Abstract
Binding between vacuolar H+-ATPases (V-ATPases) and microfilaments is mediated by an actin binding domain in the B-subunit. Both isoforms of mammalian B-subunit bind microfilaments with high affinity. A similar actinbinding activity has been demonstrated in the B-subunit of yeast. A conserved “profilin-like” domain in the B-subunit mediates this actin-binding activity, named due to its sequence and structural similarity to an actin-binding surface of the canonical actin binding protein profilin. Subtle mutations in the “profilin-like” domain eliminate actin binding activity without disrupting the ability of the altered protein to associate with the other subunits of V-ATPase to form a functional proton pump. Analysis of these mutated B-subunits suggests that the actin-binding activity is not required for the “housekeeping” functions of V-ATPases, but is important for certain specialized roles. In osteoclasts, the actin-binding activity is required for transport of V-ATPases to the plasma membrane, a prerequisite for bone resorption. A virtual screen led to the identification of enoxacin as a small molecule that bound to the actin-binding surface of the B2-subunit and competitively inhibited B2-subunit and actin interaction. Enoxacin disrupted osteoclastic bone resorption in vitro, but did not affect osteoblast formation or mineralization. Recently, enoxacin was identified as an inhibitor of the virulence of Candida albicans and more importantly of cancer growth and metastasis. Efforts are underway to determine the mechanisms by which enoxacin and other small molecule inhibitors of B2 and microfilament binding interaction selectively block bone resorption, the virulence of Candida, cancer growth, and metastasis.
Keywords: Osteoclast, vacuolar ATPase, actin, microfilaments, enoxacin, cancer, Candida, Other Cytoskeletal Elements, V-ATPases Bind Microfilaments, immunoprecipitates
Current Protein & Peptide Science
Title:Rational Identification of Enoxacin as a Novel V-ATPase-Directed Osteoclast Inhibitor
Volume: 13 Issue: 2
Author(s): Edgardo J. Toro, David A. Ostrov, Thomas J. Wronski and L. Shannon Holliday
Affiliation:
Keywords: Osteoclast, vacuolar ATPase, actin, microfilaments, enoxacin, cancer, Candida, Other Cytoskeletal Elements, V-ATPases Bind Microfilaments, immunoprecipitates
Abstract: Binding between vacuolar H+-ATPases (V-ATPases) and microfilaments is mediated by an actin binding domain in the B-subunit. Both isoforms of mammalian B-subunit bind microfilaments with high affinity. A similar actinbinding activity has been demonstrated in the B-subunit of yeast. A conserved “profilin-like” domain in the B-subunit mediates this actin-binding activity, named due to its sequence and structural similarity to an actin-binding surface of the canonical actin binding protein profilin. Subtle mutations in the “profilin-like” domain eliminate actin binding activity without disrupting the ability of the altered protein to associate with the other subunits of V-ATPase to form a functional proton pump. Analysis of these mutated B-subunits suggests that the actin-binding activity is not required for the “housekeeping” functions of V-ATPases, but is important for certain specialized roles. In osteoclasts, the actin-binding activity is required for transport of V-ATPases to the plasma membrane, a prerequisite for bone resorption. A virtual screen led to the identification of enoxacin as a small molecule that bound to the actin-binding surface of the B2-subunit and competitively inhibited B2-subunit and actin interaction. Enoxacin disrupted osteoclastic bone resorption in vitro, but did not affect osteoblast formation or mineralization. Recently, enoxacin was identified as an inhibitor of the virulence of Candida albicans and more importantly of cancer growth and metastasis. Efforts are underway to determine the mechanisms by which enoxacin and other small molecule inhibitors of B2 and microfilament binding interaction selectively block bone resorption, the virulence of Candida, cancer growth, and metastasis.
