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HF B4 Fatty Acid Synthesis
Terms in this set (121)
What are the 2 possible sources of fatty acids?
diet (TAG and phospholipids)
de novo synthesis of fatty acids
What are used to build fatty acids from de novo synthesis?
What are the 2 fates of TAGs in the body?
What are the possible fates of phospholipids in the body?
can be broken back down into fatty acids, which form eicosanoids
What do lipids other than TAGs and phospholipids become in the body?
Do dietary carbs or fat result in more de novo lipogenesis?
What are possible substrates that can be used for fatty acid biosynthesis?
monosaccharides (glucose, fructose, and galactose)
alanine and other amino acids
Describe the general formation of TAGs when citrate is the starting point
1. citrate leaves the mitochondria
2. ATP-citrate lyase forms oxaloacetate (which becomes malate to produce pyruvate for the TCA cycle to continue) and Aceytl coA, which is used for fatty acid synthesis
3. Aceytl-coA carboxylase produces malonyl coA
4. Fatty acid synthase produces palmitate
5. palmitate becomess TAG, which is exported from the liver to adipose tissue
Where does fatty acid synthesis take place?
what is the purpose of fatty acid synthesis?
convert energy in excess of immediate needs to a form that can be stored
When is fatty acid biosynthesis turned on?
fed state (insulin)
What are 6 regulatory points of the reactions that lead to fatty acid biosynthesis?
1. those of glycolysis: glucokinase, phosphofructokinase-1, pyruvate kinase
2. pyruvate dehydrogenase
3. ATP-citrate lyase
4. acetyl-coA carboxylase **RATE-DETERMINING STEP
5. Fatty acid synthase
6. glucose-g-p dehydrogenase, malic enzyme
What is the necessary cofactor for Acetyl-coA carboxylase? What part of the enzyme does it aid?
What type of reactions require biotin?
What makes the reaction of Acetyl-coA carboxylase irreversible under normal cellular conditions?
hydrolysis of ATP
General reaction of Acetyl-CoA Carboxylase
Acetyl-CoA + ATP +HCO3- -->Malonyl-CoA + ADP + Pi
What is the substrate of acetyl-coA carboxylase?
What is the main product of aceytl-coA carboxylase?
What is required, aside from Acetyl-CoA, for the acetyl-coA carboxylase reaction?
What form of acetyl-coA carboxylase has high activity?
During what state is acetyl-coA highly active?
What are the results of the fed state that cause increased activity of acetyl-coA Carboxylase?
increased citrate (to form acetyl-coA)
decreased fatty acyl-coAs
How does the fed state enhance acetyl-coA carboxylase activity?
increasing glycolytic flux and PDH activity, resulting in more citrate (insulin is a key mediator in these effects)
How does insulin increase the activity of acetyl-coA carboxylase?
within liver and adipose cells, insulin stimulates PHOSPHATASES that dephosphrylate acetyl-coA carboxylase. insulin also indirectly decreases intracellular fatty acyl-coA concentrations by inhibiting lipolysis in adipose tissue
How does starvation result in decreased activity of acetyl-coA carboxylase?
increased glucagon in the bloodstream
inhibts glycolysis and PDH activity, lowering citrate levls
glucagon also indirectly stimulates phosphorylation of acetyl-coA carboxylase.
furthermore, intracellular fatty acid concentrations increase during starvation because of enhances lipolysis in adipose tissue
What are the various ways (short-term and long-term general mechanisms) that acetyl-coA carboxylase can be regulated?
short term regulation by citrate, fatty acyl coA concentration, and phosphorylation
long term by changes in expression of its gene
Describe long-term regulation of acetyl-coA carboxylase
feeding a high carb diet enhances its expression and starvation and high-fat diets inhibit its expression
What is the rate-determining step of fatty acid biosynthesis?
acetyl-coA carboxylase (formation of malonyl coA from acetyl-coA)
Under what conditions is acetyl-coA carboxylase at its highest activity?
in the feds state of a high-carb diet
when it is dephosphorylated and citrate concentrations are high
What can allosterically inhibit acetyl-coA carboxylase?
fatty acyl-coAs (hallmarks of the starved state)
What step occurs after acetyl-coA carboxylase in fatty acid biosynthesis?
formation of palmitate
What is the overall reaction in the formation of palmitate?
