Abstract
The 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway for isoprenoid biosynthesis has come under increased scrutiny as a target for novel antimalarial, antibacterial and herbicidal agents. 1-Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is a key enzyme of the pathway that catalyzes the rearrangement and nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of 1-deoxy-D-xylulose 5-phosphate (DXP) to MEP. The unique properties of DXR make it a remarkable and rational target for drug design. First, it is a vital enzyme for synthesis of isoprenoids in algae, plants, several eubacteria including the pathogenic bacteria like Bacillus anthracis, Helicobacter pylori, Yersinia pestis, Mycobacterium tuberculosis and the malarial parasite, Plasmodium falciparum. Second, there are no functional equivalents to DXR in humans, making it an attractive target for therapeutic intervention. Third, DXR appears to be a valid target and the results from fosmidomycin (1), the only available DXR inhibitor under clinical trials, suggests synergistic effects with the lincosamide antibiotics, lincomycin and clindamycin. Despite drug design efforts in this area, no successful drug specifically designed to inhibit DXR has emerged yet. This review summarizes the recent and promising developments with respect to the current knowledge of the MEP pathway with emphasis on the understanding of the structure and the catalytic mechanism of the DXR enzyme and the global quest for therapeutically useful inhibitors of DXR.
Keywords: Isoprenoids, MEP pathway, mevalonate, fosmidomycin, FR900098, DXP reductoisomerase, DXR
Current Pharmaceutical Design
Title: Targeting the Methyl Erythritol Phosphate (MEP) Pathway for Novel Antimalarial, Antibacterial and Herbicidal Drug Discovery: Inhibition of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase (DXR) Enzyme
Volume: 13 Issue: 11
Author(s): Nidhi Singh, Gweneal Cheve, Mitchell A. Avery and Christopher R. McCurdy
Affiliation:
Keywords: Isoprenoids, MEP pathway, mevalonate, fosmidomycin, FR900098, DXP reductoisomerase, DXR
Abstract: The 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway for isoprenoid biosynthesis has come under increased scrutiny as a target for novel antimalarial, antibacterial and herbicidal agents. 1-Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is a key enzyme of the pathway that catalyzes the rearrangement and nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of 1-deoxy-D-xylulose 5-phosphate (DXP) to MEP. The unique properties of DXR make it a remarkable and rational target for drug design. First, it is a vital enzyme for synthesis of isoprenoids in algae, plants, several eubacteria including the pathogenic bacteria like Bacillus anthracis, Helicobacter pylori, Yersinia pestis, Mycobacterium tuberculosis and the malarial parasite, Plasmodium falciparum. Second, there are no functional equivalents to DXR in humans, making it an attractive target for therapeutic intervention. Third, DXR appears to be a valid target and the results from fosmidomycin (1), the only available DXR inhibitor under clinical trials, suggests synergistic effects with the lincosamide antibiotics, lincomycin and clindamycin. Despite drug design efforts in this area, no successful drug specifically designed to inhibit DXR has emerged yet. This review summarizes the recent and promising developments with respect to the current knowledge of the MEP pathway with emphasis on the understanding of the structure and the catalytic mechanism of the DXR enzyme and the global quest for therapeutically useful inhibitors of DXR.
Export Options
About this article
Cite this article as:
Singh Nidhi, Cheve Gweneal, Avery A. Mitchell and McCurdy R. Christopher, Targeting the Methyl Erythritol Phosphate (MEP) Pathway for Novel Antimalarial, Antibacterial and Herbicidal Drug Discovery: Inhibition of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase (DXR) Enzyme, Current Pharmaceutical Design 2007; 13 (11) . https://dx.doi.org/10.2174/138161207780618939
DOI https://dx.doi.org/10.2174/138161207780618939 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Blood-based biomarkers in large-scale screening for neurodegenerative diseases
Disease biomarkers are necessary tools that can be employ in several clinical context of use (COU), ranging from the (early) diagnosis, prognosis, prediction, to monitor of disease state and/or drug efficacy. Regarding neurodegenerative diseases, in particular Alzheimer’s disease (AD), a battery of well-validated biomarkers are available, such as cerebrospinal fluid ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Diabetes mellitus: advances in diagnosis and treatment driving by precision medicine
Diabetes mellitus (DM) is a chronic degenerative metabolic disease with ever increasing prevalence worldwide which is now an epidemic disease affecting 500 million people worldwide. Insufficient insulin secretion from pancreatic β cells unable to maintain blood glucose homeostasis is the main feature of this disease. Multifactorial and complex nature of ...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
- Announcements
Related Articles
-
Antimicrobial Peptides with pH-Dependent Activity and Alkaline Optima:
Their Origins, Mechanisms of Action and Potential Applications
Current Protein & Peptide Science The Technology Development Studio of the MPI-CBG: An Open Access Cell-Based Screening Facility
Combinatorial Chemistry & High Throughput Screening Anti-Tuberculosis Drug Induced Hepatotoxicity and Genetic Polymorphisms in Drug-metabolizing Genes
Current Pharmacogenomics Virtual Screening of the Guanylate Monophosphate Kinase (GMPK) Family: Investigating the Rules of Ligand Specificity
Letters in Drug Design & Discovery Vitamin D in Acute Kidney Injury
Inflammation & Allergy - Drug Targets (Discontinued) Emerging Roles for the CD36 Scavenger Receptor as a Potential Therapeutic Target for Corneal Neovascularization
Endocrine, Metabolic & Immune Disorders - Drug Targets Role of Galectins in Allergic Disorders
Recent Patents on Inflammation & Allergy Drug Discovery Active Metabolites Resulting from Decarboxylation, Reduction and Ester Hydrolysis of Parent Drugs
Current Drug Metabolism Generalized String Pseudo-Folding Lattices in Bioinformatics: State-of-Art Review, New Model for Enzyme Sub-Classes, and Study of ESTs on Trichinella spiralis
Current Bioinformatics Neuroprotective Mechanisms of Oxygen and Ethanol: A Potential Combination Therapy in Stroke
Current Medicinal Chemistry Global Clinical Trials for the Treatment of TB with Thioridazine
Recent Patents on Anti-Infective Drug Discovery Synthesis and Biological Evaluation of Curcumin-Nitroxide-Based Molecular Hybrids as Antioxidant and Anti-Proliferative Agents
Medicinal Chemistry Pentraxins and Atherosclerosis: The Role of PTX3
Current Pharmaceutical Design Adherence to Antiretroviral Therapy Among Iranian HIV/AIDS Patients
Current Clinical Pharmacology Biochips for Detection of DNA Mutations
Current Analytical Chemistry Synthesis and Cytotoxic Evaluation of Disubstituted N-Acylhydrazones Pyrazinecarbohydrazide Derivatives
Letters in Drug Design & Discovery Mesenchymal Stem Cells: A New Generation of Therapeutic Agents as Vehicles in Gene Therapy
Current Gene Therapy Frequencies of Single Nucleotide Polymorphisms in Cytochrome P450 Genes (CYP1A2, 2A6, 2B6, 3A4 and 3A5) in a Rwandan Population: Difference to Other African Populations
Current Pharmacogenomics and Personalized Medicine Synthesis and Biological Activity of 2,7-Naphthyridine Derivatives: An Overview
Current Organic Chemistry Adverse Drug Reactions Amongst Adult Patients Admitted in Lagos State University Teaching Hospital Lagos, Nigeria
Current Drug Safety