The Citric Acid Cycle

TCA: Catabolic, Anabolic, or Amphibolic

Amphibolic

Where does the TCA cycle occur?

Mitochondrial matrix

TCA is a linear, cyclic, or spiral pathway?

Cyclic

What are the main products of TCA?

3 NADH

1 FADH₂

1 ATP

(and also 1 NADH from step 0)

Which step of TCA is NADH produced?

Step 3

Step 4

Step 8

Which step of TCA is FADH₂ produced?

Step 6

Which step is GTP/ATP produced?

Step 5

Step 0 of TCA

Conversion of pyruvate to Acetyl-CoA

Catalyst: Pyruvate dehydrogenase complex

Enzymes and Coenzymes of Step 0 of the TCA cycle

3 enzymes

• PDH

• TA

• DH

5 Coenzymes

• CoA

• TPP

• lipoic acid

• FAD

• NAD+

Main function of TPP

Decarboxylate

Main function of Lipoate/Lipoic Acid

Transfers acetyl group

Main functions of NAD+/FAD

Electron carriers

What are the three enzymes in the pyruvate dehydrogenase complex?

Pyruvate dehydrogenase (E₁)

Dihydrolipoyl transacetylase (E₂)

Dihydrolipoyl dehydrogenase (E₃)

What does E₁ form?

CO₂

What does E₂ form?

Acetyl-CoA

What does E₃ form?

NADH

Step 1 of TCA

Acetyl-CoA (2C) is added to oxaloacetate (4C) to make citrate (6C)

Enzyme: Citrate synthase

Byproducts: CoA

Step 2 of TCA

Citrate (6C) is isomerized into Isocitrate (6C)

Enzyme: Aconitase

Step 3 of TCA

Isocitrate (6C) is decarboxylated into a-ketoglutarate (5C)

Enzyme: Isocitrate dehydrogenase

Byproducts: NADH and CO₂

Step 4 of TCA

a-Ketoglutarate (5C) is decarboxylated into Succinyl-CoA (4C)

Enzyme: a-Ketoglutarate dehydrogenase complex

Byproducts: NADH and CO₂

Notes: Forms a high-energy thioester bond

Step 5 of TCA

Succinyl-CoA (4C) is converted into Succinate (4C)

Enzyme: Succinyl-CoA synthetase

Byproducts: GTP → converted to ATP, and CoA

Notes: Hydrolyzes the high-energy thioester bond (so that it could phosphorylate GDP)

Step 6 of TCA

Succinate is oxidized and turns into Fumarate

Enzyme: Succinate dehydrogenase

Byproducts: FADH₂

Notes: Succinate dehydrogenase is also complex II in the ETC

Step 7 of TCA

Fumarate is hydrated (add water across a double bond) into Malate

Enzyme: Fumarase

Step 8 of TCA

Malate is oxidized into Oxaloacetate

Enzyme: Malate dehydrogenase

Byproduct: NADH

What are the main control points/enzymes of TCA?

Step 1/Citrate synthase

Step 3/Isocitrate dehydrogenase

Step 4/a-Ketoglutarate dehydrogenase

Substrate availability as a control point

Higher concentration of substrate → TCA speeds up

Lower concentration of substrate → TCA slows down

Accumulating products as a control point

Higher concentration of products → TCA slows down

Lower concentration of products → TCA speeds up

Allosteric feedback as a control point

Molecule binds to enzyme at a location other than the active site → Inhibits or activates enzyme

Ca²⁺ activates which enzymes in the TCA cycle?

Isocitrate dehydrogenase and a-Ketoglutarate dehydrogenase complex

Which mutations in TCA cycle enzymes are linked to cancer, and what tumors do they cause?

Accumulation of fumarate or succinate disrupts cellular signaling

• Fumarase mutation - Smooth-muscle tumors & kidney cancer

• Succinate dehydrogenase mutation - Adrenal gland tumors

TCA relation to catabolism

The products of other pathways become intermediates in TCA

TCA relation to anabolism

TCA intermediates can be used for the biosynthesis for other molecules

Anaplerotic reaction

Reaction that replenishes a TCA intermediate