated protein methyl transferase (PPMTase) is counteracted by polyisoprenylated methylated protein methyl esterase (PMPMEase). This is the only reversible step of the polyisoprenylation pathway as the relative amounts of the acid and ester forms are determined by the two competing reactions. Since PMPMEase and PPMTase may influence both the structural/functional conformations of PPs, a thorough study of these enzymes is essential to our understanding of the structural/functional features of PPs. PMPMEase has been reported under such pseudonyms as human carboxylesterase 1 (hCE1) because of its apparent broad substrate spectrum. The current study aimed to show the complementarity between its active site and the polyisoprenylated substrates that it metabolizes. Kinetics analysis was conducted with N-, S- and O-substituted substrates using porcine liver PMPMEase and docking analysis using Arguslab. Consistent with the biochemical analysis, the S-ethyl analog yielded an AScore binding energy of -11.32 compared to -13.48, -14.88, -16.15, and -16.81 kcal/mol for S-prenyl (C-5), S-trans-geranyl (C-10), Strans, trans-farnesyl (C-15) and S-all trans-geranylgeranyl (C-20), respectively. The all trans-geranylgeranyl moiety provides the optimal size for active site interactions. The data reveal that the trans,trans-farnesyl and all trans-geranylgeranyl groups, which are reminiscent of endogenous PPs modifications, have the highest affinity for PMPMEase. Since PPs such as monomeric G-proteins are oncogenic, PMPMEase may be viewed as a viable target for anticancer drug development. The analyses reveal the important structural elements for the design of specific PMPMEase inhibitors to serve in the modulation of oncogenic PPs activities. The results also show that hCE1s repertoire of substrates extends beyond xenobiotics to include PPs as its endogenous substrates.
Keywords: Polyisoprenylation, prenylation, human carboxylesterase 1, Ascore
Current Cancer Drug Targets
Title: Biochemical and Docking Analysis of Substrate Interactions with Polyisoprenylated Methylated Protein Methyl Esterase
Volume: 10 Issue: 6
Author(s): R. Duverna, S.Y. Ablordeppey and N.S. Lamango
Affiliation:
Keywords: Polyisoprenylation, prenylation, human carboxylesterase 1, Ascore
Abstract: Polyisoprenylated proteins (PPs) methylation by polyisoprenylated protein methyl transferase (PPMTase) is counteracted by polyisoprenylated methylated protein methyl esterase (PMPMEase). This is the only reversible step of the polyisoprenylation pathway as the relative amounts of the acid and ester forms are determined by the two competing reactions. Since PMPMEase and PPMTase may influence both the structural/functional conformations of PPs, a thorough study of these enzymes is essential to our understanding of the structural/functional features of PPs. PMPMEase has been reported under such pseudonyms as human carboxylesterase 1 (hCE1) because of its apparent broad substrate spectrum. The current study aimed to show the complementarity between its active site and the polyisoprenylated substrates that it metabolizes. Kinetics analysis was conducted with N-, S- and O-substituted substrates using porcine liver PMPMEase and docking analysis using Arguslab. Consistent with the biochemical analysis, the S-ethyl analog yielded an AScore binding energy of -11.32 compared to -13.48, -14.88, -16.15, and -16.81 kcal/mol for S-prenyl (C-5), S-trans-geranyl (C-10), Strans, trans-farnesyl (C-15) and S-all trans-geranylgeranyl (C-20), respectively. The all trans-geranylgeranyl moiety provides the optimal size for active site interactions. The data reveal that the trans,trans-farnesyl and all trans-geranylgeranyl groups, which are reminiscent of endogenous PPs modifications, have the highest affinity for PMPMEase. Since PPs such as monomeric G-proteins are oncogenic, PMPMEase may be viewed as a viable target for anticancer drug development. The analyses reveal the important structural elements for the design of specific PMPMEase inhibitors to serve in the modulation of oncogenic PPs activities. The results also show that hCE1s repertoire of substrates extends beyond xenobiotics to include PPs as its endogenous substrates.
Export Options
About this article
Cite this article as:
Duverna R., Ablordeppey S.Y. and Lamango N.S., Biochemical and Docking Analysis of Substrate Interactions with Polyisoprenylated Methylated Protein Methyl Esterase, Current Cancer Drug Targets 2010; 10 (6) . https://dx.doi.org/10.2174/156800910791859443
DOI https://dx.doi.org/10.2174/156800910791859443 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Phytochemical Therapies in Vascular Functioning: A Molecular Approach
Current Vascular Pharmacology Noninvasive Diagnosis of Chemotherapy Related Cardiotoxicity
Current Cardiology Reviews Diabetes Mellitus and Vascular Endothelial Dysfunction: Current Perspectives
Current Vascular Pharmacology Oxidative/Nitrosative Stress and Immuno-inflammatory Pathways in Depression: Treatment Implications
Current Pharmaceutical Design Ectodomain Shedding of ACE and ACE2 as Regulators of Their Protein Functions
Current Enzyme Inhibition Functional Relevance of Biased Signaling at the Angiotensin II Type 1 Receptor
Endocrine, Metabolic & Immune Disorders - Drug Targets Systemic Redox Biomarkers in Neurodegenerative Diseases
Current Drug Metabolism Natural Products to Anti-trypanosomal Drugs: An Overview of New Drug Prototypes for American Trypanosomiasis
Cardiovascular & Hematological Agents in Medicinal Chemistry Exploring the Role of Gene Therapy for Neurological Disorders
Current Gene Therapy Inflammatory Markers Associated With Diabetes Mellitus – Old and New Players
Current Pharmaceutical Design Isolated-Perfused Heart: The Preparation that has been used as a Research Tool for More than a Century
Drug Design Reviews - Online (Discontinued) Prophylaxis of Cancer
Current Cancer Therapy Reviews Conduction Disorders: The Value of Surface ECG
Current Cardiology Reviews Angiotensin II-Vasopressin Interactions in The Regulation of Cardiovascular Functions. Evidence for an Impaired Hormonal Sympathetic Reflex in Hypertension and Congestive Heart Failure
Endocrine, Metabolic & Immune Disorders - Drug Targets Therapy for Dominant Inherited Diseases by Allele-Specific RNA Interference: Successes and Pitfalls
Current Gene Therapy MicroRNA Therapeutics for Cardiac Regeneration
Mini-Reviews in Medicinal Chemistry The Role of Anti-Inflammatory Drugs in Respiratory Diseases - Pirfenidone, Penicillamine, Chloroquine and Chlorambucil
Current Respiratory Medicine Reviews Risk Prediction Models and Scores in Hypertrophic Cardiomyopathy
Current Pharmaceutical Design Valve in Valve Trans-Catheter Aortic Valve Replacement Followed by LVAD Deactivation in the Setting of Recovered Systolic Function
Current Cardiology Reviews The Role of Nitro (NO<sub>2</sub>-), Chloro (Cl), and Fluoro (F) Substitution in the Design of Antileishmanial and Antichagasic Compounds
Current Drug Targets