FATTY ACID BIOSYNTHESIS



FATTY ACID AND CHOLESTEROL BIOSYNTHESIS

WHERE: LIVER AND ADIPOSE TISSUE (HEPATOCYTES AND ADIPOCYTES

CYTOPLASM

WHEN: HIGH ENERGY CHARGE

REGULATION: PHOSPHORYLATION ( ACETYLCoA CARBOXYLASE

ALLOSTEARIC: AcCoA CARBOXYLASE (Phosphorylated form): ( CITRATE

GENE EXPRESSION: AcCoA CARBOXYLASE ( DURING STARVATION

SUMMARY:

8 AcCoA + 7ATP + 14 NADPH ( C16 SATURATED FA + 14 NADP + 7 ADP + 6 H2O + 8 CoA

PATHWAY:

1. MOVEMENT OF AcCoA FROM MITO TO CYTO

NADPH NADH

pyruvate ( malate ( OAA ( citrate ( AcCoA

H+ OAA

pyruvate citrate

AcCoA

i. ATP citrate lyase

citrate + ATP + CoA ( OAA + AcCoA + ADP + Pi

ii. Transfer of e- from NADH to NADP for biosynthesis: accounts for most of glycolytic NADH produced by glycolysis in fat cells. Produces approx 50% of required NADPH for FA synthesis. Rest from HMPS.

QUESTION: succinate [2,3 14C] ( 14C FA succinate [1,4 14C] does not. WHY NOT?

Acetyl CoA carboxylase

• AcCoA + ATP + CO2 malonylCoA + ADP + Pi

biotin

• inhibited by phosphorylation (mainly by AMPK. May also be phosphorylated (and inhibited) by PKA)

• dephosphorylated (and activated) by PP2A

• activated by insulin (by activating PP2A)

• allosteric control

• citrate activates phosphorylated form

• inhibited by palmitoyl CoA

• enzyme levels decrease as a result of fasting and increase upon refeeding

• enzyme levels increase on fat free diet

ACC1

• present in lipogenic tissues such as liver and adipose tissue

ACC2

• present in non-lipogenic tissue such as skeletal and heart muscle where it is thought to control FA oxidation; ie by making malonyl CoA to decrease activity of acyl-carnitine transferase. Mice lacking ACC2 have less body fat in spite if increased food intake - consistent with enhanced FA oxidation in these animals. Thus, malonyl-CoA produced by ACC-2 is exclusively involved in regulation of fatty acid oxidation (by inhibiting acycarnitine transferase I) , whereas that produced by ACC-1 is utilized in fatty acid synthesis. Phosphorylation of ACC, for example a result of activation of PKA by stress or exercise switches on fatty acid oxidation (via phosphorylation and inhibition of ACC-2 resulting in decreased malonyl CoA levels) while switching off fatty acid synthesis (via phosphorylation and inhibition of ACC-1).

ELONGATION AND INTRODUCTION OF DOUBLE BONDS.

• see text pages 484

• need to know: reaction catalysed by desaturase enzyme

• mammalian cells cannot introduce double bonds more than 9 carbons from carboxyl end. Therefore, linoleate (18:2Δ9,12) and α-linoleate (18:3Δ9,12,15), essential fatty acids, must be obtained from plants. These can however be elongated and additional double bonds added. See fig 16-7 for synthesis of arachidonoylCoA (20:4Δ5, 8, 11,14).

• Elongation

• occurs in both mitochondria and and E.R. In former, acetyl CoA is donor of 2 carbon units; in latter, malonyl CoA is donor.

CHOLESTEROL

see text p495

need to know:

• synthesis of HMGCoA occurs in cytoplasm (for KB synthesis it occurs in mito.)

• HMGCoA conversion to mevalonic acid and then to isopentyl pyrophosphate

• HMGCoA reductase - first committed step key regulatory enzyme

• controled by: phosphorylation, repression of transcription, and control of degradation.

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malate

cyto

mito

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