Enzymes in Medicine

Physiological Control of Enzymes

Cellular Behavior Adaptation: Changes are required to cope with different situations depending on change frequency and time they have to adapt. This includes the ability of cells to adjust enzyme levels or activities in response to external signals, thereby maintaining homeostasis.

• Slow Control:

  • Duration: Hours to days.

  • Mechanism: Involves new enzyme synthesis or degradation of existing enzymes, which can significantly alter the overall enzyme concentration in the cell.

  • Triggers: Hormonal signals or long-term adaptations to changes in the environment, metabolic needs, or developmental stages.

• Rapid Control:

  • Duration: Milliseconds to minutes.

  • Mechanism: Regulation of existing enzymes through rapid processes such as inhibition or activation, allowing for immediate cellular responses.

  • Triggers: Hormonal signals or fluctuations in metabolite concentrations, including covalent modification (phosphorylation/dephosphorylation) and allosteric control that modifies enzyme efficiency.

Enzyme Inhibition

Enzyme Inhibitors: Chemicals that reduce the rate of enzymatic reactions, offering a critical regulatory mechanism in metabolic pathways.

• Types of Inhibition:

  • Irreversible Inhibition:

  • Permanently modifies the enzyme (often via covalent bonds), leading to a permanent loss of enzyme function.

  • Example: Heavy metals (e.g., mercury), which can bind irreversibly to cysteine residues in enzymes, disabling their catalytic activity.

  • Affects Vmax but not Km, indicating that the maximum rate of reaction decreases while substrate affinity remains unchanged.

  • Reversible Inhibition:

  • Binds through weak interactions and is not permanent, allowing for potential recovery of enzyme activity under certain conditions.

Irreversible Inhibition

Also called substrate poisons; tightly binding to enzymes, leading to decreased Vmax without affecting Km.
Example: Aspirin – Irreversibly inhibits cyclooxygenase (COX), which catalyzes the formation of prostaglandins associated with inflammation, serving as an anti-inflammatory and anti-platelet agent.

• Action Mechanism: Acetylates a serine residue in cyclooxygenase, blocking the active site and preventing the normal catalytic function of the enzyme, thus reducing inflammation and blood clotting.

Reversible Inhibitors

• Competitive Inhibition:

  • Competes with substrate for active site, structurally similar to the substrate, leading to an increase in Km due to decreased substrate accessibility; Vmax remains unchanged, indicating that the reaction can still reach its maximum rate if enough substrate is present.

  • Can be overcome by increasing substrate concentration.

  • Statins are an example of competitive inhibitors of HMG-CoA reductase, used to lower blood cholesterol levels by blocking the synthesis pathway.

• Uncompetitive Inhibition:

  • Binds only to the enzyme-substrate complex (ES), not the free enzyme (E), leading to both decreased Vmax and Km, enhancing substrate binding but reducing the overall reaction rate.

  • Example: Lithium, used for treating bipolar disorder, where it appears to exert its effects through modulation of various second messenger systems dependent on enzyme activity.

• Noncompetitive Inhibition:

  • Inhibitor binds to an allosteric site, preventing catalysis but not substrate binding, which means the substrate can still bind to the enzyme but conversion to product is inhibited.

  • Results in a decrease in Vmax while Km remains unchanged, indicating that increasing substrate concentration will not overcome the inhibition.

Diagnostic Application of Enzymes

Enzymes can verify and measure certain substances' presence and concentration, serving as important biomarkers in clinical diagnostics.

• Tissue Damage & Enzyme Release: In certain medical conditions, tissue damage leads to the release of specific enzymes into the plasma, indicating disease severity. For example, in myocardial infarction, elevated levels of creatine kinase (CK) isoforms in the blood can help confirm diagnosis.

• Example of Measurements:

  • Creatine Kinase (CK): Different isoforms (CK-MM, CK-BB, CK-MB) are employed to diagnose muscle injury or myocardial infarction, with specific patterns indicating the type and extent of tissue damage.

  • Liver Enzymes: Elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) indicate liver damage or dysfunction, and their ratio can provide diagnostic insights into the cause (e.g., differentiating between alcoholic and non-alcoholic fatty liver disease).

Measurement Techniques

Enzyme activity is measured instead of mass, using the unit of enzyme activity (U), which determines the amount that converts 1 micromole of substrate per minute under defined conditions, facilitating standardization in enzymatic assays.

• Glucose Measurement Example: The glucose oxidase assay visually demonstrates glucose concentration through color change, enabling a measurable endpoint for diagnostics and allowing for the monitoring of glucose levels in patients, particularly those with diabetes.

Summary

Enzymatic regulation is crucial for adapting to physiological changes, enabling organisms to respond swiftly to alterations in their environment or metabolic state. Inhibitors play a vital role in controlling enzyme activity for medical purposes, with various types of inhibitors being utilized therapeutically and having diverse effects based on their interaction with enzymes. Additionally, enzymes are valuable for both quantitative and qualitative diagnostics, signaling important health conditions through their activity levels and assisting in clinical decision-making.