Abstract
Acetohydroxyacid synthase (AHAS) (EC 2.2.1.6) (also known as acetolactate synthase) is the first common enzyme in the branched chain amino acid (BCAA) biosynthesis pathway. This pathway is present in microorganisms and in plants but not in animals, making it an attractive target for both drug and herbicide discovery. The function of AHAS is to catalyze the conversion of two molecules of pyruvate to 2-acetolactate or to convert one molecule of pyruvate and a molecule of 2-ketobutyrate into 2-aceto-2- hydroxybutyrate. Three cofactors are required for the activity of AHAS: thiamine diphosphate (ThDP), Mg2+ and flavin-adenine dinucleotide (FAD). AHAS is the target for several classes of commercial herbicides that include the sulfonylurea and imidazolinone families. These herbicides are potent and selective inhibitors of AHAS with Ki values that can be in the low nM range. Such compounds also exhibit low application rates as herbicides (typically ~3 g ha-1) and have low mammalian toxicity (LD50 values typically >4g/kg), thereby highlighting their utility and effectiveness as biocidal agents. However, somewhat surprisingly given the central importance of AHAS in the metabolism of microorganisms, no inhibitors of this enzyme have been commercialized into antimicrobial agents. Here we provide an overview of the biochemical characterization of AHASs from bacterial and fungal sources, analyse the structural features of these enzymes that are criticial to catalysis andprovide the current data on AHAS inhibitors that have potential to be developed into antimicrobial therapeutics.
Keywords: Actetohydroxyacid synthase, antibacterial, antifungal, herbicide, sulfonylurea, imidazolinone, branched-chain amino acid, valine, leucine, isoleucine, chemotherapeutic, Mycobacterium tuberculosis, Candida albicans, Cryptococcus neoformans.
Current Pharmaceutical Design
Title:Acetohydroxyacid Synthase: A Target for Antimicrobial Drug Discovery
Volume: 20 Issue: 5
Author(s): Nason Pue and Luke W. Guddat
Affiliation:
Keywords: Actetohydroxyacid synthase, antibacterial, antifungal, herbicide, sulfonylurea, imidazolinone, branched-chain amino acid, valine, leucine, isoleucine, chemotherapeutic, Mycobacterium tuberculosis, Candida albicans, Cryptococcus neoformans.
Abstract: Acetohydroxyacid synthase (AHAS) (EC 2.2.1.6) (also known as acetolactate synthase) is the first common enzyme in the branched chain amino acid (BCAA) biosynthesis pathway. This pathway is present in microorganisms and in plants but not in animals, making it an attractive target for both drug and herbicide discovery. The function of AHAS is to catalyze the conversion of two molecules of pyruvate to 2-acetolactate or to convert one molecule of pyruvate and a molecule of 2-ketobutyrate into 2-aceto-2- hydroxybutyrate. Three cofactors are required for the activity of AHAS: thiamine diphosphate (ThDP), Mg2+ and flavin-adenine dinucleotide (FAD). AHAS is the target for several classes of commercial herbicides that include the sulfonylurea and imidazolinone families. These herbicides are potent and selective inhibitors of AHAS with Ki values that can be in the low nM range. Such compounds also exhibit low application rates as herbicides (typically ~3 g ha-1) and have low mammalian toxicity (LD50 values typically >4g/kg), thereby highlighting their utility and effectiveness as biocidal agents. However, somewhat surprisingly given the central importance of AHAS in the metabolism of microorganisms, no inhibitors of this enzyme have been commercialized into antimicrobial agents. Here we provide an overview of the biochemical characterization of AHASs from bacterial and fungal sources, analyse the structural features of these enzymes that are criticial to catalysis andprovide the current data on AHAS inhibitors that have potential to be developed into antimicrobial therapeutics.
Export Options
About this article
Cite this article as:
Pue Nason and Guddat W. Luke, Acetohydroxyacid Synthase: A Target for Antimicrobial Drug Discovery, Current Pharmaceutical Design 2014; 20 (5) . https://dx.doi.org/10.2174/13816128113199990009
DOI https://dx.doi.org/10.2174/13816128113199990009 |
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
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
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...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
-
Entropy Model for Multiplex Drug-Target Interaction Endpoints of Drug Immunotoxicity
Current Topics in Medicinal Chemistry Antimycobacterial Natural Products from Marine Pseudopterogorgia elisabethae
Current Organic Synthesis New Potential Pharmaceutical Applications of Hypericum Species
Mini-Reviews in Medicinal Chemistry The Medicinal Chemistry of Genus <i>Aralia</i>
Current Topics in Medicinal Chemistry Current Study of Natural Products for Medicinal Chemistry
Current Medicinal Chemistry Antimicrobial, Antitumor and Side Effects Assessment of a Newly Synthesized Tamoxifen Analog
Current Topics in Medicinal Chemistry A Concise Overview on Recent Advances in Pharmaceutical Aerosols and their Commercial Applications
Current Materials Science Using Genomics for Natural Product Structure Elucidation
Current Topics in Medicinal Chemistry Editorial (Thematic Issue: Challenging Organic Syntheses and Pharmacological Applications of Natural Products and their Derivatives – Part II)
Current Pharmaceutical Design QSAR Study of Androstenedione Analogs as Aromatase Inhibitors
Letters in Drug Design & Discovery Understanding the Interaction Between Human Serum Albumin and Anti-Bacterial/ Anti-Cancer Compounds
Current Pharmaceutical Design Dubious Results of Remdisivir Ultimately in Solidarity; Diversity of Severity of Illness is Doubtful
New Emirates Medical Journal Pulmonary Disease in Beta-Thalassemia
Current Respiratory Medicine Reviews Methods for Docking Small Molecules to Macromolecules: A User’s Perspective. 2. Applications
Current Pharmaceutical Design Structural Characterization, Biological Effects, and Synthetic Studies on Xanthones from Mangosteen (Garcinia mangostana), a Popular Botanical Dietary Supplement
Mini-Reviews in Organic Chemistry Editorial [Hot Topic:Nicotinamide Adenine Dinucleotide Biology and Disease(Executive Editor: W. Todd Penberthy)]
Current Pharmaceutical Design Structural Biology of Bacterial Iron Uptake Systems
Current Topics in Medicinal Chemistry Isoniazid Induced Metabolic Acidosis and Renal Dysfunction in an Elderly Patient with Chronic Renal Disease
Current Drug Safety Pharmacological Innovations for Posttraumatic Stress Disorder and Medication- Enhanced Psychotherapy
Current Pharmaceutical Design MIANN Models of Networks of Biochemical Reactions, Ecosystems, and U.S. Supreme Court with Balaban-Markov Indices
Current Bioinformatics