Enzymes: Biological Catalysts

What is a Catalyst?

Catalysts are fundamental to biochemical reactions, enabling life by accelerating chemical processes without being consumed. Enzymes, the biological catalysts, are highly specific and efficient.

• Definition: A catalyst is a substance that increases the rate or velocity of a chemical reaction without being changed in the overall process.

• Thermodynamics: Catalysts do not alter the thermodynamic favorability (ΔG) of a reaction; they only accelerate the approach to equilibrium.

• Activation Energy: Catalysts lower the activation energy (energy barrier) required for the transition state, facilitating the conversion of substrate to product.

• Example: Enzymes such as carbonic anhydrase accelerate the interconversion of CO2 and HCO3- in blood.

Major Classes of Enzymes

Classification and Examples

Enzymes are classified based on the type of reaction they catalyze. The six major classes are outlined below:

Additional info: The Enzyme Commission (EC) number system is used to classify enzymes based on their reactions.

How Enzymes Act as Catalysts: Principles and Examples

Models for Substrate Binding and Catalysis

• Lock-and-Key Model: The enzyme's active site is a rigid structure that fits the substrate precisely, like a key in a lock.

• Induced Fit Model: The enzyme's active site is flexible and molds itself around the substrate upon binding, enhancing catalytic efficiency.

• Example: Hexokinase undergoes a conformational change upon glucose binding, illustrating the induced fit model.

Mechanisms for Achieving Rate Acceleration

Enzymes employ several strategies to accelerate reactions:

• General Acid/Base Catalysis (GABC): Enzyme side chains donate or accept protons to stabilize intermediates.

• Covalent Catalysis: Formation of a transient covalent bond between enzyme and substrate.

• Electrostatic Stabilization: Stabilization of charged transition states by charged or polar residues.

• Proximity Effects: Bringing substrates into close proximity and correct orientation.

• Preferential Stabilization of the Transition State: Enzymes bind the transition state more tightly than the substrate or product.

• Protein Conformational Changes: Structural changes in the enzyme can facilitate catalysis.

Reaction Coordinate Diagram:

The reaction can be represented as:

Enzymes lower the activation energy () for the reaction.

Coenzymes, Vitamins, and Essential Metals

Coenzyme or Cofactor Function in Catalysis

Many enzymes require non-protein helpers for catalytic activity:

• Coenzymes: Organic molecules (often derived from vitamins) that participate in catalysis but are not permanently altered.

• Cofactors: Inorganic ions (e.g., metal ions) required for enzyme activity.

Metal Ions in Enzymes

Metal ions serve as essential cofactors in many enzymes, often stabilizing structures or participating directly in catalysis.

Enzyme Inhibition

Drugs, Toxins, and Enzymatic Activity

• Many prescription drugs and toxins act as enzyme inhibitors.

• Enzyme inhibitors are classified as reversible (noncovalently bound) or irreversible (covalently bound).

Reversible Inhibition

• Competitive Inhibition: Inhibitor competes with substrate for the active site. Only the substrate can be processed.

• Uncompetitive Inhibition: Inhibitor binds only to the enzyme-substrate (ES) complex, not to the free enzyme, reducing catalytic activity.

• Mixed (Noncompetitive) Inhibition: Inhibitor binds to both the free enzyme and the ES complex at a site different from the substrate, affecting both substrate binding and catalysis.

Irreversible Inhibition

• Inhibitor forms a covalent bond with the enzyme, permanently inactivating it.

• Example: Diisopropyl fluorophosphate (DFP) binds to the active site serine of acetylcholinesterase, causing paralysis.

The Regulation of Enzyme Activity

Controlling Enzyme Functions in the Cellular Context

• Substrate Level Control: Reaction rate increases with substrate concentration, but large changes are needed for significant regulation.

• Regulation at Committed Steps: Feedback inhibition or activation at pathway control points, often mediated by allosteric enzymes, efficiently maintains homeostasis.

• Covalent Modification: Enzyme activity is regulated by reversible (e.g., phosphorylation/dephosphorylation) or irreversible (e.g., zymogen activation) covalent changes.

Allostery

• Allosteric enzymes are typically multisubunit proteins that change conformation upon binding substrates or effectors.

• Homoallostery: Cooperativity in substrate binding (e.g., hemoglobin).

• Heteroallostery: Regulation by nonsubstrate effector molecules.

Covalent Modifications Used to Regulate Enzyme Activity

Reversible and Irreversible Modifications

• Many enzymes are regulated by covalent modifications that act as functional on/off switches.

• Phosphorylation: Addition of phosphate groups by protein kinases; reversed by dephosphorylation via protein phosphatases.

• Zymogen Activation: Irreversible activation of enzymes by proteolytic cleavage (e.g., digestive enzymes, blood clotting factors).

Nonprotein Biocatalysts: Catalytic Nucleic Acids

Ribonucleic Acids as Enzymes

• Some RNA molecules, called ribozymes, can catalyze chemical reactions.

• Ribozymes support the "RNA World" hypothesis, suggesting that early life used RNA for both genetic information and catalysis before the evolution of DNA and protein enzymes.