Citric Acid Cycle

Citric Acid Cycle

Acetyl CoA Metabolism

Mitochondria: Structure and Function

1. Outer Mitochondrial Membrane:

(a) a barrier to molecules w/ MW greater than 10,000

2. Intermembrane Space

(a) houses enzymes specific to mitochondria

3. Inner Mitochondrial Membrane

(a) allows diffusion only of small (<100 MW) uncharged molecules

(b) allows for very specific control of the flow of biomolecules into and out of mitochondrian
(c) Cristae- indentations that increase the surface area of the membrane
(d) contains: the components of electron transport, enzymes for the citric acid cycle

4. Matrix

Contains enzymes for:

(a) pyruvate decarboxylation
(b) citric acid cycle
(c) fatty acid b-oxidation
(d) ketone body synthesis (liver)
(e) ketone oxidation (other tissues)
(f) some amino acid metabolism

(g) some gluconeogenesis

Cytosol: Glycolysis and most of Gluconeogenesis

Metabolic Fates of Pyruvate:

Metabolism of Acetyl CoA:

Pyruvate Dehydrogenase Complex (PDH): a multi-enzyme complex

Pyruvate + CoA + NAD⁺------------> CO₂+ Acetyl CoA + NADH + H⁺

Thiamine diphosphate (TDP):

Lipoate:

Coenzyme A:

Acetyl CoA:

STEP 1a: Pyruvate binds to E₁.

STEP 1b: Pyruvate reacts with TDP causing the release of CO₂ and formation of TDP- CH(OH)CH₃
STEP 2a: Lipoate is acetylated by TDP-CH(OH)CH₃ with oxidation of the alcohol to a keto group and reduction of the lipoate disulfide bond. TDP is regenerated.
STEP 2b: Acetylated lipoate reacts with Coenzyme A (CoASH) to form acetyl CoA and reduce lipoate to dihydrolipoate.
STEP 3a: Reduced lipoate is oxidized by FAD, with the production of FADH₂.

STEP 3b: FAD is regenerated by the oxidation of FADH₂ by NAD⁺, yielding NADH.

PDH in Action

Regulation:

Feedback Inhibition: - Acetyl CoA and NADH

What goes IN: Pyruvate, CoASH, NAD⁺

What comes OUT: Acetyl CoA, NADH, CO₂

Citric Acid Cycle / Tricarboxylic Acid Cycle (TCA Cycle):

[1] Citrate Synthase: exergonic, spontaneous; condenses acetyl CoA and oxaloacetate. The CoA produced is used to produce acetyl CoA via PDH.

[2] Isocitrate Dehydrogenase: oxidation-reduction reaction, first site for NADH production.

[3] a-Ketoglutarate Dehydrogenase: oxidation-reduction reaction, second NADH is produced. Feedback inhibited by succinyl CoA.

[4] Succinyl CoA Synthetase: substrate level phosphorylation. GTP + ADP <---> GDP + ATP

[5] Succinate Dehydrogenase: oxidation-reduction reaction, FADH₂ is produced.

[6] Malate Dehydrogenase: oxidation-reduction reaction, third NADH is produced.

Energy Production:

1 NADH = 3 ATP

1 GTP = 1 ATP
1 FADH₂ = 2 ATP

3 ATP Pyruvate Dehydrogenase (from NADH)

3 ATP Isocitrate Dehydrogenase (from NADH)

3 ATP a-Ketoglutarate Dehydrogenase (from NADH)

1 ATP Succinyl CoA Synthetase (from GTP)

2 ATP Succinic Dehydrogenase (from FADH2)

3 ATP Malate Dehydrogenase (from NADH)

Total: 15 ATP (12 ATP / Turn of TCA Cycle)

Remember we get 2 Acetyl CoA molecules for each Glucose molecule so the Grand Total is: 30 ATP!

Regulation:

Enzyme	Inhibition	Stimulation
Citrate Synthase	Succinyl CoA, ATP
Isocitrate DH	NADH, ATP	ADP
a-KG DH	Succinyl CoA, NADH, GTP

Learning the Intermediate and Enzyme Names and/or the Strcutures