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183 Cards in this Set

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  • Back
What are the 2 subunits of ATP synthase? What does each do?
Fo (oligomycin) is the proton channel.
F1 is the ATP synthesis part.
Why does it take 4 protons to make ATP instead of 3?
3 are required to turn the synthase 360 degrees. However, free Pi must be in matrix to create ATP. A proton is co-transported with Pi into the matrix. This is why 4 protons make 1ATP.
What does E° tell you?
The more negative E°, the more likely a compound will release/transfer electrons.
What is the function of ubiquinone?
It transfers either 1 or 2 electrons from complex I/II to complex III.
What is the function of cytochrome C? Which membrane is it found on?
Transfer electrons between complex III and IV.
Outer mitochondrial membrane
What is the name of complex I? What about complex II? What accounts for the fact that FADH2 only gets you 1.5ATP whereas NADH gets you 2.5?
Complex I or NADH dehydrogenase.
Complex II or Succinate dehydrogenase
FADH2 feeds into complex II which doesn't pump protons.
NADH feeds into complex I which pumps 4 protons.
What are the components of the electron transport chain?
Complex I pumps 4 protons, passes electrons to Ubiquinone.
Complex II pumps no protons, also passes to Ubiquinone.
Ubiquinone passes to complex III which pumps 4 protons. Complex III (cytochrome reductase) passes to cytochrome c and reduces it.
Cytochrome c then is oxidized by complex IV which pumps 2 protons.
Finally the electrons are given to Oxygen.
Which 2 compounds inhibit complex I?
What compound inhibits complex III?
What compound inhibits complex IV?
Rotenone and amytal
How does dinitrophenol work?
Binds protons on the outer surface of the mitochondria. Moves through into matrix and releases protons. As a result, it kind of uncouples the gradient.
Name the 3 hormones that adipose tissue releases? What are their functions?
Adiponectin, resistin - peptide hormones assoc. with insulin resistance.
Leptin - controls appetite.
What type of enzyme is the insulin receptor? How does it function?
Tyrosine kinase.
It has 2 alpha and 2 beta subunits. The alpha subunits inhibit the beta subunits from phosphorylating. When insulin binds, the alpha subunits are changed so their inhibition is removed.
Name the 4 targets that the insulin receptor phosphorylates? Which 2 are the main ones?
IRS protein - main
CBL/Cap protein
Shc protein - main
Gab protein
What do the Sh2 proteins do?
The Sh2 proteins bind to phosphorylated tyrosine residues on the IRS protein. They are either kinases, phosphatases or activate G-protein cascades.
What are the roles of IRS1-IRS4?
IRS-1 is involved in cell differentiation and division due to insulin stimulus.
IRS-2 is involved in glucose uptake by the cell.
3 and 4 are unknown.
What is different about the way that the Cbl/Cap protein sends it's message?
It does not work through phosphorylation dependant kinase mechanisms. It activates lipid rafts and caveolae which increase glucose uptake in response to insulin.
What is PI3K? WHy is it called that? What happens when it does it's job?
PI3K is phosphatidylinositol 3 kinase and it is called that because it phosphorylates PIP2 at the 3' OH position.
When PIP2 is phosphorylated, it activates phosphorylation dependant kinases (PDK1). PDK1 increases glycogen synthesis, movement of GLUT4 to surface and cell division.
How do I activate PDK1?
What does it do?
Insulin binds to it's receptor
Beta subunit phosphorylates tyr residues on IRS protein which activates PI3K
PI3K phosphorylates PIP2 at the 3' position which activates PDK1
PDK1 increases glycogen synthesis, moves GLUT4 to the surface for increased glucose uptake and stimulates cell differentiation and division.
Other than activating PDK, how does PIP2 have an effect?
When it is activated by PI3K, it can activate phospholipase C which cleaves PIP2 into DAG and IP3. Both of these are 2nd messengers.
