Comprehensive Metabolism 6: TCA Cycle, Mitochondrial Shuttles, and
Glycogen Metabolism
TCA Cycle: Overview and Regulation
The Tricarboxylic Acid (TCA) cycle, also known as the Krebs cycle, is a fundamental
metabolic pathway where acetyl-CoA derived from carbohydrates, fats, and proteins is
oxidized to produce energy-rich molecules. The cycle produces NADH, FADH2, and GTP,
which are crucial for ATP generation in cellular respiration.
Unlike many metabolic pathways, the TCA cycle is not directly regulated by hormones such
as insulin, glucagon, or epinephrine. Instead, the cycle’s activity is tightly controlled by the
energy status of the cell.
Key enzymes—citrate synthase, isocitrate dehydrogenase (the rate-limiting enzyme), and
the E1 subunit of alpha-ketoglutarate dehydrogenase—are sensitive to intracellular energy
signals. High levels of ATP, NADH, and FADH2 indicate sufficient energy and inhibit these
enzymes, slowing the cycle. Conversely, elevated ADP, NAD+, and FAD stimulate their
activity, signaling an energy deficit.
Another critical factor is the availability of oxaloacetate (OAA), the molecule that combines
with acetyl-CoA to initiate the cycle. Adequate OAA levels ensure smooth progression of the
cycle.
NADH and FADH2 generated in the cycle donate electrons to the mitochondrial respiratory
chain, regenerating NAD+ and FAD, which are essential cofactors for continued TCA
function.
Anaplerotic Reactions: Maintaining TCA Cycle Intermediates
Intermediates of the TCA cycle serve as precursors for various biosynthetic pathways. For
example:
- Citrate is a starting material for fatty acid synthesis.
- Alpha-ketoglutarate is used to produce amino acids and neurotransmitters.
- Succinyl-CoA contributes to heme biosynthesis.
- Oxaloacetate is involved in amino acid synthesis and gluconeogenesis.
- Malate also participates in gluconeogenesis.
When these intermediates are diverted for such purposes, anaplerotic (filling-up) reactions
replenish the TCA cycle components to maintain its functionality.
Several amino acids can be catabolized into TCA intermediates, helping to refill the cycle:
five amino acids feed into alpha-ketoglutarate, four into succinyl-CoA, and others into
fumarate.
Glycogen Metabolism
TCA Cycle: Overview and Regulation
The Tricarboxylic Acid (TCA) cycle, also known as the Krebs cycle, is a fundamental
metabolic pathway where acetyl-CoA derived from carbohydrates, fats, and proteins is
oxidized to produce energy-rich molecules. The cycle produces NADH, FADH2, and GTP,
which are crucial for ATP generation in cellular respiration.
Unlike many metabolic pathways, the TCA cycle is not directly regulated by hormones such
as insulin, glucagon, or epinephrine. Instead, the cycle’s activity is tightly controlled by the
energy status of the cell.
Key enzymes—citrate synthase, isocitrate dehydrogenase (the rate-limiting enzyme), and
the E1 subunit of alpha-ketoglutarate dehydrogenase—are sensitive to intracellular energy
signals. High levels of ATP, NADH, and FADH2 indicate sufficient energy and inhibit these
enzymes, slowing the cycle. Conversely, elevated ADP, NAD+, and FAD stimulate their
activity, signaling an energy deficit.
Another critical factor is the availability of oxaloacetate (OAA), the molecule that combines
with acetyl-CoA to initiate the cycle. Adequate OAA levels ensure smooth progression of the
cycle.
NADH and FADH2 generated in the cycle donate electrons to the mitochondrial respiratory
chain, regenerating NAD+ and FAD, which are essential cofactors for continued TCA
function.
Anaplerotic Reactions: Maintaining TCA Cycle Intermediates
Intermediates of the TCA cycle serve as precursors for various biosynthetic pathways. For
example:
- Citrate is a starting material for fatty acid synthesis.
- Alpha-ketoglutarate is used to produce amino acids and neurotransmitters.
- Succinyl-CoA contributes to heme biosynthesis.
- Oxaloacetate is involved in amino acid synthesis and gluconeogenesis.
- Malate also participates in gluconeogenesis.
When these intermediates are diverted for such purposes, anaplerotic (filling-up) reactions
replenish the TCA cycle components to maintain its functionality.
Several amino acids can be catabolized into TCA intermediates, helping to refill the cycle:
five amino acids feed into alpha-ketoglutarate, four into succinyl-CoA, and others into
fumarate.