Export Options
About this article
Cite this article as:
J. Toro Edgardo, A. Ostrov David, J. Wronski Thomas and Shannon Holliday L., Rational Identification of Enoxacin as a Novel V-ATPase-Directed Osteoclast Inhibitor, Current Protein & Peptide Science 2012; 13 (2) . https://dx.doi.org/10.2174/138920312800493151
DOI https://dx.doi.org/10.2174/138920312800493151 |
Print ISSN 1389-2037 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5550 |
Call for Papers in Thematic Issues
Advancements in Proteomic and Peptidomic Approaches in Cancer Immunotherapy: Unveiling the Immune Microenvironment
The scope of this thematic issue centers on the integration of proteomic and peptidomic technologies into the field of cancer immunotherapy, with a particular emphasis on exploring the tumor immune microenvironment. This issue aims to gather contributions that illustrate the application of these advanced methodologies in unveiling the complex interplay ...read more
Artificial Intelligence for Protein Research
Protein research, essential for understanding biological processes and creating therapeutics, faces challenges due to the intricate nature of protein structures and functions. Traditional methods are limited in exploring the vast protein sequence space efficiently. Artificial intelligence (AI) and machine learning (ML) offer promising solutions by improving predictions and speeding up ...read more
Nutrition and Metabolism in Musculoskeletal Diseases
The musculoskeletal system consists mainly of cartilage, bone, muscles, tendons, connective tissue and ligaments. Balanced metabolism is of vital importance for the homeostasis of the musculoskeletal system. A series of musculoskeletal diseases (for example, sarcopenia, osteoporosis) are resulted from the dysregulated metabolism of the musculoskeletal system. Furthermore, metabolic diseases (such ...read more
Protein Folding, Aggregation and Liquid-Liquid Phase Separation
Protein folding, misfolding and aggregation remain one of the main problems of interdisciplinary science not only because many questions are still open, but also because they are important from the point of view of practical application. Protein aggregation and formation of fibrillar structures, for example, is a hallmark of a ...read more
Related Journals
- 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
-
The Interplay between the Gut Immune System and Microbiota in Health and Disease: Nutraceutical Intervention for Restoring Intestinal Homeostasis
Current Pharmaceutical Design Na<sup>+</sup>/K<sup>+</sup> ATPase Inhibitors in Cancer
Current Drug Targets The Role of CD40 Expression in Dendritic Cells in Cancer Biology; A Systematic Review
Current Cancer Drug Targets Molecular Targets for Nutritional Preemption of Cancer
Current Cancer Drug Targets Targeting Cytosolic Phospholipase A2α for Novel Anti-Inflammatory Agents
Current Medicinal Chemistry Recent Advances in Developing K-Ras Plasma Membrane Localization Inhibitors
Current Topics in Medicinal Chemistry Curcumin as an Anti-Cancer Agent: Review of the Gap Between Basic and Clinical Applications
Current Medicinal Chemistry Array-Based Approaches for the Identification of Epigenetic Silenced Tumor Suppressor Genes
Current Genomics Potential Association Between TLR4 and Chitinase 3-Like 1 (CHI3L1/YKL-40) Signaling on Colonic Epithelial Cells in Inflammatory Bowel Disease and Colitis-Associated Cancer
Current Molecular Medicine Radionuclide Molecular Imaging Using Affibody Molecules
Current Pharmaceutical Biotechnology Production of Orally Applicable New Drug or Drug Combinations from Natural Origin Capsaicinoids for Human Medical Therapy
Current Pharmaceutical Design Foreword
Current Drug Delivery Inhibition of Autophagy by Targeting ATG4B: Promises and Challenges of An Emerging Anti-cancer Strategy
Clinical Cancer Drugs Computational Tools in the Discovery of New G-Quadruplex Ligands with Potential Anticancer Activity
Current Topics in Medicinal Chemistry Interplay between Epigenetics & Cancer Metabolism
Current Pharmaceutical Design Nanomedicine for Cancer Therapy Using Autophagy: An Overview
Current Topics in Medicinal Chemistry DNA Damage Response Pathways and Cell Cycle Checkpoints in Colorectal Cancer: Current Concepts and Future Perspectives for Targeted Treatment
Current Cancer Drug Targets Angiogenesis Inhibitors. Drug Selectivity and Target Specificity
Current Pharmaceutical Design Synthesis and Biological Evaluation of Novel Heterocyclic Imines Linked Coumarin- Thiazole Hybrids as Anticancer Agents
Anti-Cancer Agents in Medicinal Chemistry Is Red Meat Required for the Prevention of Iron Deficiency Among Children and Adolescents?
Current Pediatric Reviews