Fatty acid synthesis

Question 1

De Novo Synthesis

Answer 1

• 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

Question 2

Acetyl-group of Acetyl CoA

Answer 2

• 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

Question 3

Step 1 of creating cytosolic acetyl CoA

Answer 3

• 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

Question 4

Step 2 of creating cytosolic acetyl CoA

Answer 4

• acetate leaves mitochondria as citrate

- citrate is cleaved by ATP-citrate lysase to produce cystolic acetyl CoA and OAA

Question 5

Why are FA only made in well fed state?

Answer 5

• 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

Question 6

Acetyl CoA carboxylase

Answer 6

• 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

Question 7

Short term regulation of ACC

Answer 7

• 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

Question 8

Short term hormone regulation of ACC

Answer 8

• Insulin=well fed=phosphatase=dephosphorylate=activate

- Glucagon=fasting=kinase=phosphorylate=deactivate

Question 9

Long term regulation of ACC

Answer 9

• high calorie, high carb diet=increase FA synthesis

- low calorie, low carb=reduce FA synthesis

Question 10

Fatty acid synthase

Answer 10

• multifunctional dimeric enzyme in eukaryotes
• 7 different enzymatic activities
• domain to covalently bind 4-phosphopantetheine

Question 11

2 sites on 4-phosphopantetheine domain of FAS

Answer 11

1. acyl carrier protein (ACP)

2. ACP carries acyl units to thiol group (cys) durring FA synthesis

Question 12

FA synthase summary

Answer 12

• 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`

Question 13

Palmitoyl thioesterase

Answer 13

-cleaves thioester bond to release saturated palmitate

Question 14

Glucose 6P dehydrogenase

Answer 14

• 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

Question 15

Malate oxidation and decarboxylation

Answer 15

• malic enzyme oxidized and decarboxylates malate to pyruvate
• NADP+ oxidizes malate to produce NADPH

Question 16

Further elongation of FA chain

Answer 16

• 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

Question 17

Desaturation of FA chains

Answer 17

• 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

Question 18

Storage of FA as components for TAG

Answer 18

• 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

Question 19

Structure of TAG

Answer 19

-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

Question 20

Storage of TAG

Answer 20

• 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

Question 21

Primary storage of Fatty Acids

Answer 21

-adipose

Question 22

Primary production of Fatty Acids

Answer 22

• liver

- makes sense because it regulates glucose and energy

Question 23

Glycerol phosphate

Answer 23

-initial acceptor of activated FA during TAG synthesis

Question 24

Acyl CoA

Answer 24

-free fatty acids must be converted to the activated form

Question 25

Synthesis of glycerol phosphate in liver AND adipose tissue

Answer 25

• produced from glucose via glycolytic pathway
• glucose –>DHAP
• DHAP is reduced to glycerol phosphate by glycerol phosphate dehydrogenase
• only in well fed state because you need hella energy

Question 26

Synthesis of glycerol phosphate ONLY IN LIVER

Answer 26

• glycerol kinase converts free glycerol–> glycerol phosphate
• direct substrate for TAG

Question 27

GLUT-4

Answer 27

• insulin dependent
• in adipose
• when glucose and insulin are low, adipose cannot synthesize glycerol phosphate
• no TAG

Question 28

Thiokinase

Answer 28

-free fatty acid==>acetyl CoA

Question 29

Starting over De Novo

Answer 29

-most of the time, clip some FA, add the free ones right back on so you do not have to completely start over making TAG

Question 30

Synthesis of TAG

Answer 30

• 4 step process
• 2 FA added to glycerol phosphate molecule
• dephosphoryation
• addition of FA by acyltransferase

Question 31

Fate of TAG in adipose tissue

Answer 31

• stored as cytosolic lipid droplets
• easily mobilized when fuel is needed
• dipolipase/adipose lipase

Question 32

Fate if TAG in liver

Answer 32

• small amounts stored in liver
• packaged with other lipids and apoproteins to form VLDL
• Nascent VLDL are secreted to the blood and function to deliver endogenously synthesized lipids to peripheral tissues

Question 33

VLDL

Answer 33

-very-low-density-lipoproteins

Question 34

Chylomicrons vs VLDL

Answer 34

• Chylomicrons deliver exogenous dietary acquired lipids

- VLDL delived de novo synthesized lipids