Serine Dehydratase - Inhibitors

Inhibitors

According to the series of assays performed by Cleland (1967), the linear rate of pyruvate formation at various concentrations of inhibitors demonstrated that L-cysteine and D-serine competitively inhibit the enzyme SDH. The reason that SDH activity is inhibited by L-cysteine is because an inorganic sulfur is created from L-Cysteine via Cystine Desulfrase and sulfur-containing groups are known to promote inhibition. In addition, researchers have shown that L-threonine competitively inhibits Serine Dehydratase as well.

Moreover, insulin is known to accelerate glycolysis and repress induction of liver serine dehydratase in adult diabetic rats. Studies have been conducted to show insulin causes a 40-50% inhibition of the induction serine dehydratase by glucagon in hepatocytes of rats. Studies have also shown that insulin and epinephrine inhibit Serine Dehydratase activity by inhibiting transcription of the SDH gene in the hepatocytes. Similarly, increasing levels of glucagon, increase the activity of SDH because this hormone up-regulates the SDH enzyme. This makes sense in the context of gluconeogenesis. The main role of SDH is to create pyruvate that can be converted into free glucose. And glucagon gives the signal to up-regulate gluconeogenesis and increase the amount of free glucose in the blood.

Homocysteine, a compound that SDH combines with Serine to create cystathionine, also noncompetitively inhibits the action of SDH. Studies have shown that homocysteine reacts with SDH's PLP coenzyme to create a complex. This complex is devoid of coenzyme activity and SDH is not able to function (See Enzyme Mechanism Section). In general, homocysteine is an amino acid and metabolite of methionine; increased levels of homocysteine can lead to homocystinuria(see section Disease Relevance).