Lipid biosynthesis Flashcards
Functions of lipids
Energy storage (TG)
Constituents of membranes
Anchors for membrane proteins (IP2/IP3)
Cofactors for enzymes (Vit K)
Signaling molecules (eicosanoids, IP3)
Pigments (retinal)
Detergents (bile salt)
Transporters
Antioxidants (Vit A)
What is the first step of fatty acids biosynthesis
Formation of Malonyl-CoA from acetyl-CoA
the enzyme responsible for conversion of acetyl-CoA to Malonyl-CoA
Acetyl-CoA Carboxylase (ACC)
Three important domains in ACC
Biotin carboxylase
Transcarboxylase
Biotin carrier protein
How the conversion of acetyl-CoA with ACC happens
Biotin carrier protein has an arm. It is used to capture bicarbonate and transfer to acetyl-CoA
Biotin carboxylase portion of ACC with the use of ATP adds CO2 to biotin carrier protein arm
Once it is carboxylated, biotin carrier protein shifts 180 degrees to transcarboxylase arm. At transcarboxylase arm there is also a docking mechanisms for acetyl-CoA
Addition of CO2 to acetyl-CoA= malonyl-CoA
What enzyme takes malonyl and converts to FAs
Fatty Acid Synthase (does not use ATP)
What is particular about Fatty Acid synthase
It consists of 6 enzymes
AND
Functions as dimer
2 types of Fatty acid Synthase and where it can be found
Type I in vertebrates and fungi
Type II in bacteria and plant
How many FAs are synthesized a time by Fatty Acid synthase dimer
2
What is the first requirement for synthesis of FAs with FAS and what happens with it
Acetyl-CoA not activated
It is captured by KS domain of the synthase
What is ACP domain and what does it do
Acyl carrier protein
It gets malonyl-CoA with the help of MAT domain
What happens after malonyl-CoA is attached
With that the carboxyl group of malonyl co a, it interacts with acetyl coa, the result is malonyl coa adds two more carbons to itself-> grow of the chain
Why ACP is an important domain
It is where the chain grows and receives malonyl-CoA
What happens after acetyl-CoA is added to malonyl-CoA
We need to get rid of double bonds and oxygen, so there is reduction happening and hydrogen is added
After the reduction of the chain occurs, what happens
The chain is transferred to KS domain, so ACP is ready to receive new malonyl-CoA
Each cycle FAS adds how many carbon to the chain and what is the limit
Adds 2 carbons
Until 16 carbons are reached (palmitate) after than new enzymes are needed
Most common FAs synthesized
Palmitate
Long chain FA are produced in
ER or in mitochondria
Palmitate is synthesized in
Cytoplasm
Two saturated FAs that synthesized
Palmitate (16:0)
Stearate (18:0)
What FAs can come from palmitate and stearate
Palmioleate (16:1)
Oleate (18:1)
Double bond at C9-10
What is needed to synthesize palmioleate and oleate
Fatty acyl-CoA desaturase by oxidative reactions
What is the issue of linoleate
It is (18:2 delta 9,12)
As it has 2 double bonds they cannot be synthesized in mammals-> essential
What is synthesized from linoleate
Arachidonate (20: delta 5,8,11,14)
Can mammals synthesize arachidonate
Yes, if linoleate is available
What are sources of acetyl-CoA how it is regulated and thus biosynthesis of FAs is regulated
From pyruvate->Puryvate decarboxylation (cytoplasm)
AA catabolism in
mitochondria
If AAs catabolism happens inside mitochondria, so how acetyl-CoA is delivered to cytoplasm
Acetyl-CoA+oxaloacetate->citrate with citrate synthase
Now citrate can be transported out of mitochondria because there are mitochondrial transporters in the mitochondrial wall
In cytoplasm: citrate lyase breaks down citrate to acetyl-CoA and oxaloacetate .
What happens when citrate is broken down in the cytoplasm
Oxaloacetate is needed to be sent back in mitochondria.
Two options:
1)Conversion to malate with malate dehydrogenase and then malate is transported through malate-alpha ketoglutarate transporter
2)OR malate can be converted to pyruvate by malic enzyme in the cytoplasm-> pyruvate transported into the mitochodria
What are other way to regulate biosynthesis of FAs except acetyl-CoA concetration
Acetyl-CoA carboxylase is the limiting enzyme
It is inhibited by phosphorylation by epinephrine and glucagon signal (PKA pathway)
Palmitoyl-CoA ( the end product) inhibit ACC -> negative feedback
Citrate accumulation in mitochondria results in activation of ACC
Catabolism of FAs
Produces ___
Take place in ___
Produces acetyl-CoA
Produces electron donors (FADH2 and NADH)
-Takes place in the mitochondria
Anabolism of FAs
requires ___
Takes place in ___
Requires acetyl-CoA and malonyl-CoA
Requires electron donor NADPH (as hydrogen donor)
Takes place in cytosol in animals
Insulin and FA synthesis relationship
Insulin promotes FA synthesis
How ACC is regulated
When it is phosphorylated it is inactive
When dietary carbohydrate coming-> a lot of carbohydrate-> high insulin leading to activation of phosphatase->dephopshorylation -> acetyl CoA to malonyl-CoA
Low glucose leads to glucagon-> GPCR-> PKA->phosphorylated ACC-> inactivation
What happens when there is accumulation of malanyl-CoA
Cells are in energy sufficiency situation.
Malanyl inhibits carnitine acyl transferase-1 that transfers FA in mitochondria -> inhibition of beta-oxidation-> less energy
The most common store form of FAs
TGs
from where we can get glycerol?
Glycolysis or release from TG metabolism
How glycerol is converted to phosphatidic acid
1) Glycerol is converted to G3P
2) Acyl transferase that takes 2 Fatty acyls and attached to G3P->phosphatidic acid ( 2 FAs and phosphate group)
What happens to phosphatidic acid
1) attachment of head group and thus -> glycerophospholipid-> membrane
2) or with phosphatidic acid is dephosphorylated to 1,2-Diacylglycerol , where third carbon is free, with phosphatidic acid phosphatase. So acyl transferase attaches another FAs->TGs
What hormone promotes synthesis of TG
Insulin
Cholesterol is
Structure membrane and precursor for signaling molecules
How do we synthesize cholesterol
Acetate -> HMG-CoA with HMG-CoA synthase
HMG-CoA to Mevalonate with HMG-CoA reductase
And then phosphorylated, polymerized and cyclized to cholesterol
Biosynthesis of cholesterol occurs in
Cytoplasm/ microsomes
What step in cholesterol synthesize can be regulated
HMG-CoA reductase
AMP-dependent protein kinase and cholesterol synthesize
When AMP rises (low energy situation), AMPK phosphorylates the enzyme-> reduced activity -> reduced cholesterol synthesize
So acetate and FAs are used for energy rather than cholesterol synthsize
Glucagon and epinephrine and cholesterol synthesize
Glucagon-> low energy
Leads to PKA pathway-> phosphorylation-> reduced activity of HMG-CoA reductase
Insulin and HMG-CoA reductase
Cascades leading to dephosphorylation-> increased activity
What does Insig do
Insulin-induced gene protein senses cholesterol levels. and triggers ubiquination of HMG-CoA reductase-> limited cholesterol synthesize
What is SREBPs and what do they do
Transcriptional factors
Sterol Regulatory Element Binding proteins activate HMG-CoA reductase by inducing its transcription
What are statins or lipitor
Drugs that inhibits HMG-CoA reductase -> to treat high cholesterol
