TOPIC 2: FATTY ACID METABOLISM (deep theory)

Why fatty acids yield more ATP per carbon than glucose

They are more reduced (more C–H bonds = more electrons to feed the ETC). Palmitate (C16) ≈ 106 ATP vs glucose (C6) ≈ 30–32

The rate-limiting step of β-oxidation (not the chemistry — the entry)

CPT I (carnitine palmitoyltransferase I) — controls entry into the mitochondrion; inhibited by malonyl-CoA

The 4 repeating β-oxidation steps in order (mnemonic "Ox–Hy–Ox–Th")

Oxidation (acyl-CoA dehydrogenase, FAD) → Hydration (enoyl-CoA hydratase) → Oxidation (β-hydroxyacyl-CoA dehydrogenase, NAD⁺) → Thiolysis (thiolase, releases acetyl-CoA)

Why fatty acid activation "costs 2 ATP" from one ATP

Acyl-CoA synthetase splits ATP → AMP + PPᵢ; PPᵢ is then hydrolysed to 2 Pᵢ, so two phosphoanhydride bonds are lost

The single molecule that reciprocally couples FA synthesis and oxidation

Malonyl-CoA: made by the first step of synthesis (ACC), directly inhibits CPT I (first step of oxidation)

Rate-limiting/committed step of FA synthesis

Acetyl-CoA carboxylase (ACC): acetyl-CoA → malonyl-CoA; cofactor biotin

Four ways oxidation and synthesis are kept apart

Compartment (matrix vs cytosol), carrier (CoA vs ACP), cofactor (NAD⁺/FAD vs NADPH), and the malonyl-CoA gate on CPT I

Where does the NADPH for FA synthesis come from

Pentose phosphate pathway (mainly) + malic enzyme

How acetyl-CoA gets from matrix to cytosol for synthesis

Citrate shuttle: citrate exported, cleaved by ATP-citrate lyase back to acetyl-CoA + OAA

Why even-chain fatty acids can't make net glucose in animals

β-oxidation yields only acetyl-CoA, which enters the TCA cycle but adds no net carbon to OAA (2 C in, 2 C lost as CO₂). No net gluconeogenic substrate

The exception: odd-chain fatty acids

Final propionyl-CoA → methylmalonyl-CoA → succinyl-CoA (needs biotin + B₁₂) — a glucogenic entry

When and why ketone bodies form

Starvation: OAA drained to gluconeogenesis, acetyl-CoA can't enter the TCA cycle, liver converts excess acetyl-CoA → acetoacetate/β-hydroxybutyrate. "Fat burns in the flame of carbohydrate"

ACC allosteric activator and its logic

Citrate — signals abundant acetyl-CoA + ATP, so promotes fat storage; also drives ACC polymerisation to the active filament

Hormonal control of ACC

Insulin activates (dephosphorylation); glucagon/epinephrine and AMPK inhibit (phosphorylation)