MCAT Biochemistry Review

Chapter 9: Carbohydrate Metabolism I: Glycolysis, Glycogen, Gluconeogenesis, and the Pentose Phosphate Pathway

9.4 Pyruvate Dehydrogenase

Pyruvate from aerobic glycolysis enters mitochondria, where it may be converted to acetyl-CoA for entry into the citric acid cycle if ATP is needed, or for fatty acid synthesis if sufficient ATP is present. The pyruvate dehydrogenase complex (PDH) reaction, shown in Figure 9.6, is irreversible and cannot be used to convert acetyl-CoA to pyruvate or to glucose. Pyruvate dehydrogenase in the liver is activated by insulin, whereas in the nervous system, the enzyme is not responsive to hormones. This makes sense because high insulin levels signal to the liver that the individual is in a well-fed state; thus, the liver should not only burn glucose for energy, but shift the fatty acid equilibrium toward production and storage, rather than oxidation (fatty acid synthesis, discussed in Chapter 11 of MCAT Biochemistry Review, starts from citrate produced in the citric acid cycle).

Figure 9.6. Pyruvate Dehydrogenase

Pyruvate dehydrogenase is actually a complex of enzymes carrying out multiple reactions in succession. The details of each of these reactions are covered in Chapter 10 of MCAT Biochemistry Review, but an overview of the enzyme is provided here because it represents one of three possible fates of pyruvate: conversion to acetyl-CoA by PDH, conversion to lactate by lactate dehydrogenase, or conversion to oxaloacetate by pyruvate carboxylase.

REAL WORLD

A deficiency in thiamine (vitamin B1) can result in:

·        Beriberi, which is characterized by congestive heart failure or nerve damage.

·        Wernicke–Korsakoff syndrome, which is characterized by difficulty walking, uncoordinated eye movements, confusion, and memory disturbances.

Giving glucose to an individual with thiamine deficiency can lead to severe lactic acidosis and other metabolic derangements because pyruvate cannot be converted into acetyl-CoA without the vitamin. This is why thiamine must be given before an infusion of glucose in individuals suspected to have thiamine deficiency (such as alcoholics).

This large complex requires multiple cofactors and coenzymes, including thiamine pyrophosphatelipoic acid, CoA, FAD, and NAD+. Insufficient amounts of any of these cofactors or coenzymes can result in metabolic derangements.

Pyruvate dehydrogenase is inhibited by its product acetyl-CoA. This control is important in several contexts and should be considered along with pyruvate carboxylase, the other mitochondrial enzyme that uses pyruvate (introduced in gluconeogenesis, later in this chapter). Essentially, the buildup of acetyl-CoA (which happens during β-oxidation) causes a shift in metabolism: pyruvate is no longer converted into acetyl-CoA (to enter the citric acid cycle), but rather into oxaloacetate (to enter gluconeogenesis).

MCAT Concept Check 9.4:

Before you move on, assess your understanding of the material with these questions.

1.    What are the reactants of the pyruvate dehydrogenase complex? What are the products?

·        Reactants: 

·        Products: 

2.    How does acetyl-CoA affect PDH complex activity? Why?