1 acetyl-coA + 7 Malonyl-coA + 14 NADPH + H+ -->
palmitate + 14 NADP+ + 7 CO2 + 8CoA + 6H2O
Description of palmitate
16 carbon fatty acid with no double bonds
Why might 2 pools of fatty acids form inside cells?
de novo synthesis of fatty acids results in palmitate, which is a fatty acid, not a fatty acyl-coA
fatty acids entering a cell from the blood stream are immediately esterified to coA.
Why do we need to turn acetyl-coA into malonyl-coA before forming fatty acids?
Adding one carbon to each aceytl-coA molecule allows us to remove one C as CO2 from each malonyl-coA molecule as we form palmitate
this loss of CO2 drive the reaction forward
simply, we have to add energy to start the pathway
When is an enzyme called synthetase vs. synthase?
synthetase involves ATP
synthase does NOT involve ATP
Fatty Acid Synthase description
enzyme with a long polypeptide chain with 7 different catalytic sites
also functions as a dimer, so technically 14 sites available
Pantotheine arm of fatty acid synthase
structural part of the enzyme that moves something from one catalytic site to the next until you build the 16 carbon palmitate.
General description of the Fatty acid synthase reaction
1. bind acetyl coA to the pantotheine arm ("priming--only occurs once in the reaction)
2. move acetylcoA to the next site on fatty acid synthase, and the pantotheine arm picks up malonyl-coA
3. condensation of Malonyl-coA and acetyl-coA to form a 4 carbon intermediate
4. reduction of the beta-carbon by NADPH + H+
5. Dehydration (lose water)
6. Reduction by NADPH + H
7. acyl chain is transferred from the pantotheine arm to the next site so that the pantotheine arm can recieve a new malonyl-coA
repeat steps 3-7 until palmitate length (16 Cs) is formed (a total of 7 times)
finally: release palmitate from FA synthase via hydrolysis
What carbon is reduced in the third step of the fatty acid synthase reaction?
What cofactor(s) are used to reduce the substrate of fatty acid synthase?
NADPH and H+
What are the 4 steps of the fatty acid synthase reaction that are repeated 7 times to form palmitate?
1. condensation (releases CO2)
3. dehydration (loss of H2O)
Which of the 4 repetitive steps in the fatty acid synthase reaction drives the overall reaction?
condensation, because it involves the loss of CO2
Which of the 4 repetitive steps in the fatty acid synthase reaction involves the loss of water?
Why are only 6 H2O produced by the fatty acid synthase reaction if the 4 main steps are repeated 7 times?
one molecule of H2O is used in hydrolysis to release palmitate from the enzyme
How is fatty acid synthase activity regulated?
ONLY by changes in its expression (aka only long-term)
mechanism is transcriptional
Where does the NADPH necessary for the fatty acid synthase reaction come from?
1. the pentose shunt (glucose-6-P dehydrogenase and 6-phosphogluconolactone dehydrogenase reactions that turn glucose into ribose-5-P and ribulose-5-P)
2. malic enzyme (which turned malate into pyruvate in the cytosol)
In the 1970's, a study was performed that involved restricting food intake in animals to one meal per day. The results showed much higher activities of aceytl-coA carboxylase and fatty acid synthase in the liver as compared to animals that nibbled throughout the day. Thus, lipogenic capacity was high in meal fed animals compared to nibblers. The public claimed this meant that eating more frequent, smaller meals would result in lower body rates. Is this a correct extrapolation of this data? Why or why not?
No; the overriding concept is that enzyme activity DOES NOT equal flux.
lots of substrate come in at once during a meal, so you increase that activity when you are fed and turn it off when you aren't. The nibbler doesn't have that reaction.
elongation of fatty acids
addition of carbons
Desaturation of fatty acids
addition of double bonds to fatty acids
Why would you want to elongate and desaturate palmitate?
1. membrane fluidity--double bonds add kinks to the molecule, causing looser packing of the phospholipids in membranes. The longer the fatty acid, the more double bonds that can be added.
2. synthesis of precursors for biologically active molecules, like eicosanoids, ligands for transcription factors, and diacylglycerols uses in signalling.
