8.4 Enzyme inhibition and activation

Enzyme inhibition and activation are crucial concepts in chemical kinetics, shaping how enzymes function in biological systems. These processes involve molecules that can either slow down or speed up enzyme-catalyzed reactions, influencing the rate at which products are formed.

Understanding enzyme inhibition and activation is essential for developing drugs and studying metabolic pathways. By manipulating these processes, scientists can control enzyme activity, leading to treatments for various diseases and insights into complex biological mechanisms.

Enzyme Inhibition and Activation

Types of enzyme inhibition

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• Competitive inhibition occurs when an inhibitor binds to the active site of the enzyme, competing with the substrate for binding (aspirin and cyclooxygenase)
  • Inhibitor structurally resembles the substrate, allowing it to fit into the active site
  • Inhibition can be overcome by increasing substrate concentration, as higher substrate levels outcompete the inhibitor
  • Increases the apparent $K_m$ without affecting $V_{max}$, as more substrate is needed to reach half-maximal velocity
• Noncompetitive inhibition involves an inhibitor binding to a site other than the active site, known as an allosteric site (heavy metals and enzymes)
  • Inhibitor binding alters the enzyme's conformation, reducing its catalytic activity
  • Inhibition cannot be overcome by increasing substrate concentration, as the inhibitor does not compete with the substrate
  • Decreases $V_{max}$ without affecting $K_m$, as the maximum reaction velocity is reduced
• Uncompetitive inhibition occurs when an inhibitor binds only to the enzyme-substrate complex (succinate dehydrogenase and malonate)
  • Inhibitor binding prevents product formation and release, trapping the enzyme in an unproductive state
  • Decreases both $V_{max}$ and $K_m$, as the inhibitor reduces the effective concentration of the enzyme-substrate complex

Effects on enzyme kinetics

• The Michaelis-Menten equation describes the relationship between reaction velocity ($v$), maximum reaction velocity ($V_{max}$), substrate concentration ($[S]$), and the Michaelis constant ($K_m$): $v = \frac{V_{max}[S]}{K_m + [S]}$
  • $K_m$ represents the substrate concentration at which the reaction velocity is half of $V_{max}$, indicating the enzyme's affinity for the substrate
• Inhibitors affect the Michaelis-Menten parameters in different ways
  • Competitive inhibition increases $K_m$ without changing $V_{max}$, as more substrate is needed to outcompete the inhibitor
  • Noncompetitive inhibition decreases $V_{max}$ without affecting $K_m$, as the inhibitor reduces the enzyme's catalytic efficiency
  • Uncompetitive inhibition decreases both $V_{max}$ and $K_m$, as the inhibitor binds only to the enzyme-substrate complex
• The Lineweaver-Burk plot (double reciprocal plot) linearizes the Michaelis-Menten equation: $\frac{1}{v} = \frac{K_m}{V_{max}} \cdot \frac{1}{[S]} + \frac{1}{V_{max}}$
  • This plot is used to determine the type of inhibition based on the pattern of lines obtained in the presence and absence of the inhibitor

Mechanisms of enzyme activation

• Allosteric activation occurs when an activator binds to an allosteric site, inducing a conformational change that enhances the enzyme's catalytic activity (fructose-1,6-bisphosphatase and AMP)
  • This mechanism allows for the regulation of metabolic pathways and signal transduction
• Cofactor binding is essential for the activity of some enzymes, as cofactors (metal ions or coenzymes) stabilize the active conformation of the enzyme
  • Examples include zinc in carbonic anhydrase and NAD+ in dehydrogenases
• Phosphorylation involves the addition of a phosphate group to specific amino acid residues (serine, threonine, tyrosine), which can activate or deactivate enzymes
  • Plays a crucial role in signal transduction and regulation of cellular processes (glycogen phosphorylase and phosphorylase kinase)
• Proteolytic activation occurs when enzymes are synthesized as inactive precursors (zymogens) and activated by proteolytic cleavage
  • Examples include the conversion of pepsinogen to pepsin and trypsinogen to trypsin

Inhibitors and activators in medicine

• Enzyme inhibitors are used in medicine to treat various conditions
  • Acetazolamide, a carbonic anhydrase inhibitor, treats glaucoma and altitude sickness by reducing aqueous humor production and increasing blood oxygenation
  • Statins (atorvastatin) inhibit HMG-CoA reductase to lower cholesterol levels and reduce the risk of cardiovascular disease
  • Protease inhibitors (ritonavir) are used in the treatment of HIV/AIDS by blocking viral protease activity and preventing viral replication
  • Allopurinol, a xanthine oxidase inhibitor, treats gout and reduces uric acid levels by preventing the conversion of xanthine to uric acid
• Enzyme activators also have medical applications
  • Sulfonylureas (glimepiride) activate ATP-sensitive potassium channels in pancreatic beta cells, stimulating insulin secretion for the treatment of type 2 diabetes
  • Benzodiazepines (diazepam) activate GABA receptors, producing sedative and anxiolytic effects by enhancing inhibitory neurotransmission
• In research, enzyme inhibitors and activators are used as tools to study the function and regulation of enzymes in biological processes
  • Examples include caspase inhibitors in apoptosis research, kinase inhibitors in cancer research, and proteasome inhibitors in protein degradation studies