The Citric Acid Cyle

Biomedical Importance

• Also known as Krebs Cycle.

• Krebs proposed the original name TCA (Tricarboxylic acid)

Functions of the Citric acid cycle
1. The final common oxidative pathway that oxidizes
acetyl CoA to CO2.
2. The source of reduced co-enzymes that provide
the substrate for the respiratory chain.
3. The link between catabolic and anabolic pathways
(amphibolic role).
4. Provides precursors for synthesis of amino acids
and nucleotides.
5. Components of the cycle have a direct or indirect
controlling effects on key enzymes of other
pathways.
Significance of Citric acid cycle
1. Complete oxidation of acetyl CoA
2. ATP generation
3. Final common oxidative pathway
4. Integration of major metabolic pathways
5. Excess carbohydrates are converted as neutral fat
6. Carbon skeletons of amino acids finally enter the citric acid cycle
7. Amphibolic pathway
8. Anaplerotic role.
STEPS of CITRIC ACID CYCLE

• Occurs in the Mitochondrial matrix.

• It involves the combination of a two-carbon acetyl-CoA from

oxidation of fuels, with a four-carbon oxaloacetate to produce a
six-carbon tricarboxylic acid, citrate.
• In the reactions that follow, the two carbons are oxidized to CO2
and oxaloacetate is regenerated and recycled.

• Oxaloacetate is considered to play a catalytic role in citric acid

cycle.
Reactions of the cycle preparatory step

• Acetyl-CoA enters the cycle and is completely oxidized.

• All the enzymes of citric acid cycle are located inside the
mitochondria.
ATP Generating steps in TCA Cycle
3 NADH generated
3 * 2.5 = 7.5 ATP
1 FADH2 generated
1 * 1.5 = 1.5 ATP
1 GTP generated
= 1 ATP
Per turn of cycle = 10 ATP are generated
Role of Vitamins in TCA cycle
Thiamine • Coenzyme for alpha-ketoglutarate
(TPP) dehydrogenase

Riboflavin • Coenzyme for succinate

(FAD) dehydrogenase

• electron acceptor for isocitrate

Niacin dehydrogenase, alpha ketoglutarate
(NAD+) dehydrogenase, malate
dehydrogenase

Pantothenic • For the synthesis of CoA used by

acid Acetyl CoA and Succinyl CoA
Regulation of Citric Acid cycle
• Inhibited by ATP, NADH, Acetyl
Citrate synthase
CoA and Succinyl CoA

Isocitrate • Activated by ADP, and inhibited

dehydrogenase by ATP and NADH

Alpha-
• Inhibited by succinyl CoA and
ketoglutarate
NADH
dehydrogenase

Availability of ADP
Integration of Major Metabolic Pathway
1. Carbohydrates: are metabolized through glycolytic pathway to
pyruvate, then converted to acetyl CoA which enters TCA.
2. Fatty acids: through beta oxidation, are broken down to acetyl
CoA and then enters this cycle.
3. Glucogenic amino acids after transamination enter at some or
other points in this cycle.
4. Ketogenic amino acids are converted into acetyl CoA.
Fat is burned on the wick of carbohydrates

• The oil in a lamp by itself cannot be lighted; the flame needs a

wick

• Oxidation of fat need the help of oxaloacetate.

• Major source of oxaloacetate is pyruvate which is a carbohydrate

oxidation product.
Excess Carbohydrates are converted to
Neutral Fat
• Excess calories are deposited as fat in adipose tissue.

• The pathway is glucose to pyruvate to acetyl CoA to fatty acid.

• Fat cannot be converted to glucose because pyruvate

dehydrogenase reaction (pyruvate to acetyl CoA) is an absolutely
irreversible step.

• No Net synthesis of Carbohydrate from Fat.

 Anabolic Reactions
• Oxaloacetate is the precursor of aspartate.
• Α-ketoglutarate can be converted
toglutamate.
• Succinyl-CoA is used for synthesis of
heme.
• Mitochondrial citrate is transported to
cytoplasm, where it is cleaved into acetyl
CoA as the starting point of fatty acid
synthesis.
Efflux of TCA cycle intermediates
Anaplerotic Role of TCA cycle

• Anaplerosis is the incorporation of carbon. Plerosis is the Greek

word for regeneration.

• The synthetic reactions depletes the intermediates of TCA cycle.

• CAC will stop unless the intermediates are replenished.

• The reactions concerned to replenish or to fill up the
intermediated of citric acid cycle are called anaplerotic
reactions or anaplerosis.
Influx of TCA cycle intermediates
Inhibitors of TCA cycle

Aconitase • Inhibited by Fluoro-acetate

Alpha
ketoglutarate • Inhibited by Arsenite
dehydrogenase

Succinate
dehydrogenase
• Inhibited by Malonate
Metabolic Defects Related to Krebs Cycle

• Some of the defects are found to affect the operation of TCA cycle.
• Pyruvate dehydrogenase – oxidizes pyruvate to Acetyl-CoA.
Defects will result to Lactic acidosis and neurological disorders.
• Pyruvate carboxylase – regenerates oxaloacetate. Defects lead to
lactic acidosis and hyperammonemia.
Thank you