Download fatty acid synthesis

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
cyto pyruvate  malate  OAA  citrate  AcCoA
mito
H+
OAA
pyruvate
malate
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 (18:29,12) and -linoleate (18:39,12,15),
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 (20:45, 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.