rate limiting enzyme

Meaning: A rate-limiting enzyme catalyzes the slowest step of a metabolic pathway, so it largely sets the flux of the whole pathway. This step is usually essentially irreversible (large negative ΔG), which makes it a natural control point. Cells regulate it through allosteric effectors, feedback inhibition by the end product, covalent modification such as phosphorylation, and hormones. Examples: phosphofructokinase-1 (glycolysis), acetyl-CoA carboxylase (fatty acid synthesis), HMG-CoA reductase (cholesterol synthesis), glycogen phosphorylase (glycogen breakdown).

On the MCAT: A passage gives a pathway and an inhibitor or activator, then asks what happens to flux or to intermediates. Inhibiting the rate-limiting enzyme lowers flux, so substrates upstream of it accumulate and products downstream fall. Inhibiting a non-rate-limiting enzyme usually changes flux little. Know that PFK-1 is activated by AMP and fructose-2,6-bisphosphate and inhibited by ATP and citrate.

Common confusion: Rate-limiting does not mean fastest or most abundant. It is the slowest, lowest-capacity step, one that runs far from equilibrium. Reactions near equilibrium are readily reversible and seldom set the pace, and adding more of a non-rate-limiting enzyme does not speed the pathway. It is often, but not always, the first or committed step.