Pyruvate dehydrogenase (PDH) is an enzyme complex
consisting of three catalytic subunits, pyruvate dehydrogenase (E1, a
tetramer), dihydrolipoamide acyltransferase (E2, a monomer), and
dihydrolipoamide dehydrogenase (E3, a dimer), and two cofactors, thiamine
pyrophosphate and lipoic acid. A sixth component, previously named X-protein
and recently renamed E3-binding protein (E3-BP), has been found to be
mutated in a few patients. The enzyme complex converts pyruvate—after it
enters the mitochondria—into acetyl-CoA, one of two essential substrates
(oxaloacetate being the other) in the production of citrate. PDHCD therefore
leads to a limited production of citrate and because citrate is the first
substrate in the tricarboxylic acid (citric acid or Krebs) cycle, the cycle
is blocked and other metabolic pathways need to be stimulated to produce
acetyl-CoA. Nevertheless, the decreased level of energy substrates (ATP)
primarily affects the CNS, because brain acetyl-CoA is synthesized almost
exclusively from pyruvate. The most common deficiency involves the E1
subunit, a heterotetramer consisting of two alpha and two beta subunits with
the defect located on the alpha subunit (E1alpha), which contains several
serine phosphorylation sites and seems to be involved in the regulation of
the whole complex. Mutations in E2, E3, and E3-BP are less often the cause
for PDHCD. The enzyme defect causes more pyruvate to be metabolized to
lactate and leads to lactic acidosis.