Block 3 Fatty Acid Synthesis Flashcards
What are the substrates for lipogenesis?
Carbs, AAs, EtOH; glucose provides glycerol backbone
When and where does lipogenesis occur? What stimulates it?
In fed state, stim by insulin (greater with high carb vs. high fat diet), in liver, adipose depot, lactating mammary gland
What are the major FAs synth in the body?
Palmitate (16:0) (except mam gland makes C8-12 also), elongate to stearate (18:0) or shorten to myristate (14:0)
What is the product of stearate and palmitate desaturation?
Stearate (18:0) to oleate (18:1); palmitate (16:0) to palmitoleate (16:1)
Where does FA synth occur? What is the activated donor? What are the required cofactors? What is the product?
In cytosol, FA + ACP, + malonyl-ACP using NADPH + H+ -> elongated to palmitic acid (C16)
What is the first step of FA synthesis?
Formation of malonyl-CoA using biotin to bind intermediate of rxn from AcCoA, using AcCoA carboxylase (spont DC later drives condensation)
What are acetyl- and malonyl-transferase? What’s the next enzyme in FA synth?
Attach AcCoA or malCoA to ACP, then react with acyl-malonyl ACP condensing enzyme to become acetoacetyl-CoA
What are the three steps following condensation to aaCoA in FA synth?
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)
What is the last enzyme and reaction of FA synth?
Thioesterase hydrolyzes C16-acyl-ACP to palmitate and ACP
Describe the makeup of FA synthase.
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)
How is FA synthase regulated?
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)
What are the required substrates for synthesis of palmitate?
8 mol AcCoA, 14 NADPH, 7 ATP
What is a citrate carrier? How does it work?
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
What are the two sources of cellular NADPH?
Oxidative branch of PPP, malic enzyme pathway (transhydrogenase pathway) using malate DH and malic enzyme
What is the major regulated step of FA synth? How is it regulated?
AcCoA carboxylase, by P and allosterically by local metabolites
How does conformation of AcCoA-C change in active vs. inactive forms?
Active: multimeric filamentous complexes, protein P-ase 2A
Inactive: dissociation to monomeric form (protomer), AMP-activated PK
How does citrate affect AcCoA carboxylase?
Partially activates carboxylase when bound
What activates PP (act AcCoA C) and PKA (inh AcCoA C)?
PP: insulin
PKA: AMP, glucagon, epi; inh by ATP
How are FA >C16 elongated?
Enzymes on cytosolic face ER membrane add malonyl-CoA (2C), condensation driven by malCoA decarboxylation
How are FA desaturated?
Introduce double bonds at specific positions using NADH & O2; not for all, so some PUFAs dietary essential (C12)
How do FA oxidation and synthesis differ?
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
What are the major regulatory steps of FA breakdown, synth? How are both regulated?
Breakdown: transport of AcCoA into mito
Synth: AcCoA carboxylase
Response to energy state of cell, availability of precursors for anabolism, globally by hormones
How does FA synth inhibit FA B-ox?
Malonyl-CoA (product 1st rxn) inhibits carnitine-acyl-transferase-1 (Fa-CoA -> Fa-carnitine)
How are synthesized FAs stored? What is the pathway?
Liver, adipocytes as TAG; Gly-3P (from DHAP) + acylCoA -> 1-acyl-gly-3P (lyso-PA) + acylCoA -> PA - PO4 -> 1,2-DAG + acylCoA -> TAG
How does FA storage differ in liver and small intestine?
Liver: can P and recycle free glycerol
Small: reacylates 2-MAG