What is the first step in elongation of palmitate?
start with palmitate and add 2 carbons, resulting in 18:0 fatty acid called stearate
What is the first desaturase used in the elongation and desaturation of palmitate?
delta9 desaturase, which adds a DB in the delta9 position from the COOH end, forming oleic acid
What are the first 3 fatty acids acted on in elongation and desaturation of palmitate?
What is the second desaturase used in elongation and desaturation of palmitate?
Which 2 desaturases do not have an elongation step between them during elongation and desaturation of palmitate?
delta9 and delta6 desaturases
What is the primary purpose of elongation and desaturation of fatty acids?
What are the general steps of elongation and desaturation of palmitate?
Description of oleic acid
Description of linoleate
description of linolenate
What are 2 18-C fatty acids can humans not synthesize, and therefore must obtain from the diet? Why enzymes are used to elongate and desaturate them?
the same enzymes used to elongate and desaturate palmitate (delta6 and delta5 desaturases, also a delta4 desaturase for linolenate)
What will result from a lack of linoleate and linolenate in the diet? why?
fatty acid deficiency, because we cannot synthesize them
What are linoleate and linolenate precursors for?
Why can't we make linoleate and linolenate?
they require delta12 and delta14 desaturases, which we do not have
Would an individual with a delta 6 desaturase deficiency have the symptoms of essential fatty acid deficiency?
yes, because you wouldn't make the 3 essential long-chain fatty acids.
What are the descriptions of the 3 essential long chain fatty acids?
What are the chain-length prefixes for fatty acid systematic names?
deca= 10 carbons
eicosa= 20 carbons
docosa= 22 carbons
hexa= 6 carbons
octa= 8 carbons
What are the double-bond endings for fatty acid systemic names?
anoic= no bonds
enoic= 1 double bond
dienoic= 2 double bonds
trienoic= 3 double bonds
tetraenoic= 4 double bonds
pentaenoic= 5 double bonds
hexaenoic= six double bonds
no double bonds
1 double bond
What are the systemic and trivial names for 16:0?
palmitic acid (palmitate)
What are the systemic and trivial names for 18:0?
stearic acid (stearate)
What are the systemic and trivial names for 18:1 delta 9?
octadecenoic oleic acid
What are the systemic and trivial names for 20:3 (delta5,8,11)?
(no trivial name listed)
What is the precursor for the omega-9 family?
What are the systemic and trivial names for 18:2(delta9,12)?
What are the systemic and trivial names for 18:3(delta6, 9, 12)?
What are the systemic and trivial names for20:4(delta5,8,11,14)?
What are the systemic and trivial names for18:3(delta9,12,15)?
What are the systemic and trivial names for 20:5 (delta5, 8, 11, 14, 17)?
no trivial name listed
What are the systemic and trivial names for 22:6 (delta 4,7,10,13,16,19)
no trivial name
What is the precursor for the omega-6 family?
AKA linoleic acid
What is the precursor for the omega-3 family?
AKA alpha-linolenic acid
What can inhibit the expression of stearoyl-coA desaturase (delta 9 desaturase) by inhibiting its transcription? Why?
linoleate, linolenate, and their longer, more unsaturated products
this makes sense because inhibiting the elongation and desaturation of palmitate through delta 9 desaturase gives them preferential acces to the delta6 and delta5 desaturases and their elongation reactions.
Why is inhibition of delta9 desaturase by linoleate, linolenate, and their products okay?
omega 9 fatty acids are not essential, and this inhibition products give preference to the formation of the essential fatty acids that the cell needs.
What is the regulation of the elongation and desaturation of fatty acids designed to do?
make sure you get enough of eicosatetraenoic acids, which are precursors to prostaglandins.
If omega 9 fatty acids are not essential, why do we even have that pathway?
it is a fallback pathway to provide lipids for membrane structure in the event of a fatty-acid deficient diet
What 3 enzymes involved in fatty acid biosynthesis are affected by transcriptional regulation?
fatty acid synthase
Role of SREBP-1c in fatty acid biosynthesis
sterol response element binding protein 1c.
The sterol response element is a cis-acting element in the promoter of the genes for:
fatty acid synthase
This element is bound by SREBP-1c. Binding enhances transcription of the gene.
