Abstract
The enzymes of the shikimate pathway represent potential molecular targets for the development of non-toxic antimicrobial agents and anti-parasite drugs. One of the most promising of these enzymes is shikimate kinase (EC 2.7.1.71), which is responsible for the fifth step in the shikimate pathway. This enzyme phosphorylates shikimic acid to yield shikimate-3-phosphate, using ATP as a substrate. In this work, the conformational dynamics of the shikimate kinase from Mycobacterium tuberculosis was investigated in its apostate in solution. For this study, the enzyme was subjected to a gradient of temperatures from 15° C to 45 ° C in the presence or absence of deuterium oxide, and the amide H/D exchange was monitored using ESI-mass spectrometry. We observed: i) the phosphate binding domain in the apo-enzyme is fairly rigid and largely protected from solvent access, even at relatively high temperatures; ii) the shikimate binding domain is highly flexible, as indicated by the tendency of the apo-enzyme to exhibit large conformational changes to permit LID closure after the shikimate binding; iii) the nucleotide binding domain is initially conformationally rigid, which seems to favour the initial orientation of ADP/ATP, but becomes highly flexible at temperatures above 30°C, which may permit domain rotation; iv) part of the LID domain, including the phosphate binding site, is partially rigid, while another part is highly flexible and accessible to the solvent.
Keywords: Tuberculosis, drug development, shikimate kinase, mass spectrometry, H/D exchange, enzymes, antimicrobial agents, anti-parasite, ESI-mass spectrometry, apo-enzyme
Current Medicinal Chemistry
Title: Shikimate Kinase (EC 2.7.1.71) from Mycobacterium tuberculosis: Kinetics and Structural Dynamics of a Potential Molecular Target for Drug Development
Volume: 18 Issue: 9
Author(s): D. M. Saidemberg, A. W. Passarelli, A. V. Rodrigues, L. A. Basso, D. S. Santos and M. S. Palma
Affiliation:
Keywords: Tuberculosis, drug development, shikimate kinase, mass spectrometry, H/D exchange, enzymes, antimicrobial agents, anti-parasite, ESI-mass spectrometry, apo-enzyme
Abstract: The enzymes of the shikimate pathway represent potential molecular targets for the development of non-toxic antimicrobial agents and anti-parasite drugs. One of the most promising of these enzymes is shikimate kinase (EC 2.7.1.71), which is responsible for the fifth step in the shikimate pathway. This enzyme phosphorylates shikimic acid to yield shikimate-3-phosphate, using ATP as a substrate. In this work, the conformational dynamics of the shikimate kinase from Mycobacterium tuberculosis was investigated in its apostate in solution. For this study, the enzyme was subjected to a gradient of temperatures from 15° C to 45 ° C in the presence or absence of deuterium oxide, and the amide H/D exchange was monitored using ESI-mass spectrometry. We observed: i) the phosphate binding domain in the apo-enzyme is fairly rigid and largely protected from solvent access, even at relatively high temperatures; ii) the shikimate binding domain is highly flexible, as indicated by the tendency of the apo-enzyme to exhibit large conformational changes to permit LID closure after the shikimate binding; iii) the nucleotide binding domain is initially conformationally rigid, which seems to favour the initial orientation of ADP/ATP, but becomes highly flexible at temperatures above 30°C, which may permit domain rotation; iv) part of the LID domain, including the phosphate binding site, is partially rigid, while another part is highly flexible and accessible to the solvent.
Export Options
About this article
Cite this article as:
M. Saidemberg D., W. Passarelli A., V. Rodrigues A., A. Basso L., S. Santos D. and S. Palma M., Shikimate Kinase (EC 2.7.1.71) from Mycobacterium tuberculosis: Kinetics and Structural Dynamics of a Potential Molecular Target for Drug Development, Current Medicinal Chemistry 2011; 18 (9) . https://dx.doi.org/10.2174/092986711795029500
DOI https://dx.doi.org/10.2174/092986711795029500 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...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
-
In Vitro Antimycobacterial Activity of New 7-Chloroquinoline Derivatives
Letters in Drug Design & Discovery The Potential of p38 MAPK Inhibitors to Modulate Periodontal Infections
Current Drug Metabolism Fragment Pharmacophore-Based Screening: An Efficient Approach for Discovery of New Inhibitors of Toll-Like Receptor 5
Combinatorial Chemistry & High Throughput Screening Hydrazones as a Privileged Structural Linker in Antitubercular Agents: A Review
Infectious Disorders - Drug Targets Editorial
Recent Patents on Inflammation & Allergy Drug Discovery Editorial [Hot Topic: New Drug Targets for the Treatment of Asthma (Guest Editor: D. Knight)]
Current Drug Targets Antimycobacterial Activity of Quaternary Pyridinium Salts and Pyridinium N-oxides - Review
Current Pharmaceutical Design Impact of Structural Domains of the Heparin Binding Hemagglutinin of Mycobacterium tuberculosis on Function
Protein & Peptide Letters An Update on the Chemistry and Medicinal Chemistry of Novel Antimycobacterial Compounds
Current Topics in Medicinal Chemistry Green Synthesis of Gold Nanoparticles Using Different Leaf Extracts of Ocimum gratissimum Linn for Anti-tubercular Activity
Current Nanomedicine A Study on the Biological Activity of 2-thioxo-imidazolidin-4-ones
Letters in Drug Design & Discovery Roles of L5-7 Loop in the Structure and Chaperone Function of SsHSP14.1
Protein & Peptide Letters Association of Pharmacokinetic and Pharmacodynamic Aspects of Linezolid with Infection Outcome
Current Drug Metabolism Armed Imidazo [1,2-a] Pyrimidines (Pyridines): Evaluation of Antibacterial Activity
Letters in Drug Design & Discovery Synthesis and Antitubercular Activity of a Series of Thiazole Derivatives
Anti-Infective Agents Isoniazid Induced Metabolic Acidosis and Renal Dysfunction in an Elderly Patient with Chronic Renal Disease
Current Drug Safety Recent Developments in Patents Targeting Toll-Like Receptor Genes
Recent Patents on DNA & Gene Sequences Stereochemistry at the Forefront in the Design and Discovery of Novel Anti-tuberculosis Agents
Current Topics in Medicinal Chemistry Quinoline Derivatives: Candidate Drugs for a Class B G-Protein Coupled Receptor, the Calcitonin Gene-Related Peptide Receptor, a Cause of Migraines
CNS & Neurological Disorders - Drug Targets Carbonic Anhydrases An Overview
Current Pharmaceutical Design