Lipid Metabolism I (zaidi) Flashcards by Tori Tyler

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

Dietary carbohydrates

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Describe the overview of Fatty acid synthesis

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

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What is the end product of fatty acid synthesis?

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

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What is the precursor of fatty acid synthesis

Acetyl CoA

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What are the 3 phases in the synthesis of fatty acids

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

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

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

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

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

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

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

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

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

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Describe the acetyl CoA carboxylase

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

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

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Who is malonyl CoA

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

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Describe phase 3 of fatty acid synthesis

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

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Describe fatty acid synthetase

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)

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What is the overall equation for the palmitate synthesis reaction

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

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

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What are the basic reactions that are catalyzed by FAS?

Condensation
Reduction
dehydration
Product release

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Describe the Condensations reactions that happen in the FAS

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

Describe the reduction reactions that occur in the FAS

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

Describe the product release of the FAS

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

What are the sources of NADPH for the fatty acid synthesis

How many NADPH are used in order to make palmitate?

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)

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

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

Describe the regulation of ATP citrate lyase

Stimulated by phosphorylation

Gene expression is induced by glucose and insulin

Gene expression is inhibited by PUFAs and leptin

Describe the regulation of Acetyl CoA carboxylase

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)

Describe the phosphorylation and dephosphorylation of ACC

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

Describe how diet is able to impact the regulation of ACC

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

Describe the regulation of FAS

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

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

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

Describe desaturation of the fatty acid

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

Describe fatty acid synthesis in humans (

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

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

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)

Describe the nomenclature of the fatty acids. Where do you start? Who are the alpha and beta carbons

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.

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

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

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

Comes from linoleic acid (an omega 6 fatty acid) make prostaglandins, thromboxanes, and leukotrienes

Describe prostaglandins and why they are important

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

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

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