Metabolism › Principles of Metabolic Regulation

Pyruvate Dehydrogenase Complex Part II

Notes

Pyruvate Dehydrogenase Complex Part II

Sections

CLINICAL CORRELATIONS

PDC-based pathology

  • Neurological symptoms: brain cells rely on citric acid cycle for ATP
  • Muscular symptoms: dysfunctional PDC produces lactic acidosis

Thiamine deficiency

  • Cofactor of E1 of PDC
  • CNS problems: brain cells cannot produce ATP
  • Results in a syndrome called Wernicke's encephalopathy

Arsenic and mercury poisoning

  • Inhibit PDC
  • Van Gogh (arsenic-based paint) & "mad hatters" (mercury-treated animal furs)

PDC REGULATION

Allosteric inhibition

  • Acetyl CoA, major product of the PDC catalyzed reaction.
  • NADH, product of PDC and citric acid cycle.

Covalent modification

PDH kinase – adds an inhibitory phosphate to PDC

  • Activated by: ATP, Acetyl CoA and NADH
  • Inhibited by: CoA, Pyruvate and NAD+

PDH phosphatase – removes inhibitory phosphate from PDC

  • Activate PDC by removing inhibitory phosphate
  • Activated by insulin and free calcium in the muscle

Full-Length Text

  • Here we will learn some of the pathologies associated with the pyruvate dehydrogenase complex as well as how the complex is regulated.
    • This is part II of a two-part tutorial.
  • To begin, recall that deficiencies in any of the PDC's cofactors produce initial symptoms of neurological and muscular problems.

Why?

Let's start with the neurological symptoms:

  • Denote that brain cells rely on the citric acid cycle to produce ATP.
    • They cannot produce sufficient energy if the PDC does not produce acetyl CoA.

Let's learn an example of this.

  • As a clinical correlation, write that thiamine deficiency results in problems in the central nervous system.
    • Without thiamine, the PDC does not produce acetyl CoA and brain cells cannot produce ATP via the citric acid cycle. - Thiamine deficiency results in a syndrome called Wernicke's encephalopathy.

Poisons that affect the enzymes of the PDC can also inhibit neurological function.

  • Show that arsenic and mercury inhibit E2 of the PDC.
    • As an example, indicate that artist Vincent Van Gogh used an arsenic-based emerald green paint that is believed to have contributed to his mental illness.
    • In turn, indicate that the term "mad hatter" was coined for hat makers that used mercury nitrite to treat animal furs.

Now, let's learn the biochemical basis for the muscular symptoms.

  • Return to our first diagram.
    • Recall that under anaerobic conditions (no O2), pyruvate remains in the cytosol and gets shunted to lactate.
  • Now, denote that in muscle, a dysfunctional PDC produces lactic acidosis.
    • It shunts pyruvate to lactate and produces the muscle soreness that normally only occurs during intense exercise.
    • This also explains why brain cells, which more sensitive to acidosis, depend on cellular respiration for most of their energy.
  • Next, as a clinical correlation, write that congenital lactic acidosis can occur with a mutation in E1 of the PDC, which prevents acetyl CoA production, and shunts pyruvate to lactate.

Now that we understand the significance of PDC function, let's learn how it is regulated.

To begin, return to our table.

  • Denote that the PDC is regulated by two key mechanisms:
    • Allosteric regulation
    • Covalent modification.

We will illustrate both of these processes. Let's start with allosteric regulation.

  • First, draw a representative PDC.
  • Label it as "active."
  • Indicate that the following high-energy products are allosteric inhibitors of the PDC:
    • Acetyl CoA, which is the major product of the PDC catalyzed reaction.
    • NADH, which is produced by the PDC and the citric acid cycle.
  • This is a negative feedback mechanism in which the products of a reaction inhibit the enzyme.

Now, let's learn how the PDC is regulated by covalent modification.

  • Draw another representative PDC below the first one.
  • Add a phosphate group to it (specifically to E1 pyruvate dehydrogenase).
  • Label it inactive.
    • The PDC is inactivated when phosphorylated.
  • Next, draw an enzyme called PDH kinase (pyruvate dehydrogenase kinase).
  • Use arrows to show that it phosphorylates the active PDC to deactivate it.
  • Next, indicate that the following high-energy products activate PDH kinase:
    • ATP, which is produced by the citric acid cycle.
    • Acetyl CoA and NADH, which are also allosteric inhibitors of the active complex.
  • By activating PDH kinase, these products inactivate the PDH complex.
    • This feedback mechanism prevents the wasteful accumulation of high-energy products.
  • Illustrate that the following substrates inactivate PDH kinase:
    • CoA
    • Pyruvate
    • NAD+
    • They inactive PDH kinase and thus ACTIVATE PDC.
  • Finally, draw another enzyme called PDH phosphatase.
  • Use arrows to show that it removes the phosphate on an inactive PDH complex to activate it.
  • Indicate that this enzyme is stimulated by the following:
    • Insulin, which is released when blood glucose rises. We describe the metabolic role of insulin in detail elsewhere.
    • Free calcium in the muscle, which is an important mechanism for exercising muscle.
    • By activating PDH phosphatase, they activate the PDC.
  • Many textbooks also reference AMP as an allosteric activator of the PDC as well as an activator of PDH phosphatase.
    • This makes sense because AMP is also marker of ATP depletion (by a mechanism that we won't discuss here), and activates the PDC to promote ATP production.