5.3 Enzyme inhibition and activation

Enzyme inhibition and activation are crucial for regulating metabolic processes. Different types of inhibition, like competitive and non-competitive, affect enzyme kinetics in unique ways. Understanding these mechanisms helps explain how drugs work and how cells control their metabolism.

Enzyme regulation involves activators and allosteric effectors that fine-tune enzyme activity. Feedback inhibition, where end products inhibit earlier enzymes in a pathway, maintains metabolic balance. These processes are vital for cellular homeostasis and adapting to changing conditions.

Types of Enzyme Inhibition

Competitive Inhibition

• Occurs when an inhibitor molecule binds to the active site of an enzyme, preventing substrate binding
• Inhibitor competes with the substrate for the active site
• Increasing substrate concentration can overcome competitive inhibition
• Inhibitor and substrate have similar structures (aspirin and acetylsalicylic acid)
• Competitive inhibitors increase the Km value without affecting the Vmax
• Lineweaver-Burk plot shows increased slope and x-intercept, but unchanged y-intercept

Non-Competitive and Uncompetitive Inhibition

• Non-competitive inhibition involves an inhibitor binding to an allosteric site, distinct from the active site
• Non-competitive inhibitors do not affect substrate binding but reduce the enzyme's catalytic efficiency
• Non-competitive inhibition decreases Vmax without changing Km (heavy metal ions like lead and mercury)
• Uncompetitive inhibition occurs when an inhibitor binds only to the enzyme-substrate complex
• Uncompetitive inhibitors decrease both Vmax and Km (some antibiotics like ampicillin)
• Lineweaver-Burk plot for non-competitive inhibition shows increased slope and y-intercept, but unchanged x-intercept
• Uncompetitive inhibition Lineweaver-Burk plot shows decreased slope, x-intercept, and y-intercept

Reversible and Irreversible Inhibition

• Reversible inhibition involves non-covalent interactions between the inhibitor and enzyme
• Reversible inhibitors can dissociate from the enzyme, allowing the enzyme to regain activity (most competitive, non-competitive, and uncompetitive inhibitors)
• Irreversible inhibition involves covalent bonding between the inhibitor and enzyme
• Irreversible inhibitors permanently inactivate the enzyme by altering its structure
• Irreversible inhibition cannot be overcome by increasing substrate concentration (pesticides and nerve agents like sarin gas)

Enzyme Regulation

Enzyme Activators and Allosteric Effectors

• Enzyme activators are molecules that increase the activity of enzymes
• Activators can bind to allosteric sites, causing conformational changes that enhance enzyme activity
• Allosteric effectors are molecules that bind to allosteric sites and modulate enzyme activity
• Positive allosteric effectors increase enzyme activity (calcium ions activating calmodulin)
• Negative allosteric effectors decrease enzyme activity (ATP inhibiting phosphofructokinase)
• Allosteric regulation allows for fine-tuning of enzymatic activity in response to cellular conditions

Feedback Inhibition and Metabolic Regulation

• Feedback inhibition is a regulatory mechanism where the end product of a metabolic pathway inhibits the activity of an earlier enzyme in the pathway
• Feedback inhibition helps maintain homeostasis by preventing the excessive accumulation of end products
• End products often act as allosteric inhibitors, binding to enzymes and reducing their activity
• Feedback inhibition allows for efficient resource allocation and prevents wasteful production of unnecessary metabolites (isoleucine inhibiting threonine deaminase in the biosynthesis pathway)
• Metabolic regulation through feedback inhibition is crucial for maintaining balanced cellular metabolism and responding to changing cellular needs (ATP and NADH levels regulating glycolysis and the citric acid cycle)