Lipid Metabolism I (zaidi)

Question 1

What is the major source of carbon for fatty acid synthesis?

Answer 1

Dietary carbohydrates

Question 2

Describe the overview of Fatty acid synthesis

Answer 2

Occurs primarily in the liver
Also occurs in the adipose tissue, brain, kidneys, and lactating mammary glands
requires coordination between the cytosolic and mitochondria reactions

Question 3

What is the end product of fatty acid synthesis?

Answer 3

Palmitic acid: 16 C with no double bonds (saturated)

Question 4

What is the precursor of fatty acid synthesis

Answer 4

Acetyl CoA

Question 5

What are the 3 phases in the synthesis of fatty acids

Answer 5

1. cytosolic entry of acetyl coA: transport of acetyl CoA from the mitochondria to the cytoplasm
2. generation of malonyl coA
3. fatty acid chain formation

Question 6

Describe the steps that are involved in phase 1 of the synthesis of fatty acids

Answer 6

1. condensation of acetyl CoA with OAA to form citrate via citrate synthetase
2. Transport of citrate from mitochondria to the cytosol via the citrate transporter
3. Citrate is converted back to acetyl CoA and OAA via citrate lyase
4. OAA is reduced to malate by malate dehydrogenase
5. malate is transported into mitochondria via malate-alpa ketoglutarate transporter and oxidized to OAA by malate dehydrogenase
6. cytosolic malate is converted to pyruvate by malic enzyme; pyruvate is transported to mitochondria with the pyruvate transporter and carboxylated to OAA

Question 7

Describe in your own words the first phase of fatty acid synthesis

Answer 7

Citrate synthase combines the acetyl CoA to OAA to form citrate which is able to get out of the mitochondria via the citrate shuttle

The citrate is then converted into OAA in the cytosol and Acetyl coA is released that can be used for FA synthesis.

OAA is then taken into malate (which is able to enter into the mitochondria) or further into the pyruvate which is able to get into the mitochondria with the pyruvate transporter

Question 8

Describe the two mechanisms that are involved in the regeneration of OAA

Answer 8

Malate is transported into the mitochondria with the malate-alpha-ketoglutarate and oxidized to OAA by malate dehydrogenase

Cytosolic malate is converted to pyruvate by malic enzyme. the pyruvate is transported to mitochondria via the pyruvate transporter and carboxylated to OAA by pyruvate carboxylase

Question 9

Describe what happens in the second phase of fatty acid synthesis… in detail

Answer 9

Acetyl coA is taken to malonyl CoA by carboxylation (a carbon is added to acetyl CoA(CO2)) with the help of Acetyl CoA carboxylase
RATE LIMITING STEP

uses ATP and biotin as cofactors

Question 10

Describe the acetyl CoA carboxylase

Answer 10

involved in the rate limiting step that converts acetyl CoA to malonyl CoA

exists in dimeric (inactive) and polymeric (active) forms

Question 11

Who is malonyl CoA

Answer 11

3C version of acetyl coA after carboxylation

substrate for fatty acid synthesis

inhibits carnitine acyltransferase (rate limiting step in degredation)

It is involved in the rate limiting step of fatty acid synthesis

Question 12

Describe phase 3 of fatty acid synthesis

Answer 12

malonyl CoA is continuously added to a growing fatty acyl chain in 7 reactions to form palmitate (16:0) in the fatty acid synthase (FAS) complex with the help of NADPH

Question 13

Describe fatty acid synthetase

Answer 13

Large multi-enzyme complex

composed of identical dimers that are arranged in a head to tail conformation

7 enzyme activities and an acyl carrier protein (ACP)

Question 14

What is the overall equation for the palmitate synthesis reaction

Answer 14

1 acetyl CoA + 7 malonyl CoA + 14NADPH +4H+

CH3(CH2)14COO- + 14 NADP+ + 8 CoA + 6H2O

Question 15

What are the basic reactions that are catalyzed by FAS?

Answer 15

Condensation
Reduction
dehydration
Product release

Question 16

Describe the Condensations reactions that happen in the FAS

Answer 16

FAS has a Cys-SH and a Pan-SH side chains.

• The acetyl CoA is paired to the Cys-SH with a thioester bond via s. acetyl transferase
• malonyl CoA is transferred to the Pan-SH with S-malonyl transferase activity
• 3 oxoacyl synthase transfers the acetyl group from the cysteine residue to malonate and reduces it to make a 4-C B-ketoacyl group

Question 17

Describe the reduction reactions that occur in the FAS

Answer 17

B-ketoacyl group is reduced to a B-hydroxyl group with the help of 3-oxoacyl reductase activity; NADPH is oxidized here

Two more reductions occur to take the B hydroxyl to a trans-none group and then to a 4-C fatty acid group that is attached at the Pan-SH

Then the molecule is transferred back to the cys-SH residue and acts as a substrate so that more malonyl bind to the pan-SH and add to the fatty acid to form palmitate

Question 18

Describe the product release of the FAS

Answer 18

Once the fatty acid undergoes 7 rounds of stuff being added to form palmitate, the acyl hydrolase (thioesterase) will please the thioester bond beterrn the Pan-SH residue and the molecule with the help of water

Question 19

What are the sources of NADPH for the fatty acid synthesis

How many NADPH are used in order to make palmitate?

