Biomedical Sciences – Metabolism and Glycogen Regulation
TCA Cycle: Recap and Regulation
The tricarboxylic acid (TCA) cycle oxidizes acetyl-CoA to generate high-energy molecules
NADH, FADH2, and GTP (which can be converted to ATP). This cycle plays a central role in
cellular energy metabolism.
Interestingly, the TCA cycle is not directly regulated by hormones such as insulin, glucagon,
or epinephrine. Instead, its activity is controlled by the cell’s energy status.
Key enzymes like citrate synthase, isocitrate dehydrogenase (the rate-limiting step), and the
E1 subunit of alpha-ketoglutarate dehydrogenase respond to energy signals: they are
inhibited by high levels of ATP, NADH, and FADH2 (indicating high energy availability), and
activated by ADP, NAD+, and FAD (signals of low energy).
The availability of oxaloacetate (OAA), a TCA cycle intermediate, is also a crucial factor
influencing cycle throughput.
Anaplerotic Reactions: Replenishing TCA Intermediates
TCA cycle intermediates are often diverted for biosynthetic purposes, such as:
- Citrate used in fatty acid synthesis
- Alpha-ketoglutarate used for amino acid and neurotransmitter production
- Succinyl-CoA involved in heme synthesis
- Oxaloacetate (OAA) serving as a precursor for amino acids and gluconeogenesis
- Malate participating in gluconeogenesis
Because these intermediates are withdrawn from the cycle, anaplerotic reactions are
essential to replenish them and maintain continuous TCA cycle activity.
Amino acids serve as important anaplerotic sources: five amino acids can be converted to
alpha-ketoglutarate, four to succinyl-CoA, and several to fumarate.
Pyruvate Carboxylase: An Important Anaplerotic Enzyme
Pyruvate carboxylase, located in mitochondria, catalyzes the ATP-dependent carboxylation
of pyruvate to oxaloacetate (OAA), replenishing TCA intermediates.
Biotin, a B-vitamin cofactor, plays a key role as a carrier of activated CO2 (carboxy-biotin)
during this reaction.
This reaction is also critical for gluconeogenesis, linking carbohydrate and energy
metabolism.
TCA Cycle: Recap and Regulation
The tricarboxylic acid (TCA) cycle oxidizes acetyl-CoA to generate high-energy molecules
NADH, FADH2, and GTP (which can be converted to ATP). This cycle plays a central role in
cellular energy metabolism.
Interestingly, the TCA cycle is not directly regulated by hormones such as insulin, glucagon,
or epinephrine. Instead, its activity is controlled by the cell’s energy status.
Key enzymes like citrate synthase, isocitrate dehydrogenase (the rate-limiting step), and the
E1 subunit of alpha-ketoglutarate dehydrogenase respond to energy signals: they are
inhibited by high levels of ATP, NADH, and FADH2 (indicating high energy availability), and
activated by ADP, NAD+, and FAD (signals of low energy).
The availability of oxaloacetate (OAA), a TCA cycle intermediate, is also a crucial factor
influencing cycle throughput.
Anaplerotic Reactions: Replenishing TCA Intermediates
TCA cycle intermediates are often diverted for biosynthetic purposes, such as:
- Citrate used in fatty acid synthesis
- Alpha-ketoglutarate used for amino acid and neurotransmitter production
- Succinyl-CoA involved in heme synthesis
- Oxaloacetate (OAA) serving as a precursor for amino acids and gluconeogenesis
- Malate participating in gluconeogenesis
Because these intermediates are withdrawn from the cycle, anaplerotic reactions are
essential to replenish them and maintain continuous TCA cycle activity.
Amino acids serve as important anaplerotic sources: five amino acids can be converted to
alpha-ketoglutarate, four to succinyl-CoA, and several to fumarate.
Pyruvate Carboxylase: An Important Anaplerotic Enzyme
Pyruvate carboxylase, located in mitochondria, catalyzes the ATP-dependent carboxylation
of pyruvate to oxaloacetate (OAA), replenishing TCA intermediates.
Biotin, a B-vitamin cofactor, plays a key role as a carrier of activated CO2 (carboxy-biotin)
during this reaction.
This reaction is also critical for gluconeogenesis, linking carbohydrate and energy
metabolism.
