ketones

---

1. Name the four enzymes of ketogenesis in the correct order of the pathway (full names).

Thiolase → HMG-CoA synthase → HMG-CoA lyase → β-hydroxybutyrate dehydrogenase.

2. What is the specific, full name of the rate-limiting enzyme of ketogenesis, and what is its abbreviation?

3-Hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase).

3. Name the enzyme that converts HMG-CoA into acetoacetate, and list the two products of this reaction.

Enzyme: HMG-CoA lyase. Products: Acetoacetate and Acetyl-CoA.

4. What specific coenzyme/cofactor is required for the conversion of acetoacetate to β-hydroxybutyrate?

NADH + H⁺ (which gets oxidized to NAD⁺).

5. What specific coenzyme/cofactor is required for the reverse reaction (oxidizing β-hydroxybutyrate back to acetoacetate during ketolysis)?

NAD⁺ (which gets reduced to NADH + H⁺).

6. Name the two enzymes involved in ketolysis (utilization) in peripheral tissues, in order.

7. Succinyl-CoA:3-oxoacid CoA-transferase (thiophorase).
8. Thiolase.

9. In the activation step of ketolysis, acetoacetate reacts with succinyl-CoA. Name the products of this reaction.

Acetoacetyl-CoA and Succinate.

10. What specific coenzyme/cofactor is required for the thiolase step during ketolysis?

CoA-SH (Coenzyme A).

11. Which specific enzyme is missing in the liver that prevents it from utilizing ketone bodies?

Succinyl-CoA:3-oxoacid CoA-transferase (also called thiophorase).

12. Which enzyme is missing in the brain under normal, fed conditions that forces it to rely on glucose instead of ketone bodies?

The brain does not lack an enzyme; it lacks significant amounts of the enzyme succinyl-CoA:3-oxoacid CoA-transferase (thiophorase) under normal conditions, though it upregulates it during prolonged starvation. (Strictly, the blood-brain barrier limits transport, but biochemically, SCOT activity is low in the brain).

13. Name the specific transcription factor that is activated by fasting to increase the gene expression (activity of synthesis) of HMG-CoA synthase.

PPARα (Peroxisome proliferator-activated receptor alpha).

14. Name the specific allosteric inhibitor that indirectly shuts down ketogenesis by preventing fatty acids from entering the mitochondria.

Malonyl-CoA. (It inhibits CPT-1, which stops fatty acid entry, reducing acetyl-CoA substrate).

15. Name the specific enzyme that produces this allosteric inhibitor (malonyl-CoA).

Acetyl-CoA carboxylase (ACC).

16. How does glucagon regulate ketogenesis at the enzyme activity level (short-term), and how does it regulate it at the synthesis level (long-term)?

Activity: cAMP-dependent phosphorylation activates hormone-sensitive lipase (releasing fatty acids). Synthesis: Increases gene transcription of HMG-CoA synthase via PPARα.

17. How does insulin inhibit ketogenesis at the enzyme activity level?

It activates protein phosphatase, which dephosphorylates and inhibits hormone-sensitive lipase (stopping fatty acid release) and activates ACC (increasing malonyl-CoA, blocking CPT-1).

18. Why is the liver able to export ketone bodies to the blood, but unable to use them itself?

Because the liver lacks succinyl-CoA:3-oxoacid CoA-transferase (thiophorase); it cannot transfer CoA from succinyl-CoA to acetoacetate to form acetoacetyl-CoA.

19. If a patient has a genetic deficiency in succinyl-CoA:3-oxoacid CoA-transferase (SCOT), which specific metabolic step fails, and what builds up in their blood?

The activation of acetoacetate to acetoacetyl-CoA fails. Acetoacetate and β-hydroxybutyrate build up in the blood (ketoacidosis).

20. Explain exactly why β-oxidation is a prerequisite for ketogenesis in terms of the TCA cycle.

β-oxidation produces massive amounts of NADH and FADH₂. The high NADH/NAD⁺ ratio inhibits the TCA cycle (at isocitrate dehydrogenase), so acetyl-CoA cannot enter the TCA cycle and is instead diverted to HMG-CoA and ketogenesis.

21. Why does the oxidation of β-hydroxybutyrate yield 2.5 more ATP than acetoacetate?

Because β-hydroxybutyrate is already reduced. It must first be oxidized to acetoacetate by β-hydroxybutyrate dehydrogenase, producing 1 NADH (which yields 2.5 ATP) before entering ketolysis.

22. Draw the complete step-by-step reaction for the formation of HMG-CoA (include substrates, products, enzyme, and any cofactors).

Acetoacetyl-CoA + Acetyl-CoA + H₂O → (HMG-CoA synthase) → HMG-CoA + CoA-SH. No cofactors required.

23. What is the specific diagnostic marker for diabetic ketoacidosis that is detected on the breath, and what is the precursor molecule that forms it?

Acetone is the breath marker; it forms spontaneously from acetoacetate via decarboxylation.

24. A patient in prolonged starvation has high ketone bodies. Name the two carbons that are lost as CO₂ when acetoacetate spontaneously breaks down.

The carbon from the carboxyl group (-COO⁻) and the adjacent carbonyl carbon are lost, yielding acetone (CH₃-CO-CH₃) and CO₂.

25. Name the specific enzyme that allows the heart and kidneys to use ketone bodies, but is absent in the liver.

Succinyl-CoA:3-oxoacid CoA-transferase (thiophorase).

26. What happens to the succinate produced during ketolysis (activation step)?

Succinate enters the TCA cycle, where it is oxidized to fumarate, malate, and eventually oxaloacetate, helping to replenish TCA intermediates (anaplerosis).

27. If acetoacetate is being completely oxidized, exactly how many Acetyl-CoA molecules are produced and how many ATP are generated from these Acetyl-CoA molecules alone?

2 Acetyl-CoA molecules are produced. They generate 20 ATP (2 × 10 ATP per Acetyl-CoA).