What mechanisms do the following proteins work through? IRS, Cbl/CAP, Shc and Gab.
What cellular changes can these make?
IRS works through PI3K to increase either PDK activity or phospholipase C activity. This stimulates glucose transport, glycogen synthesis and cell division.
Cbl/CAP works through lipid rafts/caveolae to increase glucose uptake.
Shc and Gab work through Mitogen activated protein kinases (MAPK) which stimulates cell division.
What are the 3 ways that IRS proteins are controlled?
Proteosome degradation
Ser/thr phosphorylation
How does TNFa and ffa's cause insulin resistance in obese patients?
TNFa and ffa's stimulate ser/thr kinases which phosphorylate the IRS protein preventing it from being phosphorylated at tyr residues.
What is mTOR and how does it work?
mTOR is a protein product of the IRS PI3K cascade. It phosphorylates ser residues on the IRS protein which specifically prevents PI3K from binding to IRS.
This dampens the insulin signal through feedback inhibition.
How does PKCξ work?
It phosphorylates the IRS protein which causes it to release from the insulin receptor. IkB kinase β is the instigator that starts the whole process.
How do the protein tyrosine phosphatases relate to insulin sensitivity?
The PTPases are coded for by PTPB1. They dephosphorylate the IRS protein to decrease insulin signaling. KO mice for PTPB1 show increased insulin sensitivity.
An inhibitor PTPB1 is a potential drug therapy for obesity induced Type II.
How does the SHIP2 protein work?
It does exactly the opposite of PI3K, it dephosphorylates PIP2 at the 3' position.
What are potential treatments for insulin resistance?
Inhibitors of mTOR, PKCξ and IKKβ.
Salicylates have been shown to block IKKβ for treatment of type II.
What is the PPARγ? What do they do? What drug blocks them?
Peroxisome proliferator activated receptors.
They increase CAP protein function thereby increasing glucose uptake.
They stimulate release of adipokines from adipose to cause liver to increase fat storage and production.
What are the relative melting points of fatty acids?
Unsaturated fats have very low melting points - often liquids at room temperature.
Short chain saturated fats have lower MP's than longer chain saturated fats.
What is structure of palmitic acid?
What is structure of stearic acid?
What is structure of oleic acid?
What is structure of linoleic acid?
What is structure of linolenic acid?
What is structure of arachidonic acid?
Which fatty acid bond is more prevalent in our bodies cis or trans?
Cis is more prevalent. Trans are found in plant fats
How does the omega system differ in nomenclature?
You number the carbons from the CH3 end instead of the COOH end.
Are most polyunsaturated fats conjugated or non-conjugated? What does this mean?
They are non-conjugated
Conjugated means that every carbon is involved in 1 double bond.
Non-conjugated means there is a methylene group between C=C
When would you use phosphatidal instead of phosphatidyl?
In the case of plasmalogens when the bond between fatty acid and glycerol is an ether bond not an ester bond.
What is saponification?
The formation of soap when fatty acid of longer than 20 carbons reacts with heat and base.
What do we need to get fatty acids into the mitochondria?
We need to activate them with HSCoA, the enzyme acyl-CoA synthetase and ATP.
Acyl-CoA synthetase can also be called thiokinase.
What do we do with Acyl-CoA once we have formed it in the cytosol?
We esterify it with carnitine and the enzyme carnitine palmitoyl transferase 1. The product is acylcarnitine.
We can now move it into the intermembrane space.
What enzyme is needed to move acylcarnitine into the matrix of the mitochondria?
Carnitine acylcarnitine translocase because it exchanges carnitine in the matrix for acylcarnitine from the space.
Where is CPTII found? What does it do?
Carnitine palmitoyl transferase II is found on the matrix side of the inner mitochondrial membrane.
It cleaves the acyl-CoA off of carnitine for β oxidation.
What inhibits CPT1?
