Abstract
The polyisoprenylation pathway incorporates a reversible step that metabolizes polyisoprenylated methylated proteins from the ester to the carboxylate form. Polyisoprenylated protein methyl transferase (PPMTase) catalyses the esterification whereas polyisoprenylated methylated protein methyl esterase (PMPMEase) hydrolyzes them. Significant changes in the balance between the two enzymes may alter polyisoprenylated protein function possibly resulting in disease. Previous studies show that PMPMEase is the serine hydrolase, Sus scrofa carboxylesterase. Its susceptibility to the nonspecific serine hydrolase inhibitor, phenylmethylsulfonyl fluoride (PMSF) paved the way for its use as a prototypical compound to design and synthesize a series of putative high affinity specific inhibitors of PMPMEase. Pseudo first-order kinetics revealed an over 680-fold increase in kobs/[I] values from PMSF (6 M-1s-1), S-phenyl (L-50, 180 M-1s-1), S-benzyl (L-51, 350 M-1s-1), S-trans, trans-farnesyl (L-28, 2000 M-1s-1), to S-trans-geranylated (L-23, 4100 M-1s-1) 2-thioethanesulfonyl fluorides. C10 S-alkyl substitution revealed a kobs/[I] value (1800 M-1s-1) that was 298 times greater than that for PMSF. The compounds induced the degeneration of human neuroblastoma SH-SY5Y cells with EC50 values of 49, 130 and < 1000 μM for L-28, L-23 and PMSF, respectively. The increased affinity with the polyisoprenyl derivatization is consistent with the observed substrate specificity and the reported hydrophobic nature of the active site. These results suggest that (1) PMPMEase is a key enzyme for polyisoprenylated protein metabolism, (2) regulation of its activity is essential for maintaining normal cell viability, (3) abnormal activities may be involved in degenerative diseases and cancers and (4) its specific inhibitors may be useful in combating cancers.
Keywords: Cell death, esterase inhibitors, methyl esterase, molecular docking, neuroblastoma, polyisoprenylation, pseudo-first order kinetics, sulfonyl fluorides, Sus scrofa carboxylesterase, Polyisoprenylated protein methyl transferase, Porcine liver esterase, human carboxylesterase 1
Current Cancer Drug Targets
Title: Polyisoprenylation Potentiates the Inhibition of Polyisoprenylated Methylated Protein Methyl Esterase and the Cell Degenerative Effects of Sulfonyl Fluorides
Volume: 11 Issue: 6
Author(s): B. Aguilar, F. Amissah, R. Duverna and N. S. Lamango
Affiliation:
Keywords: Cell death, esterase inhibitors, methyl esterase, molecular docking, neuroblastoma, polyisoprenylation, pseudo-first order kinetics, sulfonyl fluorides, Sus scrofa carboxylesterase, Polyisoprenylated protein methyl transferase, Porcine liver esterase, human carboxylesterase 1
Abstract: The polyisoprenylation pathway incorporates a reversible step that metabolizes polyisoprenylated methylated proteins from the ester to the carboxylate form. Polyisoprenylated protein methyl transferase (PPMTase) catalyses the esterification whereas polyisoprenylated methylated protein methyl esterase (PMPMEase) hydrolyzes them. Significant changes in the balance between the two enzymes may alter polyisoprenylated protein function possibly resulting in disease. Previous studies show that PMPMEase is the serine hydrolase, Sus scrofa carboxylesterase. Its susceptibility to the nonspecific serine hydrolase inhibitor, phenylmethylsulfonyl fluoride (PMSF) paved the way for its use as a prototypical compound to design and synthesize a series of putative high affinity specific inhibitors of PMPMEase. Pseudo first-order kinetics revealed an over 680-fold increase in kobs/[I] values from PMSF (6 M-1s-1), S-phenyl (L-50, 180 M-1s-1), S-benzyl (L-51, 350 M-1s-1), S-trans, trans-farnesyl (L-28, 2000 M-1s-1), to S-trans-geranylated (L-23, 4100 M-1s-1) 2-thioethanesulfonyl fluorides. C10 S-alkyl substitution revealed a kobs/[I] value (1800 M-1s-1) that was 298 times greater than that for PMSF. The compounds induced the degeneration of human neuroblastoma SH-SY5Y cells with EC50 values of 49, 130 and < 1000 μM for L-28, L-23 and PMSF, respectively. The increased affinity with the polyisoprenyl derivatization is consistent with the observed substrate specificity and the reported hydrophobic nature of the active site. These results suggest that (1) PMPMEase is a key enzyme for polyisoprenylated protein metabolism, (2) regulation of its activity is essential for maintaining normal cell viability, (3) abnormal activities may be involved in degenerative diseases and cancers and (4) its specific inhibitors may be useful in combating cancers.
