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Related Concept Videos

Enzymes02:34

Enzymes

Inside living organisms, enzymes act as catalysts for many biochemical reactions involved in cellular metabolism. The role of enzymes is to reduce the activation energies of biochemical reactions by forming complexes with its substrates. The lowering of activation energies favor an increase in the rates of biochemical reactions.
Enzyme deficiencies can often translate into life-threatening diseases. For example, a genetic abnormality resulting in the deficiency of the enzyme G6PD...
Structure-Activity Relationships and Drug Design01:28

Structure-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...
Induced-fit Model01:13

Induced-fit Model

Most chemical reactions in cells require enzymes—biological catalysts that speed up the reaction without being consumed or permanently changed. They reduce the activation energy needed to convert the reactants into products. Enzymes are proteins, that usually work by binding to a substrate—a reactant molecule that they act upon.
Enzymes exhibit substrate specificity, meaning that they can only bind to certain substrates. This is mainly determined by the shape and chemical characteristics of...
Introduction to Mechanisms of Enzyme Catalysis01:13

Introduction to Mechanisms of Enzyme Catalysis

For many years, scientists thought that enzyme-substrate binding took place in a simple "lock-and-key" fashion. This model stated that the enzyme and substrate fit together perfectly in one instantaneous step. However, current research supports a more refined view scientists call induced fit. The induced-fit model expands upon the lock-and-key model by describing a more dynamic interaction between enzyme and substrate. As the enzyme and substrate come together, their interaction causes a mild...
Introduction to Mechanisms of Enzyme Catalysis01:13

Introduction to Mechanisms of Enzyme Catalysis

For many years, scientists thought that enzyme-substrate binding took place in a simple "lock-and-key" fashion. This model stated that the enzyme and substrate fit together perfectly in one instantaneous step. However, current research supports a more refined view scientists call induced fit. The induced-fit model expands upon the lock-and-key model by describing a more dynamic interaction between enzyme and substrate. As the enzyme and substrate come together, their interaction causes a mild...
Enzyme Inhibition01:30

Enzyme 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.

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Synthesizing Amino Acids Modified with Reactive Carbonyls in Silico to Assess Structural Effects Using Molecular Dynamics Simulations
05:57

Synthesizing Amino Acids Modified with Reactive Carbonyls in Silico to Assess Structural Effects Using Molecular Dynamics Simulations

Published on: April 26, 2024

Computational structure-based redesign of enzyme activity.

Cheng-Yu Chen1, Ivelin Georgiev, Amy C Anderson

  • 1Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.

Proceedings of the National Academy of Sciences of the United States of America
|February 21, 2009
PubMed
Summary
This summary is machine-generated.

Computational redesign of gramicidin S synthetase A (GrsA-PheA) improved enzyme specificity for noncognate substrates. Structure-based protein design successfully identified active enzyme mutants beyond evolutionary pathways.

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Published on: January 16, 2016

Area of Science:

  • Biochemistry
  • Computational Biology
  • Enzyme Engineering

Background:

  • Nonribosomal peptide synthetases (NRPS) are crucial for synthesizing complex peptides.
  • Gramicidin S synthetase A (GrsA) is an NRPS involved in gramicidin S biosynthesis.
  • The phenylalanine adenylation domain (PheA) of GrsA exhibits specific substrate recognition.

Purpose of the Study:

  • To computationally redesign the GrsA-PheA domain to recognize noncognate substrates.
  • To enhance the specificity of GrsA-PheA for novel substrates.
  • To validate and improve computational enzyme redesign methodologies.

Main Methods:

  • Structure-based computational redesign of the GrsA-PheA domain.
  • In silico prediction of enzyme mutants with altered substrate specificity.
  • Experimental validation of computationally designed enzyme mutants.
  • Enhancement of computational enzyme redesign protocols.

Main Results:

  • Computationally designed GrsA-PheA mutants showed significantly improved specificity for target noncognate substrates.
  • Experimental validation confirmed the enhanced substrate specificity of the top-ranked mutants.
  • Methodological enhancements led to further improvements in target substrate specificity.
  • A mutant exhibited 1/6 activity for a noncognate substrate compared to the wild-type enzyme/substrate.

Conclusions:

  • Structure-based protein design is a viable approach for creating enzymes with novel substrate specificities.
  • Computational redesign can identify functional enzyme variants not found through natural evolution.
  • The developed methodology offers a powerful tool for enzyme engineering and directed evolution.