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De novo fatty acid synthesis- A quick revision (part-1)
- De novo synthesis(from precursors)- Carbohydrates, protein, and other molecules obtained from diet in excess of the body’s need can be converted to fatty acids, which are stored as triglycerides
De novo fatty Acid Synthesis
- Fatty acids are synthesized by an extra mitochondrial system
- This system is present in many tissues, including liver, kidney, brain, lung, mammary gland, and adipose tissue.
- Acetyl-CoA is the immediate substrate, and free palmitate is the end product.
- Its cofactor requirements include NADPH, ATP, Mn2+, biotin, and HCO3– (as a source of CO2).
Sources of NADPH
- NADPH is involved as donor of reducing equivalents
- The oxidative reactions of the pentose phosphate pathway are the chief source of the hydrogen required for the reductive synthesis of fatty acids.
- Tissues specializing in active lipogenesis—i.e., liver, adipose tissue, and the lactating mammary gland—possess an active pentose phosphate pathway (Figure-1).
Figure-1- The reaction 1 and 2 are catalyzed by Glucose-6-P dehydrogenase and 6-phospho gluconate dehydrogenase respectively.
- Other sources of NADPH include the reaction that converts malate to pyruvate catalyzed by the “Malic enzyme” (NADP malate dehydrogenase) – figure-2 and the extra mitochondrial Isocitrate dehydrogenase reaction (probably not a substantial source, except in ruminants) figure-3.
Figure-2- It is a reversible reaction, pyruvate produced in the reaction reenters the mitochondrion for further utilization
Figure-3-There are three isoenzymes of Isocitrate dehydrogenase. One, which uses NAD+, is found only in mitochondria. The other two use NADP+ and are found in mitochondria and the cytosol. Respiratory chain-linked oxidation of Isocitrate proceeds almost completely through the NAD+-dependent enzyme.
Sources of Acetyl co A
- Acetyl co A is produced primarily from pyruvate, ketogenic amino acids, fatty acid oxidation and by alcohol metabolism
- It is a substrate of TCA cycle and a precursor for fatty acids, ketone bodies and sterols.
Enzymes and cofactors involved in the process of Fatty acid synthesis
Two main enzymes-
- Acetyl co A carboxylase
- Fatty acid Synthase
Both the enzymes are multienzyme complexes
Coenzymes and cofactors are-
Transportation of Acetyl co A (Figure-4)
- Fatty acid synthesis requires considerable amounts of acetyl-CoA
- Nearly all acetyl-CoA used in fatty acid synthesis is formed in mitochondria
- Acetyl co A has to move out from the mitochondria to the cytosol
- Acetate is shuttled out of mitochondria as citrate
- The mitochondrial inner membrane is impermeable to acetyl-CoA
- 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.
- In the cytosol, citrate is cleaved by citrate lyase regenerating acetyl-CoA.
Figure-4- Transportation of acetyl co A out of the mitochondria through citrate transporter
Fate of Oxalo acetate (Figure-5)
The other product of Citrate cleavage, oxaloacetate can be-
- Channeled towards glucose production
- Converted to malate by malate dehydrogenase
- Converted to Pyruvate by Malic enzyme, producing more NADPH, that can be used for fatty acid synthesis
- Pyruvate and Malate pass through special transporters present in the inner mitochondrial membrane
Figure-5- Fate of Oxalo acetate
To be continued …..
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