Enzyme inhibition: What does a classical uncompetitive inhibitor do?

Introduction:
Uncompetitive inhibition is a distinct inhibition mode in which the inhibitor interacts only with the enzyme–substrate complex (ES). Understanding this mechanism clarifies characteristic kinetic signatures and how Vmax and Km are affected together.

Given Data / Assumptions:

• Classical Michaelis–Menten steady-state conditions.
• The inhibitor (I) binds only to ES, not to free E.
• Binding is reversible for the classical definition.

Concept / Approach:
When I binds ES to form ESI, the complex is catalytically incompetent, reducing the effective ES available for product formation. Because I binding depends on ES, inhibition becomes more pronounced at higher [S].

Step-by-Step Solution:
1) Scheme: E + S ⇌ ES → E + P; ES + I ⇌ ESI (inactive).2) Kinetic consequence: Both apparent Vmax and apparent Km decrease (parallel lines in Lineweaver–Burk plots).3) Rationale: Removing ES (via ESI) lowers Vmax, and shifting the equilibrium E + S → ES to maintain ES lowers Km (increased apparent affinity).

Verification / Alternative check:
Diagnostic: Parallel double-reciprocal plots at varying inhibitor concentrations; Eadie–Hofstee lines shift with unchanged slope/Vmax/Km ratios characteristic of uncompetitive inhibition.

Why Other Options Are Wrong:

• (b) Irreversible binding is not classical uncompetitive; that would be mechanism-based inactivation.
• (c) An “active” ESI would not be inhibitory.
• (d) Irreversible binding that increases rate contradicts inhibition.
• (e) Binding only to free E describes competitive inhibition.

Common Pitfalls:
Confusing uncompetitive with noncompetitive or mixed inhibition; forgetting that uncompetitive inhibition requires substrate-bound enzyme.

Final Answer:
Binds reversibly to the enzyme–substrate (ES) complex to yield an inactive ESI complex.