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Fed state
Glycerol-P Glucose Glycerol
Triacylglycerol
Fatty acyl CoA Fatty acid
Malonyl CoA
Starved state
Glycerol-P Glucose Glycerol
Triacylglycerol
Fatty acyl CoA gluconeogenesis Pyruvate Acetyl CoA TCA cycle Malonyl CoA Fatty acid
FA biosynthesis and breakdown occur by different pathways and take place in different parts of the cell.
Biosynthesis requires malonyl-CoA
Pyruvate
Malonyl CoA
O -OOC-CH -C-S-CoA 2 =
Malonyl-CoA
HCO3-
+
Acetyl-CoA
Step 1.
Condensation of an activated acyl group and two carbons derived from malonyl-CoA
Step 2.
Step 3.
The elimination of water creates a double bond.
Step 4.
The double bond is reduced to form the corresponding saturated fatty acyl group.
When reaches 16 carbons, the product leaves the cycle. All the reactions in the synthetic process are catalyzed by a multi-enzyme complex, fatty acid synthase.
Step 1.
Condensation of the activated acetyl and malonyl groups to form acetoacetyl-ACP, catalyzed by b-ketoacylACP synthase.
Step 2.
Reduction. The acetoacetyl-ACP is reduced to bhydroxybutyryl-ACP, catalyzed by b-ketoacylACP reductase (needs NADPH + H+)
Step 3.
Dehydration to yield a double bond in the product, transD2-butenoyl-ACP, catalyzed by b-hydroxyacyl-ACP dehydratase.
Step 4.
Reduction of the double bond to form butyryl-ACP, catalyzed by enoyl-reductase. Another NADPH dependent reaction.
The overall reaction for the synthesis of palmitate from acetyl-CoA can be considered in two parts.
Part 1.
First, the formation of seven malonyl-CoA molecules:
7Acetyl-CoA + 7CO2 + 7ATP 7malonyl-CoA + 7ADP + 7Pi
Part 2.
Then the seven cycles of condensation and reduction
Acetyl-CoA + 7malonyl-CoA + 14NADPH + 14H+ palmitate + 7CO2 + 8CoA + 14NADP+ + 6H2O The biosynthesis of FAs requires acetyl-CoA and the input of energy in the form of ATP and reducing power of NADPH.
Location of FA synthesis
FA synthase complex is found exclusively in the cytosol. The location segregates synthetic processes from degradative reactions.
In hepatocytes: the [NADPH]/[NAD+] ratio is very high (~75) in the cytosol, furnishing a strongly reducing environment for the reductive synthesis of fatty acids and other biomolecules.
In hepatocytes and adipocytes, cytosolic NADPH is largely generated by the malic enzyme and by the pentose phosphate pathway.
Nearly all acetyl-CoA used in fatty acid synthesis is formed in mitochondria from pyruvate oxidation.
Cytosol site of acetate utilization Mitochondria site of acetate manufacture
Intra-mitochondrial acetyl-CoA first reacts with oxaloacetate to form citrate, in the TCA cycle catalyzed by citrate synthase.
Citrate then passes into the cytosol through the mitochondrial inner membrane on the citrate transporter.
The other product -oxaloacetate cannot return to the mitochondrial matrix directly. Instead, oxaloacetate is reduced to malate
Malate returns to the mitochondrial matrix on the malatea-ketoglutarate transporter in exchange for citrate.
O -OOC-CH -C-S-CoA 2 =
Malonyl-CoA
i. ii.
Fatty acyl groups are first activated by formation of fatty acyl-CoA molecules. then transferred to ester linkage with L-glycerol 3-phosphate.
R C O CH
O
H2 C O P O CH 2 O_ Phosphatidic Acid CH 2
CH 3 N CH 3
+
CH 3 Choline
Cytosolic NADPH is largely generated by the malic enzyme and by the pentose phosphate pathway. FA biosynthesis occurs in the cytosol FA biosynthesis is regulated by the activity of acetyl-CoA carboxylase Synthesized FA are either stored as TG or made into membrane lipids