Fatty Acid Synthesis Flashcards
What occurs in the liver in a well fed state?
In the well-fed state, in hepatocytes, insulin favors the pathways of: • Glycolysis • Glycogen synthesis • de novo synthesis of Fatty acids • Cholesterolsynthesis
Summarize the production of cytosolic acetyl CoA
Acetyl CoA formed in mitochondria cannot cross the mitochondrial membrane into the cytosol.
- Acetyl CoA has to be converted to citrate.
- At very high citrate levels, citrate leaves into the cytosol.
- Citrate lyase uses citrate in cytosol to form acetyl CoA and oxaloacetate
What are the sources of NADPH for fatty acid synthesis?
The NADPH required to provide reducing equivalents for FA biosynthesis is produce by:
- Pentose phosphate pathway
• Major pathway. - Malic enzyme (NADP+ dependent
malate dehydrogenase)
Describe the mechanism of de novo synthesis of fatty acid synthesis
The overall synthesis of palmitate from acetyl CoA requires NADPHs, ATPs and can be broken down into the following steps:
- Formation of Malonyl CoA by acetyl CoA carboxylase
- Synthesis of palmitate by fatty
acid synthase (FAS).
• Palmitate is a 16C saturated FA - Elongation of palmitate by elongases
- Desaturation by desaturases
Describe the modification of dietary and endogenous fatty acids
The palmitate produced by fatty acid synthase is typically modified (usually by addition of 2C units (from malonyl CoA) to the carboxylate end to give rise to the other fatty acids.
Fatty acids from dietary sources may be modified.
These modifications may include:
• Chain elongation primarily in the endoplamic reticulum to produce longer fatty acids:
• Elongation is by separate enzymes (different from FAS) known as elongases.
• The brain can produce very-long-chain fatty acids (VLCFAs 22C-24C e.g DHA) required for synthesis
of brain lipids.
• Desaturation, producing unsaturated fatty aci
Describe fatty acid denaturation system
Fattyacyl-CoAdesaturases introduce double bonds at positions 5, 6 or 9 in humans.
- The fatty acid desaturase system is an electron transport system in the ER that involves cytochrome b5 desaturase and NADPH- cytochrome b5 reductase
- Because linoleate and linolenate have double bonds beyond position 9, they are dietary essential fatty aci
What are essential fatty acids?
Mammals lack the enzymes that can desaturate beyond the Δ9 position in the hydrocarbon chain
- Plants, including algae, can desaturate beyond the Δ9 position (ie. Δ12, Δ15 desaturases)
- Hence dietary essential fatty acids
- Linoleate and
- α-linolenate
What is the significance of essential fatty acids?
Animals cannot convert a fatty acid of the ω6 family
to a fatty acid of the ω3 family.
Animals can use a fatty acid of the same family, elongate at the carboxyl end and desaturate between D9 and the carboxyl end.
Linoleic acid, omega 6—> arachidonic acid. Is used to form eicosanoids (prostaglandins, thromboxane, leukotrienes)
a-linoleic acid, omega 3—> EPA—> eicopentasoic acid, omega 3–> DHA, omega 3
- DHA in phospholipids of the brain - provides a microenvironment with high fluidity.
- DHA is important for brain functions and the visual cycle in the retina
Humans rely on exogenous sources of EPA & DHA in their diet to supplement the endogenously synthesized fatty acids
What is triacylglycerol?
Excess FA are stored as TAGs
✓Glycerol 3-phosphate is produced
in the liver and adipose tissue
✓TAGs may be synthesized in the liver, adipose tissue and in the intestinal mucosa
Is there a regulated step or enzyme?
Yes, Acetyl CoA carboxylase (ACC) is the rate-limiting enzyme in FA biosynthesis
Describe the carboxylation of acetyl CoA to form malonyl CoA in de novo synthesis of FA
The first committed step of fatty acid biosynthesis is catalyzed by Acetyl CoA carboxylase (ACC);
• ACC is the Rate-limiting enzyme for fatty acid synthesis
How is denovo fatty acid synthesis regulated?
How is acetyl CoA carboxylase regulated?
- Substrate availability: cytosolic acetyl CoA
- Allosteric: activated by citrate and inhibited by palmitoyl CoA
- Covalent: activated by dephosphorylation and inhibited by phosphorylation • Polymer is active, protomer is inactive
- Enzyme induction by insulin
- Does de novo synthesis of Fatty acids take place at high or low blood glucose concentration?
- It is activated at high blood glucose (insulin) and inhibited at low blood glucose (glucagon)
Describe short term allosteric regulation of Acetyl CoA Carboxylase in de novo synthesis of FA
Citrate shifts the equilibrium towards polymer formation using protomers - Activation
Palmitoyl CoA shifts the equilibrium towards protomer formation (depolymerization) - Inhibition
Describe the feedforward activatiion by citrate
Acetyl CoA Carboxylase (ACC):
Feed-forward activation by citrate
Citrate is only found in cytosol when mitochondrial citrate levels are very high.
- At this time, citrate has to be used for de-novo synthesis of fatty acid (or cholesterol synthesis).
- Once in the cytosol, citrate up- regulates ACC and leads to polymer formatiom
Describe feedback iinhibition of acetyl CoA
Acetyl CoA Carboxylase (ACC):
Feedback inhibition by fatty acyl CoA
• Free palmitates have detergent character !
• Free CoA is needed to form palmitoyl CoAs which
can be esterified.
- The free CoA pool in cytosol is limited and once fatty acyl CoAs are used to synthesize TAGs or phospholipids, then free CoA is generated again.
- An accumulation of long-chain fatty acyl CoA indicates that synthesis of TAGs is slow and that the pool of free CoA is getting low.
• Hence, fatty acid synthesis is slowed down, so that less palmitates are formed
