Fatty acid synthesis Flashcards
De Novo Synthesis
- in adults: most fatty acid synthesis is in LIVER, LACTATING MAMMARY GLANDS, SOME IN ADIPOSE
- synthesized in the cytosol
- cytosolic acetyl CoA is the carbon source for growing fatty acid chains
- energy source: ATP and NADPH
Acetyl-group of Acetyl CoA
- generated in mitochondria
- required for FA production in cytosol
- CoA cannot cross mitochondrial membrane so convert to citrate to cross and back with CoA/ATP to get cytosolic acetyl CoA
Step 1 of creating cytosolic acetyl CoA
- mitochondrial acetyl CoA is generated by oxdation of pyruvate
- Beta oxidation of long carbon chain-CoA
- catabolism of ketone bodies and amino acids
- add a carbon to acetyl CoA
- there is stored energy between existing carbon and the one added
Step 2 of creating cytosolic acetyl CoA
- acetate leaves mitochondria as citrate
- citrate is cleaved by ATP-citrate lysase to produce cystolic acetyl CoA and OAA
Why are FA only made in well fed state?
- you need accumulation of citrate in mitochondria
- isocitrate dehydrogenase must be inhibited for citrate to build up
- ATP inhibits isocitrate dehydrogenase
- have large amounts of ATP only in well fed state
Acetyl CoA carboxylase
- uses CO2 and ATP hydrolysis to carboxylate the acetyl group of acetyl CoA
- carboilation and decarboxylation provide energy for C-C condensations to elongate FA chains
- RATE_LIMITING and REGULATED
Short term regulation of ACC
- activated by citrate
- depolymerized(deactivated) by product (long FA chain)
- AMP-activated protein kinase phosphorylates and inhibits ACC
- PKA activates AMPK
- ACC deactivated by glucagon and epinephrine
Short term hormone regulation of ACC
- Insulin=well fed=phosphatase=dephosphorylate=activate
- Glucagon=fasting=kinase=phosphorylate=deactivate
Long term regulation of ACC
- high calorie, high carb diet=increase FA synthesis
- low calorie, low carb=reduce FA synthesis
Fatty acid synthase
- multifunctional dimeric enzyme in eukaryotes
- 7 different enzymatic activities
- domain to covalently bind 4-phosphopantetheine
2 sites on 4-phosphopantetheine domain of FAS
- acyl carrier protein (ACP)
2. ACP carries acyl units to thiol group (cys) durring FA synthesis
FA synthase summary
- initiation of elongation requires transfer of the butyryl to the cysteine residue holding site of FAS
- Acetyl CoA carbozylation to generate malonyl CoA is RATE LIMITING AND REGULATED STEP
- steps are repeated 7 times and add 2 C per time
- final FA is 16 carbons
- termination=palmitoyl-S-CoA`
Palmitoyl thioesterase
-cleaves thioester bond to release saturated palmitate
Glucose 6P dehydrogenase
- primary source of NADH
- from HMP shunt
- rate limiting and irreversible
- uses NADP+ as coenzyme acceptor to oxidize glucose 6P
- from each glucose 6P, 2 NADPH are produced
Malate oxidation and decarboxylation
- malic enzyme oxidized and decarboxylates malate to pyruvate
- NADP+ oxidizes malate to produce NADPH
Further elongation of FA chain
- palmitate can be further elongated at smooth ER
- uses 2 C from malonyl CoA and reduced by NADPH
- requires specialized enzyme
- brain lipids need >22 very long FA so brain enzymes can do it
Desaturation of FA chains
- smooth ER contains desaturases for LCFA
- make Cis double bonds between C 9/10
- 18:1(9) is MORE COMMON
- 16:1(9) is LESS COMMON
Storage of FA as components for TAG
- FA esterified via carboxyl group to the carbons of glycerol
- esterified FA lose charge and become neutral TAG
- TAG are unlikely to interact with water, so they interact with eachother
Structure of TAG
-vary in length and saturation to encourage variety
Carbon 1: saturated FA of varied length(likely 16)
Carbon 2: unsaturated FA of varied length(likely larger than 16)
Carbon 3: saturated OR unsaturated of varied length
Storage of TAG
- two end molecules should have potential to be saturated
- TAG is…
- only slightly soluble in water
- unable to form micelles independently
- ABLE to coalesce and form anhydrous, cystolic oil droplets
Primary storage of Fatty Acids
-adipose
Primary production of Fatty Acids
- liver
- makes sense because it regulates glucose and energy
Glycerol phosphate
-initial acceptor of activated FA during TAG synthesis
Acyl CoA
-free fatty acids must be converted to the activated form
