Biochemistry Lecture 19: TCA Cycle

TCA Cycle Overview

• The TCA cycle, also known as the citric acid cycle or Krebs cycle, describes a series of reactions that fully oxidize sugars, fats, and proteins.
• In 1937, Sir Hans Krebs summarized existing scientific knowledge to define this cycle, with contributions from other scientists like Albert Szent-Györgyi identifying related enzymes.

Function and Products

• The cycle processes one acetyl CoA to produce:
  • 2 molecules of CO2
  • 3 NADH
  • 1 FADH2
  • 1 GTP
• The NADH and FADH2 produced are used in the electron transport chain for ATP production.

Entry into the TCA Cycle

• Pyruvate, generated from glycolysis, must be converted to acetyl CoA via the pyruvate dehydrogenase complex.
• This conversion releases CO2 and produces NADH.

Pyruvate Dehydrogenase Complex

• Catalyzes oxidative decarboxylation of pyruvate to form acetyl-CoA, found in bacterial cytosol and mitochondrial matrix.
• Composed of three subunits (E1, E2, E3); mammalian cells have a total of 294 protein subunits.

TCA Cycle Reactions

• Reaction 1: Acetyl CoA combines with oxaloacetate to form citrate, catalyzed by citrate synthase.
• Reaction 2: Aconitase converts citrate to D-isocitrate via an intermediate, cis-aconitate.
• Reaction 3: Isocitrate dehydrogenase converts isocitrate to α-ketoglutarate through oxidative decarboxylation, linking to nitrogen metabolism and glutamate synthesis.

Additional Enzymatic Steps

• Fumarase catalyzes the hydration of fumarate to form L-malate.
• Malate dehydrogenase regenerates oxaloacetate, producing NADH in the final step of the TCA cycle.

Biosynthetic Pathway Precursors

• The TCA cycle supplies intermediates for various biosynthetic pathways:
  • Fatty acids synthesized from citrate.
  • Amino acids derived from α-ketoglutarate via transamination.
  • Purine and pyrimidine nucleotides synthesized from α-ketoglutarate and oxaloacetate.
  • Gluconeogenesis conversion of oxaloacetate to glucose.
  • Succinyl CoA involved in heme group synthesis.

Subcellular Localization

• In mammalian cells, TCA cycle enzymes are located in the mitochondrial matrix.
• In prokaryotic cells (e.g., E. coli), all enzymes function in the cytosol.
• Pyruvate enters mitochondria through a symporter, consuming energy during transport.

Clinical Relevance

• Understanding the TCA cycle is vital for comprehending cellular metabolism and energy production, with implications in biochemistry, physiology, and medicine.