Malonyl-CoA which is the substrate required for fa synthesis
What is the 1st step in β oxidation? What enzyme and cofactor are used?
Create a double bond btw alpha and beta carbons.
Enzyme is acyl-CoA dehydrogenase and the cofactor is FAD
Which step in β oxidation requires FAD?
The first step of creating a double bond between alpha and beta carbons.
What type of double bond is formed in the 1st step of β oxidation?
A trans double bond btw alpha and beta carbons.
What enzyme does the 2nd step of β oxidation use and what does it do?
Enoyl-CoA hydratase and it adds water across the double bond to form a hydroxyl group on the β carbon (3-hydroxyacyl-CoA)
What enzyme does the 3rd step of β oxidation and what does it do?
3-hydroxyacyl-CoA dehydrogenase and it converts the OH group on the β carbon into a C=O to form 3-ketoacyl-CoA
What is the 4th step of β oxidation? What enzyme catalyzes this reaction?
Thiolase adds HSCoA to the β carbon and cleaves off acetyl-CoA. The products are an acyl-CoA product 2 carbons shorter and acetyl-CoA.
Thiolase can also be known as acetyl-CoA acetyltransferase
How many acetyl-CoA do you get from β oxidation of an 18 carbon fatty acid?
How many FADH2, NADH, ATP, H20?
18/2 = 9 Acetyl-CoA
9-1 = 8FADH2, 8NADH, 8H20
7x1.5 = 12 (FADH2)
8x2.5 = 20 (NADH)
9x10 = 90 (acetyl-CoA)
Total ATP 122 - 2 (activation) = 120
What is the first step in ketone body formation? What enzyme is involved?
Add acetyl-CoA to acetoacetyl-CoA (the last 4 carbons of β oxidation) to form HMG-CoA.
HMG-CoA synthase
In ketone body generation instead of adding acetyl-CoA to acetoacetyl-CoA to form HMG-CoA why not just leave a 6 carbon fragment from β oxidation?
Because the acetyl-CoA is not added in a straight chain. It is added to the C=O on the β carbon where a OH group has now formed.
What do we do with HMG-CoA when we are making ketones?
Using HMG-CoA lyase, we remove acetyl-CoA leaving us with acetoacetate.
T/F the acetyl-CoA added to form HMG-CoA is the same acetyl-CoA that gets kicked off when formed ketone bodies?
False, it is a different 2C fragment.
What enzyme and cofactor are required for formation of β-hydroxybutyrate from acetoacetate?
β-hydroxybutyrate dehydrogenase and NADH is oxidized to NAD.
What is the difference in structure between β-hydroxybutyrate and acetoacetate?
β-hydroxybutyrate is a straight chain whereas acetoacetate is branched. The β carbon also has a hydroxyl instead of C=O which is why we need NADH.
How do we form acetone?
It is spontaneous decarboxylation from acetoacetate
What happens to ketones once they get to other tissues?
The β hydroxybutarate is converted into acetoacetate. This generates 1 NADH.
Succinyl-CoA gives up CoA to acetoacetate to form acetoacetyl-CoA.
Due to this, acetoacetyl-CoA bypasses the first 3 steps of β oxidation.
Finally thiolase cuts the acetoacetyl-CoA into 2 acetyl-CoA.
Ketones do not generate the same amount of ATP as normal β oxidation of a 4C fragment.
What is the difference between fasting, prolonged fasting and DM in terms of tissue usage?
Fasting - protein provides a lot of glucose for brain and RBC's. Adipose provides ketones and ffa's for heart, kidney and muscle.
Prolonged fasting - protein no longer provides glucose. Adipose provides ketones for brain and ffa's for muscle, heart and kidney. Ketone bodies end up in urine.
DM - Muscle breakdown is huge and brain uses glucose from this. Heart, kidney and muscle use ketones and ffa's. Ketones and glucose end up in urine.
How do you breakdown odd carbon unsaturated fatty acids? How do you change ATP yield calculation?
