Pyruvate carboxylase (PC) is a biotin-dependent
mitochondrial enzyme that converts pyruvate and CO2 to oxaloacetate,
one of two essential substrates (beside acetyl-CoA) in the production of
citrate. As a result of this enzyme defect, the citric acid cycle cannot
start because its first substrate (oxaloacetate) is missing or available
only in low concentrations. The accumulation of pyruvate, the metabolite
proximal to the enzyme defect, results in activation of alternate pyruvate
pathways with increased production of lactic acid and acetyl-CoA, which then
is converted into ketones because the tricarboxylic acid cycle pathway is
closed. Glucose production is affected because the now lacking oxaloacetate
is also involved in gluconeogenesis, which puts patients at risk for
hypoglycemia during fasting periods. Because the tricarboxylic acid cycle is
not available, energy delivery is entirely dependent on glycolysis. Compared
to the tricarboxylic acid cycle, however, glycolysis is highly inefficient
and results in the depletion of glucose. Oxaloacetate is also involved in
the generation of aspartate, which is required for the synthesis of
argininosuccinate, an intermediate metabolite in the urea cycle. This
results in decreased urea production and hyperammonemia. Furthermore,
oxaloacetate also participates in the malate-aspartate shuttle, which
represents the principal mechanism for the transport of reducing equivalents
from the cytoplasm into the mitochondria. The reduction of oxaloacetate to
malate by cytoplasmic malate dehydrogenase also results in oxidation of the
reduced form of nicotinamide adenine dinucleotide (NADH) to nicotinamide
adenine dinucleotidase (NAD+). Malate (carrying the electrons) then
enters the mitochondria, where mitochondrial malate dehydrogenase reverses
the previous action, resulting in conversion of malate to mitochondrial
oxaloacetate. During oxidative phosphorylation in the mitochondria, these
electrons of NADH get coupled to the ATP production. PC is also involved in
lipogenesis and the formation of some nonessential amino acids (aspartate,
glutamate).