Answer 19

Malic enzyme: when malate is changed to pyruvate 1 NADPH is produced

PPP makes about 12 NADPH total (2-12; but 12 at the most)

Question 20

What are the 3 enzymes that are involved in the regulation of fatty acid synthesis and which phase are they found in?

Answer 20

1. ATP citrate lyase is found in phase 1 that takes the citrate to the OAA in the cytoplasm
2. Acetyl CoA carboxylase in phase II that takes acetyl CoA to malonyl CoA and is the RATE limiting step
3. Fatty acid synthase in Phase 3 that adds everything together

Question 21

Describe the regulation of ATP citrate lyase

Answer 21

Stimulated by phosphorylation

Gene expression is induced by glucose and insulin

Gene expression is inhibited by PUFAs and leptin

Question 22

Describe the regulation of Acetyl CoA carboxylase

Answer 22

ACC is inactive when it is in dimer form and active in polymer form

It is inactivated by phosphorylation and activated by dephospho rylation

It is positively allosterically regulated by citrate and inhibited by long chain fatty acids (palmitate because if you have a lot of products then you dont want to keep going and possibly waste ish)

Question 23

Describe the phosphorylation and dephosphorylation of ACC

Answer 23

Insulin will dephosphorylate and activate the enzyme via protein phosphatase

Epinepherine and glucagon will inactivate the enzyme via the activation of protein kinase A which will phosphorylate and inactivate the enzyme

AMP will activate the AMP kinase which will phosphorylate ACC, inactivating it

Question 24

Describe how diet is able to impact the regulation of ACC

Answer 24

a high carb and low fat diet will up-regulate gene expression

Question 25

Describe the regulation of FAS

Answer 25

Presence of phosphorylated sugars increase the activity of FAS via allosteric effects

Insulin and glucocorticoid hormones increase synthesis

High carb/low fat diets increase synthesis

high fat diets or starvation lowers synthesis (because you need the energy)

high PUFA suppresses synthesis

Question 26

Describe the process of elongation and why it is needed including any other molecules that are required in order to achieve this

Answer 26

Palmitate must be converted to a longer chain fatty acid in the Smooth ER and mitochondria (if it is in the SER then it will use malonyl CoA as a donor and the mitochondria uses acetyl CoA as a carbon donor)

This is important because the brain needs fatty acids that are longer, so the fatty acid is lengthened by 2C at a time with the help of NADPH

Question 27

Describe desaturation of the fatty acid

Answer 27

Introduction of double bonds in the fatty acid.

The double bonds can only be added in the SER with the help of Acyl CoA desaturates, oxygen, and NADPH

There are 4 desaturates that can add double bonds between the 4, 5, 6, or 9th carbons

Question 28

Describe fatty acid synthesis in humans (

Answer 28

humans are not able to synthesis fatty acids with a double bond beyond carbons 9 and 10

need to ingest fatty acids (essential fatty acids) like omega 3 and omega 6

Question 29

Describe essential fatty acids and why they are important including which ones are specifically important and what they make in the body

Answer 29

humans are not able to synthesize omega 3 and omega 6 fatty acids so we need to ingest them

The two important ones are linoleic (18:2) and linolenic (18:3)

Linoleic can make arachidonic acid (20:4) which is a precursor for a lot for eicosanoids

Linolenic acid can make EPA (20:5) and DHA (22:6)

Question 30

Describe the nomenclature of the fatty acids.

Where do you start? Who are the alpha and beta carbons

Answer 30

You start at the methyl end of the molecule. The alpha carbon is the carbon that is after the carbonyl, and Beta is the one after that. The omega carbon is at the opposite end of the F.A.

Question 31

What are the benefits of the omega 3 and 6 fatty acids

Answer 31

good for the immune system, CV system, nervous system, vision, and cell membrane

Question 32

Describe the role of arachidonate in the body including where she comes from and what she makes

Answer 32

Comes from linoleic acid (an omega 6 fatty acid)

make prostaglandins, thromboxanes, and leukotrienes

Question 33

Describe prostaglandins and why they are important

Answer 33

20 carbon fatty acids with a 5 C ring that are local hormones that are able to influence cells through GPCR binding. They stimulate inflammation, regulate blood flow to organs, control ion transport in membranes, modulate synaptic transmission, and induce sleep

Question 34

Describe how aspirin is able to work (clinical example on the second to last slide)

Answer 34

Aspirin blocks the enzyme that converts arachidonate to prostaglandin H2 which interferes with a bunch of different pathways, possibly explaining why aspirin helps with a wide array of ish