β oxidation is run until the cis double bond is at 3 position. Enoyl-CoA isomerase converts this into a trans double bond at 2 position which is now the normal acyl-CoA structure for β oxidation.
It yields 1.5 less ATP because FADH not generated in forming double bond.
How do you breakdown even carbon unsaturated fatty acids?
β oxidation is run until your trans double bond exist at 2 position and the existing cis double bond at 4 position. Using dienoyl-CoA reductase, you combine the 2 bonds into a 3 position trans bond and then using enoyl-CoA isomerase, you move the trans double bond to the 2 position. Now β oxidation can run as usual.
What happens if you have to degrade an odd numbered fatty acid? What enzymes and cofactors are used?
You use β oxidation until proprionyl-CoA exists. Using proprionyl-CoA carboxylase, ATP and biotin you add a carbon to form methylmalonyl-CoA. Then with methylmalonyl-CoA mutase and B12, you form succinyl-CoA.
What is the similarity between pyruvate carboxylase and proprionyl-CoA carboxylase?
Both use ATP and biotin.
How do you breakdown branched chain fatty acids?
Using alpha oxidation. The alpha carbon in this case is COOH and the β is CH2. You add OH to B carbon, you then convert it into C=O and then decarboxylate the compound to give CO2 and RCOOH.
What enzymes and cofactors are used in alpha oxidation?
Monooxygenase, O2, Fe2+ and ascorbate are used to form OH group on β carbon.
Then the OH is oxidized and NAD is reduced with a dehydrogenase enzyme.
Finally, ATP, NAD+ and ascorbate are used to decarboxylate the compound.
What genetic disease results when alpha oxidation is deficient?
Refsum's disease.
How do we form bile acids? What cofactors and enzymes are used?
We use ω oxidation to convert CH3 to COOH forming a dicarboxylic acid.
Monooxygenase and NADPH - notice NADPH
Where does fa synthesis occur? What about elongation of fatty acids and desaturation?
Synthesis occurs in the cytosol.
Elongation occurs in the mitochondria
Desaturation occurs in the ER.
What is the rate limiting step in fa synthesis? What enzyme and cofactors are required?
The formation of malonyl-CoA from acetyl-CoA.
Acetyl-CoA carboxylase, biotin, ATP and HCO3- are required for the formation.
How do we control fa synthesis? What are the control molecules?
We control acetyl-CoA carboxylase.
Citrate allosterically activates ACC.
Palmitoyl-CoA inhibits it for feedback inhibition.
Glucagon increases cAMP which phosphorylates the enzyme inactivating it.
What allows fatty acid synthetase to have 2 binding sites?
ACP is attached which has an SH binding site. FAS has it's own SH binding site.
How do you prep for fa synthesis?
Attach acetyl-CoA to FAS SH with acetyl transferase
Attach malonyl-CoA to ACP SH with malonyl-CoA.
What is the 1st step of fa synthesis? What enzyme is required?
Transfer the acetyl-CoA group on the FAS protein to malonyl-CoA on the ACP protein. Lose COOH to form β-ketoacyl.
Enzyme: β-ketoacyl synthetase.
How many CO2 are encorporated into a fatty acid?
None, the CO2 added in forming malonyl-CoA is lost when transferring acetyl-CoA to malonyl-CoA on the ACP protein.
What is the 2nd step of fa synthesis? What enzyme is required? What cofactor is required?
You convert the β carbon C=O to C-OH.
Enzyme: β-ketoacyl reductase
IMPORTANT: NADPH is used here for the first time.
What is the 3rd step of fa synthesis? What structure is formed? What type of double bond is formed?
Use a hydratase enzyme to take H2O off the C-OH and form a double bond btw alpha and β carbon.
Trans double bond.
What is the 4th step of fa synthesis? What enzyme and cofactors are used?
Reduce the double bond btw α and β carbons to a single bond.