How does addition of essential fatty acids to diet affect the transcription of acetyl-coA carboxylase, fatty acid synthase, and stearoyl-coA desaturase?
increases the transcription of all
How does SREBP-1c regulate fatty acid synthesis?
SREBP is a transcription factor. the "pro" form of the protein is tethered to the ER membrnae.
Fed conditions stimulate its movemtn to the golgi, where it comes in contact with 2 proteases, S2P and S1P.
These proteases cleave themolecule and releases the helix-loop-helix portion of the molecule, which is the TF.
The HLH portion travels to the nucleus, where it can bind response elements in the promoters of the genes for FAS, ACBX, and SCD.
Transcription is activated and these enzymes are expressed.
Where is SREBP normally found (before activation)
tethered to the ER membrane
What initiates movement SREBP from the ER membrane? Where does it go?
moves to the golgi
What cleaves SREBP in the golgi?
S2P and S1P (proteases)
What portion of the SREBP is a TF?
Where would you find the SREBP protein when there is no insulin in the environment?
in the ER
How do polyunsaturated fatty acids of the omega-6 and omega-3 families inhibit SREBP?
they inhibit the movement of SREBP from the ER to the golgi;
this means that S2P and S1P won't get to interact with SREBP to cleave it, and this inhibits transcription of lipogenic genes
What would be the consequence of a deficiency of S2P on the amount of acetyl-coA carboxylase and fatty acid synthase in cells? How would this affect the flux of linoeate to arachidonic acid?
1. it would decrease the amount of acetyl coA carboxylase and fatty acid synthase because S2P can't activate the SREBP's Helix-loop helix transcription factor
2. it would increase flux of linoleate to arachidonic acid because the other 2 fatty acids can't be formed, due to decrease of acetyl coA
What 3 tissues have the highest rates of triacylglycerol synthesis?
(mammary gland as well during lactation)
What are the 2 main ways to make triacylglycerol?
1. re-esterify mon-acylglycerol with 2 fatty acids
2. synthesize the backbone de novo from DHAP
Where do the reactions that form triacylglycerol take place?
membrane of the smooth ER
General triacylglycerol synthesis
(keep adding total of 3 fatty acyl-CoAs), involves acyl transferases
What differs between synthesis of VLDL in the liver and formation of chylomicrons
1. uses apo B100, which is not edited
2. made in liver cells
3. secreted directly into bloodstream
What are the 2 possible sources of lipids that can be used to make VLDLS?
1. de novo synthesis
2. diet via uptake of chylomicron remnant
What determines the rate of VLDL synthesis?
amount of TAG in the liver cell
Why does the liver form VLDLs?
once we have made the triacylglycerol, we don't want it all to build up in the liver, so we must ship it out (through the same general mechanism used to make chylomicrons)
Mechanism for VLDL synthesis
1. make apo B100
2. apo B100 translated in the rough ER, moves to smooth ER, interacts with TAG droplets, moves to golgi, secreted directly into the bloodstream as a VLDL
Metabolism of VLDL in the periphery is the only source of what in the body?
What determines whether or not an IDL is formed as an intermediate in VLDL metabolism in the periphery?
simply a function of how much TAG was removed from the lipoprotein lipase
What enzyme removes TAG from VLDL and IDL to make LDL and HDL?
lipoprotein lipase on endothelial cell membranes
When during VLDL metabolism do few IDL form?
when CII levels are high and LPL is very active
When during VLDL metabolism do many IDL form?
if CIII is high and LPL activity is lower (note: not off)
What lipoprotein may be as atherogenic as LDL?
Describe VLDL metabolism in the bloodstream
1. acted upon by apo E, Apo CII/CIII from HDL
--CII stimulates, CIII inhibits
2. as we remove TAG from the VLDL (using lipoprotein lipase), we generate particles that are more dense (have less lipids)
3. If we form an IDL< it can undergo further removal by LPL to form LDL and HDL
What apo protein does LDL not have?
What tissues can clear LDL
multiple (not just the liver)
How do HDL and IDL form?
biproducts of removal of TAG from IDLs via LPL
What tissue(s) can clear IDL?
just the liver
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