Related Experiment Video
Updated: Jun 18, 2026
08:06
The Use of a β-lactamase-based Conductimetric Biosensor Assay to Detect Biomolecular Interactions
Published on: February 1, 2018
Substituted aryl malonamates as new serine beta-lactamase substrates: structure-activity studies
S A Adediran1, D Cabaret, J-F Lohier
1Department of Chemistry, Wesleyan University, Middletown, CT 06459, USA.
Bioorganic & Medicinal Chemistry
|November 26, 2009
Summary
Substituted aryl malonamates, featuring a retro-amide linkage, act as substrates for beta-lactamases and DD-peptidases. A phosphonate analogue irreversibly inhibits these enzymes, confirming covalent interaction with beta-lactam-recognizing enzymes.
Area of Science:
- Medicinal Chemistry
- Enzymology
- Organic Synthesis
Background:
- Beta-lactamases are enzymes that confer bacterial resistance to beta-lactam antibiotics.
- DD-peptidases are bacterial enzymes involved in cell wall synthesis.
- Aryl phenaceturates are known substrates for these enzymes.
Purpose of the Study:
- To synthesize and characterize substituted aryl malonamates as analogues of aryl phenaceturates.
- To investigate the enzymatic hydrolysis of these malonamates by beta-lactamases and DD-peptidases.
- To explore the structure-activity relationships influencing enzyme interaction and inhibition.
Main Methods:
- Synthesis of a series of substituted aryl malonamates.
- Enzymatic assays using purified class A and class C beta-lactamases and soluble DD-peptidases.
- Kinetic analysis of substrate turnover and inhibitor activity.
- Structure-activity relationship studies based on substituent effects.
Main Results:
- Aryl malonamates are substrates for class A and C beta-lactamases and DD-peptidases, similar to phenaceturates.
- N-alkylation of malonamates retains susceptibility to beta-lactamase hydrolysis.
- A phosphonate analogue of malonamates acts as an irreversible inhibitor of beta-lactamases.
- Substituents alpha to the ester carbonyl group affect enzyme turnover similarly to phenaceturates.
Conclusions:
- Compounds with retro-amide side chains demonstrate covalent access to the active sites of beta-lactam-recognizing enzymes.
- Malonamate derivatives offer a platform for developing novel beta-lactamase inhibitors.
- Understanding enzyme-substrate interactions is crucial for designing effective antibacterial agents.
Related Concept Videos
01:16Adrenergic Agonists: Chemistry and Structure-Activity Relationship
Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...
01:30Enzyme Inhibition
Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
01:28Structure-Activity Relationships and Drug Design
Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence its...
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence its...
01:23Inhibitors of Gram-positive Cell Wall Synthesis
Bacterial cell walls are typically rigid structures composed mainly of peptidoglycan, a mesh-like polymer that provides mechanical strength and maintains cell shape. The synthesis of peptidoglycan is a crucial process in bacterial growth and serves as a primary target for many antibiotics.Mechanism of Action of Beta-Lactam AntibioticsBeta-lactam antibiotics, such as penicillin, inhibit peptidoglycan synthesis in actively growing cells. These antibiotics share a characteristic four-membered...
01:19Allosteric Proteins-ATCase
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
00:49Ligand Binding and Linkage
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence the...