Enzyme: Enoyl reductase
NADPH is once again used right here
What 2 steps of fa synthesis do we use NADPH?
Reducing the β C=O to an OH (step 2)
Reducing the C=C to single bond (step 4).
What is the last step of fa synthesis?
Using a transferase, we move the acyl fragment from the ACP protein to the FAS protein so that a new malonyl-CoA can join at the ACP protein
How many acetyl-CoA, malonyl-CoA, NADPH, ATP and CO2 do we need to make palmitic acid?
8 acetyl-CoA
7 malonyl-CoA
14 NADPH (2 for each cycle, except for the first kind of)
7 ATP to form malonyl-CoA
7 CO2 to add to malonyl-CoA but none of these are encorporated, just used.
What is the source of NADPH for the following tissues?
Liver, brain, muscle
Liver gets it from the pentose phosphate shunt.
Brain gets it from cytosolic isocitrate dehydrogenase
Muscle gets it from malic enzyme, converting OAA into malate.
What is C75? How does it work?
It is a new drug for obesity. It blocks FAS which increases malonyl-CoA which inhibits certain neuropeptides responsible for appetite.
What are the steps of fatty acid elongation?
Reverse of β oxidation.
Thiolase to add acetyl-CoA to palmitic acid.
Dehydrogenase (EXCEPT WITH NADPH) to create OH group.
Hydratase to convert OH to a double bond.
Finally dehydrogenase (ONCE AGAIN WITH NADPH INSTEAD) to form a single bond.
How do you make unsaturated fatty acids? What enzyme is needed? What are the contraints?
You use the desaturase (monooxygenase) enzyme to create a cis double bond anywhere except past carbon 9.
Why do we need linoleic and linolenic acid in the diet?
Because both have double bonds past carbon 9 which our desaturase enzyme can't make.
How do we make arachidonic acid? What about docosahexaenoic acid?
Take linoleic acid 18:2∆9,12.
Add a 6C double bond to form
Then add 2C to give you 20:3∆8,11,14 (arachidonic acid)
Similar process except use linolenic acid.
When are linoleic and linolenic acid not required in the diet?
When arachidonic and docosahexaenoic acid are provided.
What method can only the intestines use to make TGLs? What enzymes are required?
Taking monoglyceride and adding acyl groups to form TGL.
Monoacylglycerol acyl transferase and Diacylglycerol acyl transferase
What method can only liver and intestines use to make TGL's?
Take glycerol, phosphorylate it with glycerokinase to form α-Glycerophosphate.
Add 2Acyl-CoA to form 1,2-Diacylglycerol (phosphatidic acid).
Use phosphatidate phosphohydrolase to remove the phosphate to form diglyceride.
What method can all liver, adipose and intestines all use to make TGL's?
Use α-Glycerophosphate dehydrogenase and NADH to convert C=O in middle to CH2-OH.
Now you have α-Glycerophosphate.
Convert this to phosphatidic acid and the rest is easy.
Why do alcoholics develop fatty livers?
Alcohol dehydrogenase generates NADH when converting ethanol to acetaldehyde.
Acetaldehyde is then converted into acetate by acetaldehyde dehydrogenase which also generates NADH.
Increases in NADH stimulate α-Glycerophosphate dehydrogenase which converts DHAP into α-Glycerophosphate. This increases TGL formation.
What enzyme breaks down TGL's in adipose tissue and what are the products formed?
Triglyceride lipase converts TGLs into diglycerides and ffa's.
Diglycerides are further broken down into glycerol and ffa's.
Why can't adipose tissue make TGL's out of glycerol?
Because it lacks glycerokinase which is required to convert glycerol into α-Glycerophosphate.
This is also why during fa breakdown in adipose tissue, the glycerol cannot be used and is sent to the liver for processing.
Where does the formation of glycerophospholipids occur?
What is a precursor to their formation?
In the ER.
