Lipid biosynthesis Flashcards
Lipids fulfill a variety of biological functions
- Energy __ (_)
- Constituents of _
- Anchors for __ (/)
- Cofactors for _ (__)
- Signaling __ (__, _)
- Pigments (__)
- Det__ (b_ s_)
- Tran__
- Ant__ (Vit __)
Lipids fulfill a variety of biological functions
- Energy storage (TG)
- Constituents of membranes
- Anchors for membrane proteins (IP2/PIP3)
- Cofactors for enzymes (Vit K)
- Signaling molecules (eicosanoids, IP3)
- Pigments (retinal)
- Detergents (bile salt)
- Transporters
- Antioxidants (Vit A)
What is the phase 1 of biosynthesis of Fatty Acids?
Biosynthesis of FA starts with activation which occurs through formation of Malonyl-CoA which is made of acetyl-CoA-> cells have to decide- whether to use Acetyl CoA for energy, for ketone body synthesis of FA synthesis
AcetylCoA becomes activated when it is converted to Malonyl CoA by Acetyl-CoA Carboxylase (ACC)- Carboxylates Acetyl CoA
What does ACC use to carboxylate Acetyl-CoA
bicarbonate ion and energy
What are the domains of ACC?
- Biotin carboxylase portion
- Biotin carrier domain
Transcarboxylase domai
- Biotin carrier domain
Describe how does ACC function
Biotin carrier protein has an arm that takes bicarbonate ion and transfer it to Acetyl- CoA via trans-carboxylation - biotin carboxylase function
Biotin arm is held by biotin carrier protein
Carboxylation of biotin arm is achieved by Biotin carboxylase portion
Once biotin is carboxylated, arm turns 180 degrees and shifts to the right domain- transcarboxylase domain- which has a docking mechanism for acetyl CoA
Docking domain takes the carboxyl group and adds it to Acetyl-CoA converting it to Malonyl-CoA
Describe types of fatty acid synthase
- Type I in vertebrates and fungi
- Type II in bacteria and plant
Describe FA synthase. When is it used?
Once Malonyl CoA is made it can go into FA synthesis FA synthase (doesn't use ATP) is used which is an enzymatic complex made out of 6 individual protein It always functions in a dimer - whenever synthesis occurs, there are always 2 copies - 2 FA are synthesized at a time
Describe phase 2 of FA synthesis
Phase 2: Addition of 2 carbons to fatty acyl chain
Acetyl CoA is needed which is captured by KS (ketoacyl ACP-synthase) domain of FA synthase from cytoplasm
Acetyl-CoA becomes attached to KS domain
Malonyl CoA attaches to ACP domain (acyl carrier protein- carries acyl chain that made)
Carboxyl group of Malonyl CoA interacts with Acetyl COA present on KS domain - Acetyl CoA and Malonyl CoA are put together
Now malonyl CoA has 2 carbons added to it-> chain grows by 2 carbons at ACP- site of chain growth. CO2 is produced
ACP receives Malonyl CoA
Reduction-Dehydration-Reduction occurs to turn unsaturated O-double bonded chain to unsaturated carbon-hydrogen chain
Growing chain of fatty acids has to be transferred to KS domain -> ACP is free to receive new malonyl CoA
2 more carbons can be added until 16 carbon chain is made-palmitate
What is the cite of the chain growth of FA synthase?
ACP domain (acyl carrier protein)
__ is the most common FA made by fatty acids synthase - can synthesized it a its max __
Palmitate is the most common FA made by fatty acids synthase - can synthesized it a its max capacity
What are the condition to make a fatty acid longer than 16C?
New enzymes are required to make a longer chain
Elongation does occur, but FA have to be transported to other compartments of the cell such as ER or mitochondria- sites of elongation
__ is a precursor for longer chain FA
Palmitate is a precursor for longer chain FA
Long-chain FA are produced in __ (also __)
Long-chain FA are produced in ER (also Mitochondria)
FA such as Palmitate (16:0) and Stearate (18:0) are desaturated by __by __
FA such as Palmitate (16:0) and Stearate (18:0) are desaturated by Fatty acyl-CoA desaturase by oxidative reactions
Are desaturase enzymes specific or versatile?
desaturase enzymes are specific for each length
What does (18:2Δ9,12) mean
18 carbon long
2 double bonds at carbon 9 and 12
What is special about linoleate?
Linoleate (18:2Δ9,12) cannot be synthesized in mammals (essential)
Arachidonate (20:4Δ5,8,11,14) is synthesized from linoleate
What are the sources of Acetyl-CoA
pyruvate decarboxylation - cytoplasm (available for FA synthesis straightaway) AA catabolism (mito) (has to be transported into cytoplasm for FA synthesis)
Describe the relationship between Acetyl-CoA and citrate
Citrate is the transport form of Acetyl-CoA
- Oxaloacetate is transported into the cytoplasm by converting it into citrate: (first reaction of TCA cycle) Acetyl-CoA + oxaloacetate → citrate (Citrate synthase-> transporter in mitochondrial inner membrane)
- Citrate → acetyl-CoA + oxaloacetate (Citrate lyase in cytoplasm)-> Acetyl-Coa is now available for FA synthesis in the cytoplasm
Describe the relationship between malate and oxaloacetate
Malate is the transport form of oxaloacetate- Malate can be transported into mitochondria by malate alpha-ketoglutarate transporter
Oxaloacetate (cyt)→Malate (Malate dehydrogenase in cytoplasm)
Malate goes into Mito through __
Malate is converted to __ in __
Malate goes into Mito through malate-a-ketoglutarate transporter
Malate is converted to pyruvate in cytoplasm
Can malate be converted to pyruvate?
