Energy noncompetitive inhibition

However, this case is extremely rare in nature. An example is the noncompetitive inhibition of phenyllactate versus an amide substrate for carboxypeptidase. In this case, the initial collision complex of substrate and enzyme has an interaction with the terminal carboxyl and the arginine on the enzyme, as well as with the rest of the polypeptide chain, but the aromatic group of the terminal amino add is not in Ae specificity pocket. For it to seat itself requires twisting of the amide bond, which is the rate limiting and energy requiring step of the reaction. Thus, phenyllactate can slip into this pocket and prevent proper seating of the substrate. With an ester substrate, where rotation of the ester bond is not hindered, the collision complex has the specificity pocket filled, and phenyllactate is a competitive inhibitor (Auld Holmquist, 1974). 

Pyriminil toxicity occurs primarily because it inhibits NADH ubiquinone oxidoreductase activity of complex I in mammalian mitochondria resulting in preferential toxicity to high-energy-demanding cells such as nerves and pancreatic jS-cells. However, pyriminil may also act as a nicotinamide antagonist and interfere with the synthesis of NADH/NADPH, furthering neural and jS-cell toxicity. Inhibition of mitochondrial respiration in nerves causes somatic, autonomic, and central nervous system neuropathies while inhibition in jS-cell causes an immediate, irreversible insulin-dependent diabetes mellitus condition. Pyriminil also acts as a noncompetitive inhibitor of rat acetylcholinesterase. 

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