Related Experiment Video
Updated: Oct 18, 2025
A Novel Saturation Mutagenesis Approach: Single Step Characterization of Regulatory Protein Binding Sites in RNA Using Phosphorothioates
Published on: August 21, 2018
Sugar-Phosphate Toxicities
Erin F Boulanger1, Anice Sabag-Daigle1, Pankajavalli Thirugnanasambantham2,3
1Department of Microbial Infection and Immunity, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA.
Abstract:
Accumulation of phosphorylated intermediates during cellular metabolism can have wide-ranging toxic effects on many organisms, including humans and the pathogens that infect them. These toxicities can be induced by feeding an upstream metabolite (a sugar, for instance) while simultaneously blocking the appropriate metabolic pathway with either a mutation or an enzyme inhibitor. Here, we survey the toxicities that can arise in the metabolism of glucose, galactose, fructose, fructose-asparagine, glycerol, trehalose, maltose, mannose, mannitol, arabinose, and rhamnose. Select enzymes in these metabolic pathways may serve as novel therapeutic targets. Some are conserved broadly among prokaryotes and eukaryotes (e.g., glucose and galactose) and are therefore unlikely to be viable drug targets. However, others are found only in bacteria (e.g., fructose-asparagine, rhamnose, and arabinose), and one is found in fungi but not in humans (trehalose). We discuss what is known about the mechanisms of toxicity and how resistance is achieved in order to identify the prospects and challenges associated with targeted exploitation of these pervasive metabolic vulnerabilities.
Insights
Metabolic pathway disruptions cause toxic intermediate accumulation. Targeting specific microbial metabolic enzymes, like those in arabinose or rhamnose pathways, offers potential therapeutic strategies against pathogens.
Area of Science:
- Biochemistry
- Metabolic Engineering
- Pathogen Biology
Background:
- Cellular metabolism generates phosphorylated intermediates.
- Accumulation of these intermediates can lead to toxicity in hosts and pathogens.
- Metabolic pathway inhibition, via mutation or inhibitors, can induce these toxicities.
Purpose of the Study:
- To survey toxicities arising from various sugar and polyol metabolic pathways.
- To identify potential novel therapeutic targets within these metabolic pathways.
- To evaluate the feasibility of targeting conserved versus pathogen-specific metabolic vulnerabilities.
Main Methods:
- Review and analysis of known metabolic pathways for glucose, galactose, fructose, fructose-asparagine, glycerol, trehalose, maltose, mannose, mannitol, arabinose, and rhamnose.
- Assessment of enzyme conservation across prokaryotes, eukaryotes, and humans.
- Discussion of existing knowledge on toxicity mechanisms and resistance.
Main Results:
- Identified toxicities associated with the metabolism of multiple sugars and polyols.
- Highlighted pathogen-specific metabolic enzymes (e.g., in fructose-asparagine, rhamnose, arabinose pathways) as potential drug targets.
- Noted broad conservation of some targets (e.g., glucose, galactose) makes them less suitable for selective therapeutic intervention.
Conclusions:
- Exploiting metabolic vulnerabilities presents a promising avenue for therapeutic development.
- Pathogen-specific metabolic pathways offer the greatest potential for targeted drug discovery.
- Understanding toxicity mechanisms and resistance is crucial for successful therapeutic strategies.
More Related Videos
17:28Human Pluripotent Stem Cell Based Developmental Toxicity Assays for Chemical Safety Screening and Systems Biology Data Generation
Published on: June 17, 2015
08:17A High-Throughput Enzyme-Coupled Activity Assay to Probe Small Molecule Interaction with the dNTPase SAMHD1
Published on: April 16, 2021
Related Concept Videos
01:26Toxic Reactions: Overview
Toxicity falls into two primary categories: local and systemic.
Local toxicity appears at the exposure site, such as protein denaturation caused by caustic substances.
In contrast, systemic toxicity requires the toxic agent's absorption and distribution,...
01:28Biosynthesis of Nucleic Acids
01:19Phase II Reactions: Miscellaneous Conjugation Reactions
A key example involves the conjugation of cyanide ions, which impair cellular respiration and alter hemoglobin into non-oxygen-carrying cyanmethemoglobin. To neutralize this threat, a sulfur atom from thiosulphate is transferred to the cyanide ion, catalyzed by the enzyme rhodanese, resulting in an inactive compound called thiocyanate. The production of...
01:01Phosphodiester Linkages
Phosphodiester bond forms when a phosphoric acid molecule (H3PO4) links with two hydroxyl groups (–OH) of two other molecules, forming two ester bonds. Two water molecules are released in this process. The phosphodiester bond is commonly found in nucleic acids (DNA and RNA) and plays a critical role in their structure and function.
Phosphodiester Bonds Link Nucleotides Together
DNA and RNA are polynucleotides or long chains of nucleotides that are linked together. A nucleotide is...
01:07Teratogenicity
01:19Phase II Reactions: Sulfation and Conjugation with α-Amino Acids