Export Options
About this article
Cite this article as:
Aguilar B., Amissah F., Duverna R. and S. Lamango N., Polyisoprenylation Potentiates the Inhibition of Polyisoprenylated Methylated Protein Methyl Esterase and the Cell Degenerative Effects of Sulfonyl Fluorides, Current Cancer Drug Targets 2011; 11 (6) . https://dx.doi.org/10.2174/156800911796191015
DOI https://dx.doi.org/10.2174/156800911796191015 |
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
-
Gene Expression Signatures of Lymph Node Metastasis in Oral Cancer: Molecular Characteristics and Clinical Significances
Current Cancer Therapy Reviews Endocannabinoid System: Emerging Role from Neurodevelopment to Neurodegeneration
Mini-Reviews in Medicinal Chemistry Image-Guided Nanoparticle-Based siRNA Delivery for Cancer Therapy
Current Pharmaceutical Design The Neurotrophic and Antiangiogenic Functions of PEDF: A Reflection of its Variable Phosphorylation States
Current Genomics Clinical Pharmacogenetics in Oncology: the Paradigm of Molecular Targeted Therapies
Current Pharmaceutical Design The mTOR/4E-BP1/eIF4E Signalling Pathway as a Source of Cancer Drug Targets
Current Medicinal Chemistry The Effect of Phase Transition Temperature on Therapeutic Efficacy of Liposomal Bortezomib
Anti-Cancer Agents in Medicinal Chemistry Cilostazol: Therapeutic Potential Against Focal Cerebral Ischemic Damage
Current Pharmaceutical Design Indoleamine 2,3-Dioxygenase in Immune Suppression and Cancer
Current Cancer Drug Targets Potential Benefits of Glitazones for Cancer and Vascular Disease
Current Drug Therapy ACE2-Ang-(1-7)-Mas Axis in Brain: A Potential Target for Prevention and Treatment of Ischemic Stroke
Current Neuropharmacology Proteasome Regulators: Activators and Inhibitors
Current Medicinal Chemistry Endoplasmic Reticulum Protein Quality Control in Neurodegenerative Disease: The Good, the Bad and the Therapy
Current Medicinal Chemistry p35 Deficiency Accelerates HMGB-1-mediated Neuronal Death in the Early Stages of an Alzheimer's disease Mouse Model
Current Alzheimer Research Identification of Novel Structurally Diverse Anaplastic Lymphoma Kinase Inhibitors Based on Pharmacophore Modeling, Virtual Screening and Molecular Docking
Combinatorial Chemistry & High Throughput Screening GqPCR-mediated Signalling in the Spotlight: From Visualization Towards Dissection and Quantification
Current Pharmaceutical Biotechnology Small Interfering RNAs and Antisense Oligonucleotides for Treatment of Neurological Diseases
Current Drug Targets Drug Transporters and Multiple Drug Resistance in the Most Common Pediatric Solid Tumors
Current Drug Metabolism Nanofibre Based Smart Pharmaceutical Scaffolds for Wound Repair and Regenerations
Current Pharmaceutical Design The Ubiquitin-Proteasome System as a Prospective Molecular Target for Cancer Treatment and Prevention
Current Protein & Peptide Science