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
-
Cloning and Transcriptional Regulation of Genes Responsible for Synthesis of Gangliosides
Current Drug Targets NO Chimeras as Therapeutic Agents in Alzheimers Disease
Current Alzheimer Research Review on the Protective Effects of PACAP in Models of Neurodegenerative Diseases In Vitro and In Vivo
Current Pharmaceutical Design Protein Kinases and their Modulation in the Central Nervous System
Current Medicinal Chemistry - Central Nervous System Agents AFM-Based Single Molecule Techniques: Unraveling the Amyloid Pathogenic Species
Current Pharmaceutical Design The Impact of Folate Status on the Efficacy of Colorectal Cancer Treatment
Current Drug Metabolism Biochemical Markers for Brain Injury Monitoring in Children with or without Congenital Heart Diseases
CNS & Neurological Disorders - Drug Targets Differential Susceptibility of Naive and Differentiated PC-12 Cells to Methylglyoxal-Induced Apoptosis: Influence of Cellular Redox
Current Neurovascular Research Histone Methyltransferase Inhibitors: Novel Epigenetic Agents for Cancer Treatment
Current Medicinal Chemistry Crosstalk of Long Non-coding RNAs and EMT: Searching the Missing Pieces of an Incomplete Puzzle for Lung Cancer Therapy
Current Cancer Drug Targets HER2 in the Era of Molecular Medicine: A Review
Current Cancer Therapy Reviews The NK-1 Receptor is Involved in the Antitumoural Action of L-733,060 and in the Mitogenic Action of Substance P on Human Pancreatic Cancer Cell Lines
Letters in Drug Design & Discovery The Interaction of Histone Deacetylase Inhibitors and DNA Methyltransferase Inhibitors in the Treatment of Human Cancer Cells
Current Medicinal Chemistry - Anti-Cancer Agents On the Physiological Role of Cytosolic 5’-nucleotidase II (cN-II): Pathological and Therapeutical Implications.
Current Medicinal Chemistry Neuroprotective Effects of Fisetin in Alzheimer’s and Parkinson’s Diseases: From Chemistry to Medicine
Current Topics in Medicinal Chemistry Antiinflammatory Activity of Melatonin in Central Nervous System
Current Neuropharmacology Involvement of the Septo-Hippocampal Cholinergic Pathway in Association with Septal Acetylcholinesterase Upregulation in a Mouse Model of Tauopathy
Current Alzheimer Research Gene Expression-Based Pharmacodynamic Biomarkers: The Beginning of a New Era in Biomarker-Driven Anti-Tumor Drug Development
Current Molecular Medicine Targeting Neuronal Nicotinic Receptors in Cancer: New Ligands and Potential Side-Effects
Recent Patents on Anti-Cancer Drug Discovery Metallothionein as a Scavenger of Free Radicals - New Cardioprotective Therapeutic Agent or Initiator of Tumor Chemoresistance?
Current Drug Targets