Fatty Acid Biosynthesis Flashcards
When are fatty acids synthesized?
Whenever excess calories is ingested
- Major source of C for synthesis of fatty acids is dietary carbohydrate
Which tissue are fatty acids synthesized?
Primarily in the liver
To a lesser extent in adipose tissue
What happens when excess dietary carbohydrate is consumed?
Glucose is converted to acetyl CoA
Acetyl CoA provides the 2C unit that condense in a series of reactions on the fatty acid synthase complex, producing palmitate that is converted to other fatty acids
Where is fatty acid synthase complex located?
In the cytosol (and therefore uses cytosolic acetyl-CoA)
What site are fatty acids synthesized?
Cytosol
What are the redox coenzymes involved in fatty acid synthesis?
NADP+/NADPH
What site are fatty acids degraded?
Mitochondria
What are the redox coenzymes involved in fatty acid degradation?
NAD+/NADH
Fatty acid occurs in the cytosol and starts with Acetyl Co-A. What is the problem associated with that?
- Most acetyl CoA is produced in the mitochondria
- Acetyl CoA is unable to travel through the mitochondrial membrane
Using mitochondrial derived Acetyl CoA in the cytosol
- Pyruvate produced in the cytosol then transferred to the mitochondria
- Pyruvate + pyruvate dehydrogenase –> Acetyl CoA
- Fatty acid (in the mitochondria) + beta oxidation –> acetyl CoA
- Acetyl CoA + oxaloacetate –> citrate
- Citrate crosses the mitochondrial membrane and enters the cytoplasm
- Citrate + ATP-citrate lyase –> acetyl CoA
- Or AA in the cytosol can be converted to acetyl coA
What is the rate limiting step in fatty acid synthesis?
conversion of acetyl CoA to Malonyl CoA by acetyl carboxylase
Reaction is irreversible
What is malonyl Co-A?
The immediate donor of the 2C units added to the growing fatty acid chain on the fatty acid synthase complex
How is malonyl Co-A synthesized?
Acetyl Co-A carboxylase adds a carboxyl group to acetyl Co-A in the presence of ATP and biotin
How is the rate limiting step of fatty acid synthesis regulated?
What stimulates it?
What inhibits it?
- It is less active when phosphorylated and more active when dephosphorylated.
- Insulin dephosphorylates it and therefore activates it
- Citrate stimulates it (feed forward regulation)
- Palmitoyl CoA inhibits it (feedback inhibition - product of the pathway inhibits it)
Describe the fatty acid synthase complex
- It contains 2 identical subunits in a head to tail arrangement
- Each subunit has seven catalytic activities
- The Acyl Carrier Protein (ACP) segment contains a phosphopantetheine
What is the prosthetic group in the ACP?
Phosphopantetheine
What is the purpose of Phosphopantetheine
The thiol group on phosphopantetheine reacts with malonyl CoA to form a thioester during fatty acid synthesis
What is the initial step in fatty acid biosynthesis?
- an acetyl moiety is transferred from acetyl Co-A to the ACP phosphopantetheine sulfhydryl group of one subunit
- The acetyl moiety is then transferred to the cysteinyl sulfhydryl group of the other subunit
- Malonyl moiety from malonyl-CoA then attaches to the ACP phosphopantetheine sulfhydryl group of first subunit
- The acetyl and malonyl moieties condense with the release of malonyl carboxyl group as CO2
- A 4C b-keto acyl chain is now attached to the ACP phosphopantetheinyl sulfhydryl group.
What is the second step in fatty acid biosynthesis?
- Reduction of the 4C keto group to an alcohol
- Removal of water to form a double bond
- Reduction of the double bond
What is the net result of the second step in fatty acid biosynthesis?
The original acetyl group is elongated by 2C
What provides the reducing equivalents for the reactions in the second step of fatty acid biosynthesis?
NADPH
How many subunits does fatty acid synthase has?
2 identical subunits
What two domains do fatty acid synthase have?
acyl carrier protein (ACP) domain - with a phosphophantetheine residue (P-SH)
Cysteinyl sulfhydryl group (Cys-SH)
Describe the synthesis of palmitate on the fatty acid synthase complex
- Acetyl moiety is transferred from acetyl-CoA to P-SH of one subunit & then to Cys-SH of the other subunit
- The acetyl & malonyl moieties condenses and malonyl carboxyl group is released as CO2
- Reduction of the 4C keto group to an alcohol
- Removal of water to form a double bond
- Reduction of the double bond
The C4 fatty acyl chain is transferred to Cys-SH and condenses with a malonyl group
The fatty acid is a dimer, how does this affect the release of palmitate?
Bc it is a dimer, there are two active sites which function simultaneously and independently both releasing palmitate
Where are fatty acids elongated?
In the ER
How are FA elongated?
- After synthesis on the fatty acid synthase complex, palmitate is activated, forming palmitoyl-CoA
2, Palmitoyl-CoA is elongated, two carbons at a time, by a series of reactions that occur in the ER
- Malonyl-CoA serves as the donor of the two carbon units (NADPH providing the reducing equivalents)
- The major elongation reaction that occurs in the body involves the conversion of palmitoyl CoA (C16) to stearyl-CoA (C18), involving a reduction step, removal of water and reduction of the double bond
5, Very long-chain fatty acids (C22 to C24) are also produced, particularly in the brain
Where does desaturation of fatty acids occur?
In the ER
What are required for desaturation of FA?
O2
NADH
cytochrome b5
What are the common desaturation reactions?
Palmitic acid to palmitoleic acid
Stearic acid to oleic acid
Polyunsaturation
Slide 17
Importance of linoleic acid
Slide 18
It is a precursor of arachidonic acid which is a precursor of prostaglandins
Linoleic acid + elongation + desaturation (x2) –> arachidonic acid –> prostaglandins
A molecule of palmitic acid, attached to carbon 1 of the glycerol moiety of a triacylglycerol, is ingested and digested. The fatty acid is stored in a fat cell and ultimately is oxidized to carbon dioxide and water in a muscle cell. Choose the molecular complex in the blood in which the palmitate residue is carried from the lumen of the gut to the surface of the gut epithelial cell.
A. VLDL B. Chylomicron C. Fatty acid–albumin complex D. Bile salt micelle #. LDL
Ch 33