1,2-diacylglycerol phosphate (phosphatidic acid)
When forming PC or PE, which compound is CDP activated?
The choline or ethanolamine is CDP activated and then added to the 1,2-diacylglycerol (diglyceride)
When forming PC or PE, do you use phosphatidic acid or diglyceride? What about PI?
You use diglyceride for PC and PE and you use phosphatidic acid for PI
When forming PI, which compound is CDP activated?
The phosphatidic acid is CDP activated in this case
How do you attach the CDP to ethanolamine or choline? What about CDP-phosphatidic acid?
The choline or ethanolamine is phosphorylated with ATP. Then CTP adds to the phosphorylated portion kicking off PPi and yielding CMP.
Well phosphatidic acid is already phosphorylated, so just add the CTP.
Which 2 phospholipids can you easily interconvert? How do you do this?
Phosphatidylethanolamine and phosphatidylserine.
To form PS, you just exchange the serine for ethanolamine.
To form PE from PS, you have to decarboxylate.
Name 2 ways to make phosphatidylcholine?
Add CDP-choline to diglyceride or use SAM to triple methylate PE.
What happens to the position of PE in the membrane as you methylate it?
PE moves to the outside, the more methyls you add to form PC.
Name 3 functions of phospholipids?
They form membranes for cellular structural support
PIP2 can be cleaved by phospholipase C to yield 2nd messengers IP3 and DAG.
You can cleave PI with phospholipase A2 to yield arachidonic acid for prostaglandin synthesis.
How does DAG cause it's 2nd messenger effects?
It activates protein kinase C which phosphorylates a number of protein products (including IRS proteins for insulin signalling)
How does IP3 cause it's 2nd messenger effects?
It binds to the ER and causes Ca2+ release which activates certain proteins and other protein kinases.
What is the precursor to all sphingolipids?
How do you make this?
Add serine to palmitic acid to form dehydrosphinganine. Then reduce with NADPH to form sphinganine and introduce a double bond for sphingosine.
Finally, the most important step, add a fatty acyl to the serine residue in an AMIDE BOND to form ceramide.
How do you make sphingomyelin? What about cerebrosides? What about sulfatide and gangliosides?
Add CDP choline to ceramide
Add UDP-gal or UDP-glu to ceramide
For sulfatide add the activated sulfur compound PAPS to cerebroside.
For gangliosides add a number of sugar residues and sialic acid.
What is wrong in Niemann-Pick's disease?
Sphingomyelinase is missing so sphingomyelin builds up
What is wrong in Gaucher's disease?
Lack of glucocerebrosidase
As a result glu-ceramide increases.
What is wrong in Tay-Sachs disease?
Lack of hexosaminidase A
Normally breaks down N-acetylgalactosamine ceramide to ceramide
N-acetyl builds up in cells.
Which organelles contain high levels of PC, sphingomyelin, cholesterol and cardiolipin
ER contains high PC
Plasma membrane contains high sphingomyelin and cholesterol
Mitochondrial membranes contain high cardiolipin
What is a way to tell that an RBC is old by looking at the phospholipids?
Normally PC, sphingomyelin and cholesterol are high on the outside of the membrane and PE is high on the inside.
When an RBC is diseased, PC and sphingomyelin are on the inside.
What are 2 markers of apoptosis?
PS shifts to the outside of the membrane because ATP is usually required to keep it on the inside.
Cytochrome C is released from the mitochondria and the nucleus becomes pyknotic.
What is the difference between membrane bound proteins and cytoplasmic proteins?
They DO NOT contain more hydrophobic residues but do have hydrophobic residues every 3 aa's or so.
List the 5 functions of membrane proteins
Act as transporters (GLUT)
Act as communication between cells (receptors)
Act as markers (ABO blood)
Hormone receptors
Enzymatic activity
How do spleen macrophages detect aging RBC's?
How could you mimic the action?
