Lipid Synthesis Flashcards
What happens to excess acetyl CoA?
Beta oxidation breaks fatty acid into acetyl CoA, which enter Kreb cycle and electron transport chain to produce energy.
Excess acetyl CoA
- Enter adipocytes and are stored
- Converted into ketone bodies
Ketone bodies
- Produced by the liver
- Excreted into the bloodstream when needed, such as starvation conditions when glucose level is low for the brain
- Accumulate to high levels during fasting or starvation conditions
- Produced when oxaloacetate supply cannot keep pace with fatty acid breakdown
- Oxaloacetate binds to acetyl-CoA to produce citrate, but when Oxaloacetate, citrate is low, acetyl-CoA will be in excess, hence converted into ketone bodies, gluconeogenesis will be triggered when glucose is low, which requires Oxaloacetate, hence it becomes insufficient as oxaloacetate is needed for both Kreb cycle and gluconeogenesis.
Why oxaloacetate supply cannot keep up with fatty acid breakdown?
Oxaloacetate is needed in both gluconeogenesis and Krebs cycle.
So during fasting, glucose level is low and gluconeogenesis will be triggered and this process needs oxaloacetate.
But Oxaloacetate is also needed to sustain Krebs cycle.
These 2 processes will therefore ‘use’ Oxaloacetate and leads to excess acetyl CoA -> ketone bodies.
Why we can get fat on a carbohydrate rich diet?
Carbohydrates can be converted to fat
Glucose produces acetyl CoA and it can be used to make fatty acid, hence a person can get fat on a carbohydrate rich diet.
Structure of acetyl CoA
C double bonded to O, CH3 and S-Coenzyme A, 3 chemical groups in total. 2 carbon molecule.
How are fatty acids are synthesized from acetyl-CoA
Condensation of acetyl-CoA to form long hydrocarbon chains
Fatty acid synthesis occurs in the cytosol of liver cells, adipocytes and mammary glands during lactation.
Without malonyl ACP and acetyl ACP, fatty acid synthesis cannot occur.
Formation of malonyl CoA from acetyl CoA
Acetyl CoA is carboxylated to Malonyl CoA via acetyl CoA carboxylase, in the process HCO3- bicarbonate ion and ATP is converted into Phosphate ion and ADP.
Malonyl CoA chemical structure is similar to Acetyl CoA, but its H3C is converted to CH2-COO-.
This reaction is non-reversible
ACP is acyl carrier protein
Formation of acetyl ACP from acetyl CoA
Acetyl CoA is converted to acetyl ACP via acetyl transacylase, where ACP is used and CoA is released.
In this reaction, S-CoA is replaced with ACP. Acetyl ACP is just acetyl CoA without S-CoA and replaced with ACP
Formation of malonyl ACP from malonyl CoA
Malonyl CoA is converted to malonyl ACP via malonyl transacylase, where ACP is used and CoA is released.
In this reaction, CoA is replaced with ACP, malonyl CoA is just malonyl CoA without S-CoA and replaced with ACP
Fatty acid synthesis process
Acetyl ACP (2carbon molecule) + Malonyl ACP(3carbon molecule)
Malonyl ACP is a donor for 2 carbon for every addition of 2 carbon.
Condensation reaction where 1 CO2 is being released in each reaction.
ACP is reusable, as it is a carrier protein.
Hydroxy ACP
NADPH is a coenzyme for the synthesis of fatty acids , also used commonly in synthetic pathways.
Every step has a specific enzyme but we call them collectively as fatty acid synthase
Steps of fatty acid synthesis
Acetyl ACP + Malonyl ACP-> Acetoacetyl-ACP via a condensation reaction which removes ACP and H2O.
Acetoacetyl ACP is reduced to alpha-3-hydroxybutryl ACP, by converting NADPH to NADP+ in the process.
a-3-hydroxybutryl- ACP is dehydrated to crotonyl ACP by removal of 1 water molecule
Crotonyl ACP is reduced to butyryl ACP, by converting NADPH to NADP+ in the process
Know how to link glycolysis, gluconeogenesis, glycogenolysis, cori cycle, ketogenesis, kreb cycle via pyruvate, acetyl CoA
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Carnitine Acyl Transferase deficiencies description type 1 and 2
Carnitine acyl transferase deficiency is aninherited genetic metabolic disorder characterized by an enzymatic defect that preventslong-chain fatty acidsfrom being transported into themitochondriafor utilization as an energy source.
It is the common inherited disorder of lipid metabolism affecting theskeletal muscleof adults.
Without CAT, we cannot mobilize beta oxidation, which is used to produce energy from fats to power skeletal muscle movements.
Mechanism of action of carnitine
Mitochondria is a double membrane organelle, there is a outer mitochondrial membrane and inner mitochondrial membrane, between the membrane is the intermembrane space and beyond the inner membrane is the mitochondrial matrix.
A long chain fatty acid is brought to the outer mitochondrial membrane, Acyl CoA synthetase present at the outer mitochondrial membrane, it uses ATP and CoASH as cofactors to add a CoA to the fatty acid, activating the fatty acid.
It can then be acted upon by CPT1 located on the outer membrane, it removes CoASH from the fatty acid and add a carnitine, allowing it to enter the intermembrane space.
A transporter located on the inner mitochondrial membrane called carnitine acylcarnitine translocase allow the fatty acid carnitine and allow it to enter the matrix.
CPT2 in the matrix takes a CoASH and removes carnitine and adds a Coenzyme A to the fatty acid, creates fatty acyl CoA. The fatty acyl CoA can then undergo beta oxidation and creates acetyl CoA as a product, carnitine is regenerated in the matrix. It can be pumped back into cytosol via the same transport molecule and be reused as a shuttle for another long chain fatty acid.
In the matrix, Carnitine acetyltransferase can act on carnitine to produce acetyl carnitine by transferring a acetyl group to carnitine. Carnitine get acetylated to form acetyl carnitine, CoASH is produced in this process. Acetyl carnitine can also be recycled back into the cytosol in this form
Describe CAT(1)
catalyzes the rate-limiting step in -oxidation, which is the conversion of the acyl-CoAs and free carnitine to acylcarnitines and free CoAs.
CAT I is up-regulated when intracellular levels of malonyl-CoA are low, as is seen with fasting. Its activity is physiologically inhibited by high levels of malonyl-CoA
