Block 3 Fatty Acid Synthesis

Question 1

What are the substrates for lipogenesis?

Answer 1

Carbs, AAs, EtOH; glucose provides glycerol backbone

Question 2

When and where does lipogenesis occur? What stimulates it?

Answer 2

In fed state, stim by insulin (greater with high carb vs. high fat diet), in liver, adipose depot, lactating mammary gland

Question 3

What are the major FAs synth in the body?

Answer 3

Palmitate (16:0) (except mam gland makes C8-12 also), elongate to stearate (18:0) or shorten to myristate (14:0)

Question 4

What is the product of stearate and palmitate desaturation?

Answer 4

Stearate (18:0) to oleate (18:1); palmitate (16:0) to palmitoleate (16:1)

Question 5

Where does FA synth occur? What is the activated donor? What are the required cofactors? What is the product?

Answer 5

In cytosol, FA + ACP, + malonyl-ACP using NADPH + H+ -> elongated to palmitic acid (C16)

Question 6

What is the first step of FA synthesis?

Answer 6

Formation of malonyl-CoA using biotin to bind intermediate of rxn from AcCoA, using AcCoA carboxylase (spont DC later drives condensation)

Question 7

What are acetyl- and malonyl-transferase? What’s the next enzyme in FA synth?

Answer 7

Attach AcCoA or malCoA to ACP, then react with acyl-malonyl ACP condensing enzyme to become acetoacetyl-CoA

Question 8

What are the three steps following condensation to aaCoA in FA synth?

Answer 8

1) aaACP + NADPH reduction to D3HB-ACP
2) dehydration to crotonyl-ACP
3) + NADPH reduction to butyryl-ACP (now substrate for further condensation with malCoA)

Question 9

What is the last enzyme and reaction of FA synth?

Answer 9

Thioesterase hydrolyzes C16-acyl-ACP to palmitate and ACP

Question 10

Describe the makeup of FA synthase.

Answer 10

Multienzyme complex: malCoA transferase, b-ketoacyl red (ACP linker), b-hydroxyacyl-dehydratase, enoyl red, AcCoA transacetylase, b-ketoacyl synthase (cys link, condenser), ACP with P-pantetheine linker to all active sites)

Question 11

How is FA synthase regulated?

Answer 11

Insulin stimulates FAS expression via USF and SREBP (suppressed by PUFA in liver), exp of SREBP-1 (and FAS) in fat inh by leptin (produced by fat in response to excess fat storage)

Question 12

What are the required substrates for synthesis of palmitate?

Answer 12

8 mol AcCoA, 14 NADPH, 7 ATP

Question 13

What is a citrate carrier? How does it work?

Answer 13

Moves AcCoA from mito to cytosol by converting to citrate with OAA. In cytosol, back to OAA + malate DH -> malate + malic enzyme -> NADPH + CO2 + pyr -> into mito -> OAA by PDC

Question 14

What are the two sources of cellular NADPH?

Answer 14

Oxidative branch of PPP, malic enzyme pathway (transhydrogenase pathway) using malate DH and malic enzyme

Question 15

What is the major regulated step of FA synth? How is it regulated?

Answer 15

AcCoA carboxylase, by P and allosterically by local metabolites

Question 16

How does conformation of AcCoA-C change in active vs. inactive forms?

Answer 16

Active: multimeric filamentous complexes, protein P-ase 2A
Inactive: dissociation to monomeric form (protomer), AMP-activated PK

Question 17

How does citrate affect AcCoA carboxylase?

Answer 17

Partially activates carboxylase when bound

Question 18

What activates PP (act AcCoA C) and PKA (inh AcCoA C)?

Answer 18

PP: insulin
PKA: AMP, glucagon, epi; inh by ATP

Question 19

How are FA >C16 elongated?

Answer 19

Enzymes on cytosolic face ER membrane add malonyl-CoA (2C), condensation driven by malCoA decarboxylation

Question 20

How are FA desaturated?

Answer 20

Introduce double bonds at specific positions using NADH & O2; not for all, so some PUFAs dietary essential (C12)

Question 21

How do FA oxidation and synthesis differ?

Answer 21

B-ox: in mito, FAD and NAD+ are e- acceptor, L-BHA group, C2 is AcCoA
Synth: in cytoplasm, ACP is acyl group carrier, NADPH is e- donor, uses D-BHA group, C2 is malCoA

Question 22

What are the major regulatory steps of FA breakdown, synth? How are both regulated?

Answer 22

Breakdown: transport of AcCoA into mito
Synth: AcCoA carboxylase
Response to energy state of cell, availability of precursors for anabolism, globally by hormones

Question 23

How does FA synth inhibit FA B-ox?

Answer 23

Malonyl-CoA (product 1st rxn) inhibits carnitine-acyl-transferase-1 (Fa-CoA -> Fa-carnitine)

Question 24

How are synthesized FAs stored? What is the pathway?

Answer 24

Liver, adipocytes as TAG; Gly-3P (from DHAP) + acylCoA -> 1-acyl-gly-3P (lyso-PA) + acylCoA -> PA - PO4 -> 1,2-DAG + acylCoA -> TAG

Question 25

How does FA storage differ in liver and small intestine?

Answer 25

Liver: can P and recycle free glycerol
Small: reacylates 2-MAG