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Pyruvate Dehydrogenase Complex Part I

Notes

Pyruvate Dehydrogenase Complex Part I

Sections

PYRUVATE DEHYDROGENASE COMPLEX (PDC)

  • Pyruvate + CoA + NAD+ --> Acetyl CoA + CO2 + NADH
  • Located in mitochondrial matrix
  • Irreversible reaction

PDC ENZYMES

E1, pyruvate dehydrogenase/pyruvate decarboxylase

  • Catalyzes pyruvate to acetyl (releases CO2)
  • Cofactor: thiamine pyrophosphate (Vitamin B1)

E2, dihydrolipoyl transacetylase

  • Attaches CoA to acetyl
  • Cofactor: lipoic acid (not vitamin-derived) & coenzyme A (pantothenic acid/vitamin B5)

E3, dihydrolipoyl dehydrogenase

  • Reduces NAD+ to NADH
  • Cofactor: NAD+ (niacin/vitamin B3) & FAD (riboflavin/vitamin B2)

Lipoic acid is only cofactor for PDC that is not vitamin-derived

CLINICAL CORRELATION

PDC-based pathology

  • Deficiencies in vitamins or PDC cofactors produce initial neurological/muscular symptoms

Full-Length Text

  • Here we will learn about the pyruvate dehydrogenase complex, which links glycolysis to the citric acid cycle under aerobic conditions.
    • This is part I of a two-part tutorial.
    • In part II we will learn how the complex is regulated, and introduce some of the pathologies associated with it.
  • To begin, start a table to learn the three key enzymes in the pyruvate dehydrogenase complex.
  • Denote that they are:
    • E1, pyruvate dehydrogenase (E1 is also called pyruvate carboxylase decarboxylase, we use these names interchangeably).
    • E2, dihydrolipoyl transacetylase.
    • E3, dihydrolipoyl dehydrogenase.
  • Multiple copies of each of these enzymes aggregate to form the pyruvate dehydrogenase complex.

To begin, let's illustrate where the pyruvate dehydrogenase complex (PDC) is located in the cell.

  • First, draw the outer membrane of a cell.
  • Label the cytosol.
  • Draw the double-membrane of the mitochondrion within the cytosol as follows:
    • Draw an outer membrane.
    • Draw an inner membrane with invaginations.
    • Label the space between the membranes as the intermembrane space.
    • Label the space within the inner membrane as the matrix.
  • Now, show that glycolysis occurs in the cytosol: it produces 2 molecules of pyruvate from glucose (draw one for simplicity).
  • Show that pyruvate, is actively transported into the mitochondrial matrix.
  • Indicate that this only occurs under aerobic conditions (O2 present).
  • Show that under anaerobic conditions (no O2), pyruvate remains in the cytosol: pyruvate gets shunted to the cytosolic enzyme lactate dehydrogenase, which catalyzes the formation of lactate.
    • Yeast and other bacteria can also produce ethanol from pyruvate.

Now, let's illustrate the conversion of pyruvate to acetyl CoA.

  • Draw acetyl CoA as a two-carbon acetyl-group bound to coenzyme A.
  • Next, indicate that the pyruvate dehydrogenase complex (PDC) catalyzes the conversion of pyruvate to acetyl CoA.
  • Indicate that the reaction is irreversible.
    • Pyruvate is now committed to this pathway.
  • Show that the third carbon in pyruvate is released as carbon dioxide.
    • This is the first carbon dioxide produced by cellular respiration.
  • Show that one NAD+ is reduced to form NADH.
    • Each PDC subunit produces a different product in this reaction, which we describe shortly.
  • Finally, draw a circle of arrows to illustrate the citric acid cycle, which also occurs in the matrix.
  • Show that Acetyl CoA enters the cycle.
    • Thus, the PDC bridges glycolysis with cellular respiration in the presence of oxygen.

Now, let's illustrate the PDC enzymes and their function in more detail.

  • Draw three shapes to represent the three relevant enzymes: E1, E2 and E3.

Each of these enzymes performs a different reaction; let's learn them now.

  • Write their enzymatic activities as follows:
    • E1 (pyruvate dehydrogenase) is a decarboxylase. Recall that E1 is often called pyruvate carboxylase decarboxylase.
    • E2 (dihydrolipoyl transacetylase) is a transacetylase.
    • E3 (dihydrolipoyl dehydrogenase) is a dehydrogenase.

Now, let's illustrate each of their reactions.

  • Show that E1 produces CO2 from pyruvate.
    • Thus, pyruvate loses a carbon molecule here.
  • Show that E2 adds coenzyme A to the remaining two-carbon acetyl group to produce Acetyl CoA.
  • Finally, illustrate that E3 reduces NAD+ to NADH.

Note that each of these enzymes requires a cofactor to facilitate these reactions.

  • Draw a chart to list them.
    • E1 requires thiamine pyrophosphate.
    • E2 requires lipoic acid and coenzyme A.
    • E3 requires NAD+ and FAD.
  • We can remember them with the following mnemonic: 1 Teacher, 2 Loud Classrooms, 3 Needy Freshmen.
  • The PDC cannot function without these cofactors, and many of them are vitamin-derived.
  • Highlight the following cofactors to indicate that they are vitamin-derived:
    • Thiamin pyrophosphate, which is from Vitamin B1.
    • Coenzyme A, which is from pantothenic acid or Vitamin B5.
    • NAD+, which is from niacin for Vitamin B3.
    • FAD, which is from riboflavin or Vitamin B2.
  • Lipoic acid is not vitamin-derived and made in the body.
  • As a clinical correlation, denote that PDC based pathology includes deficiencies in any of these vitamins or cofactors, which can produce initial symptoms of neurological and muscular problems.
    • We will learn why in part II.