MBIO 2710 / Topic 9: Fatty Acid Synthesis

FA synthesis is literally the opposite of FA breakdown… but w/ 3 differences. What are these differences?

> β-oxi occurs in mitochondria, while FA synth occurs in cytoplasm.

> Citrate required as an activating molecule for FA synth.

> CO₂ is a necessary reactant as part of activation step.

Why is the difference that in location for FA anabolism and catabolism important?

> Anabolism & catabolism both want AcCoA but in diff ways.

> Catabolism wants to break down FAs to make AcCoA.

> Anabolism wants to use AcCoa.

Compartmentalization is key.

How does citrate affect acetyl‑CoA carboxylase (ACC) activity?

> Monomeric ACC: floating single units don’t work efficiently.

> Citrate binding: promotes polymerization → forms multimeric ACC.

> Result: ASs are close together → E works much faster.

Why is involving of CO₂ with ACC the RDS?

Fixing CO₂ from its free gaseous form is entropically unfavourable.

How does the ACP function differently in prokaryotes vs eukaryotes?

> Prokaryotes: ACP is a separate protein that shuttles the growing FA chain from E to E.

> Eukaryotes: ACP is a domain of the large multienzyme complex (FAS), shuttling the growing FA chain from AS to AS within the same complex.

What is the cost per round including startup for FA synthesis?

> 2 NADPH.

> 1 ATP.

> 2 AcCoA (1 MalonylCoA & 1 AcCoA used only once)

Why do we need a separate reaction to convert citrate back to AcCoA?

> Citrate synthesis reaction is irreversible.

> Need to make a new rxn to return it back to AcCoA.

Why can’t citrate synthase just run in reverse?

Energetics

> Forward rxn highly exergonic (‑ΔG) b/c of thioester hydrolysis.

> Reverse rxn would be extremely unfavourable w/o ATP hydrolysis.

Enzyme specificity

> Citrate synthase specific for forward rxn only.

> Need ATP‑citrate lyase (uses ATP) for citrate → AcCoA.

What are the four ways that citrate regulates metabolism?

> Activates energy storage in carbs via gluconeogenesis via F16BP.

> Inhibits energy release in carbs via glycolysis F16BP.

> Activates energy storage in lipids via ACC polymerization.

> AcCoA source via anaplerotic rxn.

What are the three levels of control in fatty acid synthesis?

> Regulation of enzymatic activity (fast).

> Transcriptional control (slow).

> Hormonal control (systemic).

How does enzymatic activity regulate fatty acid synthesis?

> Enzymes can be turned on/off immediately by covalent mods or by allostery.

> Ensures quick response to changes in physiological & environmental conditions.

(e.g. ACC activated by dephosphorylation & inhibited by phosphorylation)

How does transcriptional control regulate fatty acid synthesis?

> Gene expression regulated to how much enzyme made.

> Changes the amount of ACC, FA synthase, etc.

> Slower b/c requires transcription and translation.

(e.g. high-carb diet = gene expression for fat synthesis enzymes)

How does hormonal control regulate fatty acid synthesis?

> Physiology response via hormones.

> Adjusts enzymatic activity and substrate availability.

> Integrates signals from multiple organs.

(e.g. insulin = energy storage; epinephrine = energy release)

Specifically, how does epinephrine & insulin regulate fatty acid synthesis via hormonal control?

> Epi formed during periods of fight-or-flight activates PK via AC & cAMP → PK activates pancreatic lipases & β-oxi.

> Ins formed during periods of high blood glucose levels → activates fatty acid synthesis.

How does cholesterol inhibit HMG-CoA reductase?

> Cholesterol (or downstream sterol metabolites) inhibit HMG-CoA reductase via proteolysis for long-term control.

> Prevents overproduction of mevalonate → terpene products.

How does insulin & glucagon regulate HMG-CoA reductase?

> Insulin activates via dephosphorylation → energy storage → promote cholesterol & steroid synthesis.

> Glucagon inhibits via phosphporylation→ energy release → shut downs aforementioned synthesis.

What is the general flow of cholesterol metabolism?

Acetyl-CoA → cholesterol → fatty acyl cholesterol → LDL → LDLRs → HDL → bile acid excretion

What are the three key regulation points of cholesterol metabolism?

> HMG-CoA reductase. Regulated by cholesterol, insulin, glucagon, and transcription.

> acylCoA-cholesterol acyl transferase. Regulated via activation by cholesterol & high levels of it.

> LDL receptor. Synthesis regulated via how much intracellular cholesterol is present.

(e.g. for LDL receptor synthesis: cell “full” → downregulates LDLR synthesis → stops pulling lDL and vice versa if cell “hungry”)

How do LDL & LDL receptors regulate blood cholesterol?

> LDL delivers cholesterol from liver → tissues.

> LDL receptors on tissues pull LDL out of blood.

> More receptors = more LDL cleared from blood; fewer receptors = LDL accumulates → increase blood cholesterol.

How do HDL & LDL receptors regulate blood cholesterol?

> HDL removes excess cholesterol from tissues → back to liver.

> When tissue cholesterol goes down, cells upregulate LDL receptors = need more cholesterol.

> Upregulated receptors → tissues pull more LDL from blood → more LDL cleared from blood.

Why is cholesterol control LDL → LDLR → HDL?

> LDL delivers cholesterol.

> LDLRs regulate how much is cleared vs. left in blood.

> HDL clean excess & support receptor activity.

What are bile acids & how do they connect to cholesterol levels?

> Made from cholesterol in liver; help digest fats

> Major way to excrete cholesterol (some lost in feces)

> ↑ Bile acid synthesis → ↓ liver cholesterol → ↑ LDL receptors → more LDL cleared from blood.

How does HDL, at the molecular lvl, clean up your arteries?

Contains acyl transferases which convert cholesterol to cholesterol esters → transports cholesterol back to liver → bile salts.

> What is Familial Hypercholesterolemia (FH)?

> How does FH affect LDL receptors in heterozygotes?

> How does FH affect LDL receptors in homozygotes?

> A genetic defect causing fewer LDL receptors → ↑ LDL in blood

> 1 defective gene → ~50% normal LDL receptor levels

> 2 defective genes → very few LDL receptors

What is the consequence of fewer LDL receptors in FH?

LDL accumulates in blood → plaque formation → atherosclerosis = buildup of fatty plaques inside arteries.

How do statins (e.g., compactin/lovastatin) lower cholesterol?

> Inhibit HMG-CoA reductase → ↓ liver cholesterol synthesis

> Liver cholesterol drops → upregulates LDL receptors

> Pulls in more LDL (dietary/circulating cholesterol) from blood → ↓ blood cholesterol

i.e. Liver is forced to use circulating cholesterol (from diet or existing LDL) instead of making its own.

How do bile acid resins work?

> Resins bind bile salts in intestine → prevent reabsorption → bile salts excreted.

> Liver bile acid pool goes down.

How do bile acid resins lower blood cholesterol?

> Bind bile salts in intestine → stop recycling → ↑ excretion in feces

> Liver bile salts pool ↓ → must make more using cholesterol

> Liver cholesterol ↓ → upregulates LDL receptors → pulls more LDL from blood

> Overall: more cholesterol leaves body as bile salts → ↓ blood cholesterol