Malate can be converted into pyruvate by malic enzyme (TCA cycle enzyme) which occurs in the cytoplasm. Produces NADPH
-> Pyruvate can be transported into mitochondria where it can be converted into oxaloacetate-> citrate
Through which enzyme is FA synthesis mainly regulated? Why? How?
ACC enzyme is regulated as it is the main enzyme that commits Acetyl CoA to FA synthesis by converting Acetyl CoA into Malonyl CoA
ACC is inhibited by phosphorylation
Anything that phosphorylates such as PKA pathway inhibits AAC- > no FA synthesis
It is inhibited by epinephrine and glucagon signal
End product - of FA synthesis - Palmitoyl-CoA inhibits ACC
Citrate accumulation in mitochondria has a positive effect on ACC
What does catabolism of FA produce and where does it take place?
Catabolism of fatty acids
– Produces acetyl-CoA
– Produces electron donors (e.g. NADH, FADH2) – Takes place in the mitochondria
What does anabolism of FA require and where does it take place?
Anabolism of fatty acids
– Requires acetyl-CoA and malonyl-CoA – Requires electron and hydrogen donor NADPH
– Takes place in cytosol in animals
Insulin __ FA synthesis
Insulin promotes FA synthesis
Describe glucose/ feeding effect on FA synthesis
When there are dietary carbs - there’s a lot of glucose which is catabolized through glycolysis which leads to formation of Acetyl CoA
A lot of glucose-> insulin levels increase which lead to phosphorylation cascade which activates phosphatase protein enzyme- dephosphorylates ACC and activates it
Acetyl CoA can now be activated into malonyl CoA -> FA synthesis occurs
What is the effect of muscle contraction on FA synthesis?
During periods of vigorous muscle contraction or during fasting, the fall in [ATP] and the rise in [AMP] activate AMPK, the AMPactivated
protein kinase AMPK phosphorylates several target enzymes, including acetyl-CoA carboxylase, which catalyzes malonyl-CoA synthesis
What is the effect of low glucose on FA synthesis?
low glucose-> glucagon (GPCR)-> PKA/AMPK is activated-> Phosphorylation and deactivation of ACC so Acetyl CoA can be used for energy instead of FA synthesis
What is the effect of Malonyl accumulation of energy production?
A lot o Malonyl CoA-> cell have enough energy-> inhibition of carnitine acyl-transferase I which transports FA into mitochondria (begging of beta-oxidation)-> no energy production as no transport of acetyl CoA
Insulin promotes synthesis of __ and storage of _
Insulin promotes synthesis of TG and storage of fa
Glycerol backbone can come from __ or __
Glycerol backbone can come from glycolysis or TG degradation
Describe synthesis of TG
Glycerol backbone can come from glycolysis or TG degradation
Glycerol is converted to glycerol 3-phosphate
Acyl transferase enzymes take 2 fatty acyls and adds them to glycerol 3-phosphate - 1 acyls to each carbon 1 and 2 and phosphate group added to the 3rd carbon -> phosphatidic acid (glycerol backbone with 2 FA and 1 phosphate group)
phosphatidic acid can be converted to membrane lipids such as glycerophospholipids (attach proteins or carbs) and become parts of membrane
or
phosphatidic acid can be dephosphorylated by phosphatidic acid phosphatase -> 1,2-diacylglycerol - another carbon for 3rd FA is now available -> triglyceride synthesis is completed by acyl transferases which add FA to glycerol backbone
Where does cholesterol synthesis occur?
Cholesterol synthesis happens in cytoplasm or within microsomes where some synthetic enzymes are present
__ + __= acetyl CoA
Acetate + CoA= acetyl CoA
Describe cholesterol synthesis
Synthesis of cholesterol involves conversion of Acetate to HMG-CoA with enzyme HMG-CoA synthase
HMG-CoA is then converted into Mevalonate by HMG-CoA reductase (also involved in ketone body synthesis)- condensation
Mevalonate is then phosphorylated, polymerized and cyclated to make cholesterol
What is the rate limiting enzyme in cholesterol synthesis? What is it inhibited by>
HMG-CoA reductase
It is inhibited by phosphorylation
How does AMP affect cholesterol synthesis? Why?
High levels AMP is an indicator of low energy
High AMP increases AMPK activity
Active AMPK will phosphorylate HMG-CoA reductase and reduce its activity -> cholesterol synthesis is reduced
This allows fatty acids to be used for energy production rather than cholesterol production
How does glucagon and epinephrine affect cholesterol synthesis? Why?
Glucagon, which is produced when there is low glucose= low energy lead to PKA pathway-> phosphorylation of HMG-CoA reductase and its inhibition
How does insulin affect cholesterol synthesis? Why?
Insulin cascade activates a phosphatase that dephosphorylated HMG-CoA reductase, increasing its activity and inducing cholesterol synthesis
Insulin increases cholesterol synthesis
What is Insig
Insig (Insulin induced gene protein) senses cholesterol levels -> triggers ubiquitination of HMG-CoA reductase-> destruction
Insulin increases cholesterol synthesis, but there’s controlled activation of cholesterol synthesis as insulin also triggers a gene that degrades cholesterol producing enzyme
What are SREBPs?
Transcription factors SREBPs (Sterol Regulatory Element Binding Proteins) activate HMG-CoA reductase by being involved in its expression
What is the effect of statins on cholesterol production?
Statins (Lipitor) inhibits HMG-CoA reductase- treats high cholesterol
Where does cholesterol synthesis occur?
Cytoplasm/microsomes
