Dirty Biochemistry: Ketone Body Synthesis

Overview

• Ketone Body Synthesis: Formation of ketone bodies from fatty acids in the liver.
  • Occurs when glucose is unavailable.
  • Happens in starvation or if TCA (Krebs) cycle is dysfunctional.
• States of Occurrence:
  • Starvation
  • Diabetic Ketoacidosis (DKA)
  • Chronic Alcoholism

Process of Ketone Body Synthesis

1. Starting Point: Acetyl CoA
   • Begins with two Acetyl CoA molecules.
2. Formation of Acetoacetyl CoA:
   • Enzyme: Thiolase
3. Conversion to HMG-CoA:
   • Enzyme: HMG-CoA Synthase
   • Requires an additional Acetyl CoA
4. Conversion to Acetoacetate:
   • Enzyme: HMG-CoA Lyase
   • Acetoacetate is the first ketone body formed.
5. Pathways from Acetoacetate:
   • To Acetone: Enzyme Acetoacetate Decarboxylase
   • To Beta-hydroxybutyrate: Enzyme Beta-hydroxybutyrate Dehydrogenase

Ketone Bodies

• Types: Acetoacetate, Acetone, Beta-hydroxybutyrate
• Stepwise Formation: Similar to catecholamine synthesis.

Conditions for Ketone Synthesis

• Starvation:
  • Pathophysiology: Gluconeogenesis depletes oxaloacetate.
  • Prevents TCA cycle from functioning.
  • Requires alternative fuel (ketones).
• Diabetic Ketoacidosis (DKA):
  • Mechanism: Low insulin, high glucagon causes gluconeogenesis, depleting oxaloacetate.
  • Similar to starvation in ketone formation.
• Alcoholism:
  • Mechanism: Increased NADH/NAD+ ratio (due to ethanol metabolism).
  • Prevents oxaloacetate formation, hindering TCA cycle.

Key Enzymes & Mnemonics

• Rate-Limiting Enzyme: HMG-CoA Synthase
  • Mnemonic: "H OMG I'm starving" to remember ketone synthesis in starvation using HMG-CoA synthase.
• Red Blood Cells: Cannot use ketones as fuel.
  • Mnemonic: RBCs = Really Basic Cells.
• Urine Ketone Dips: Detect only acetoacetate.
  • Mnemonic: "A-peet-oacetate" for urine detection.
• Fruity Breath: Acetone exhaled gives fruity smell, important in diagnosis.

Summary

• Pathway: Understand the biochemical pathway and how ketone bodies are formed.
• Rate-Limiting Enzyme: HMG-CoA Synthase is crucial.
• Conditions: Recognize conditions causing ketone synthesis.
• Key Takeaway: Oxaloacetate depletion is central to ketone body formation whether via starvation, DKA, or alcoholism due to impaired TCA cycle function.