Allosteric Inhibition: Mechanism, Examples, and Metabolic Significance

Introduction

Enzymes are biological catalysts that speed up specific chemical reactions within cells.
They facilitate essential biochemical processes in living organisms.
Enzymes function by binding to substrate molecules at specific active sites, accelerating chemical reactions.
The regulation of enzyme activity is crucial for their proper function.
Various mechanisms exist to control enzyme activity.
One key regulatory mechanism is allosteric regulation.
In allosteric regulation, a regulatory molecule (activator or inhibitor) binds to a site other than the enzyme’s active site.
This specific binding site is called the allosteric site.
Allosteric enzymes possess both active sites and allosteric sites.
The Michaelis–Menten (MM) model does not adequately explain allosteric regulation.

Allosteric inhibition is a regulatory mechanism where an allosteric inhibitor binds to a specific allosteric site.
This binding causes a conformational change in the enzyme’s structure, reducing its activity.
Allosteric inhibition is reversible; when the inhibitor dissociates, the enzyme regains its original conformation and activity.
Allosteric inhibitors are regulatory molecules that interact with enzymes at allosteric sites.
They inhibit the binding of substrate or ligand molecules.
Unlike competitive inhibitors, allosteric inhibitors do not compete with the substrate for binding at the active site.
Instead, they bind to the allosteric site, indirectly altering the enzyme’s shape or activity.

Allosteric binding regulates enzyme activity through two mechanisms: noncompetitive inhibition and uncompetitive inhibition.

Both mechanisms reduce or inhibit the desired chemical reaction.

The inhibitor molecule (I) binds to the allosteric site of the enzyme (E) before the substrate-binding event.
This binding alters the enzyme’s structure, which can modify the active site.
As a result, the substrate (S) cannot bind effectively, reducing the enzyme's ability to catalyze the reaction and form products (P).

Occurs after the substrate has already bound to the enzyme, targeting the enzyme-substrate (ES) complex.
The inhibitor binds specifically to the ES complex, forming the enzyme-substrate-inhibitor (ESI) complex.
This slows down the conversion of the ES complex into products, making the catalytic step less efficient.

Allosteric enzymes exhibit cooperativity in substrate binding, a phenomenon where the binding of a ligand influences the affinity of other binding sites.
Cooperativity can either increase or decrease the enzyme's affinity for additional ligand binding.
Two main models explain cooperativity in allosteric enzymes:

Introduced by Monod, Wyman, and Changeux in 1965.
Enzymes with multiple subunits exist in two conformational states: relaxed (R) state or tense (T) state.
All subunits remain in the same state, either T or R, maintaining symmetry.
In the absence of ligands, the T state is favored.
Ligand binding shifts the equilibrium toward the R state, increasing enzyme activity.

Proposed by Koshland, Nemethy, and Filmer in 1966.
Binding of a ligand causes a conformational change only in the subunit it binds to.
This change influences neighboring subunits, leading to cooperative behavior.
Unlike the MWC model, this model does not maintain symmetry, allowing a mix of T and R states during the binding process.

Involved in pyrimidine nucleotide synthesis, essential for DNA and RNA formation.
Cytidine triphosphate (CTP) acts as an allosteric inhibitor.
When CTP binds to the allosteric site, it causes a conformational change that reduces enzyme activity.
This feedback inhibition prevents excessive pyrimidine nucleotide production.

A key enzyme in glycolysis, the glucose breakdown pathway for energy production.
High ATP levels act as an allosteric inhibitor.
ATP binding to the allosteric site reduces PFK-1 activity.
This regulation prevents excessive glucose breakdown when the cell has sufficient energy.

Essential for fatty acid synthesis.
Palmitoyl-CoA and long-chain fatty acyl-CoAs act as allosteric inhibitors.
These inhibitors bind to the allosteric sites of ACC, signaling an excess of fatty acids.
This inhibition reduces fatty acid synthesis, preventing unnecessary accumulation.

Allosteric inhibition is a crucial mechanism for controlling enzyme activity.
It plays a key role in metabolic pathway regulation through feedback control.
Prevents overproduction of metabolites by inhibiting enzymes when their products accumulate.
Used in drug development to design target-specific proteins.
Helps maintain homeostasis by regulating enzyme activity and cell signaling.

Allosteric Enzymes: Characteristics, Models, and Examples (ConductScience.com)
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