RBC's normally have sialic acid attached to their surface proteins. This sialic acid has a negative charge and allows them to repel one another. When RBC's age, they lose this sialic acid as it breaks off. Macrophages can recognize this missing sialic acid and destroy the RBC.
If you use neuraminidase, you can remove the sialic acid enzymatically.
What is the very first step in cholesterol synthesis? What enzyme is used?
Take 2 acetyl-CoA and combine them into acetoacetyl-CoA in the reverse of the last step of B-oxidation.
The enzyme is thiolase which is actually named for the reverse reaction.
What is the second step of cholesterol synthesis? What enzyme is used?
The second step is adding another acetyl-CoA to acetoacetyl-CoA to form HMG-CoA.
The enzyme that does this is HMG-CoA synthase (same in ketone body formation)
What is the rate limiting step of cholesterol formation?
What enzyme is it?
What cofactors are used?
What control do we have of this enzyme?
Where does this reaction take place?
The rate limiting step is HMG-CoA reductase converting HMG-CoA into mevalonate.
HMG-CoA reductase uses NADPH and it controlled by cholesterol through negative feedback. In addition, this is where the statin drugs work.
This reaction takes place in the ER.
Discuss the formation of cholesterol from mevalonate including numbers?
6 x Mevalonate = Isopentenyl pyrophosphate
2 x Isopentenyl pyrophosphate = Geranyl pyrophosphate
Geranyl pyrophosphate + Isopentenyl pyrophosphate = Farnesyl pyrophosphate
Farnesyl pyrophosphate X 2 = Squalene X 1 = cholesterol
Name all the controls of HMG-CoA reductase including
Genetic, covalent and allosteric controls
Cholesterol and farnesyl pyrophosphate inhibit transcription and translation of the HMG-CoA enzyme. They also increase protease activity to degrade it.
Cholesterol allosterically inhibits the enzyme
Glucagon increase cellular cAMP which phosphorylates the protein. THIS INACTIVATES IT
Insulin lowers cAMP which dephosphorylates HMG-CoA reductase which ACTIVATES IT.
What type of inhibition do statin drugs have on HMG-CoA reductase?
They are competitive inhibitors of HMG-CoA.
What are the uses of Farnesyl pyrophosphate?
Forming ubiquinone, dolichyl, anchor proteins and geranyl geranylated proteins
How do you make a cholesterol ester? What enzymes can be used?
Attach a fatty acid to the OH group on the A ring in the form of acyl-CoA.
Either ACAT (acylcholesterol acyl transferase) or LCAT (lecithin cholesterol acyl transferase).
Where are ACAT and LCAT found?
ACAT is found in the tissues and LCAT in the plasma.
Where does LCAT get it's substrate from?
LCAT cuts a monounsaturated fatty acid off of lecithin (PC) and transfers it to cholesterol.
What is the relationship with oleic acid and LCAT?
If you eat a diet rich in oleic acid, PC will have oleic acid at the R2 position.
LCAT will then take this oleic acid and transfer it to cholesterol and store the oleic acid. This is good.
What does a deficiency in LCAT cause?
It causes the serum free cholesterol to rise in the blood and the CholE to drop. Normally the ratio is 25% free, 75% CholE.
T/F ACAT uses lecithin to form cholesterol esters in the tissues?
False, ACAT can add any fatty acyl-CoA to cholesterol for storage.
What are the two major bile acids?
What is the main difference between them and cholesterol?
Cholic acid and chenodeoxycholic acid
The proprionic group of cholesterol was cleaved by ω and β oxidation. This left a COOH group at this position.
Other than that, numerous positions are hydroxylated.
What is the normal ratio of cholic acid to chenodeoxycholic acid?
80% cholic
20% chenodeoxycholic acid.
What are the steps of bile formation? Include rate limiting step and enzyme
Cholesterol is converted into 7-a-hydroxycholesterol by cholesterol 7-a-hydroxlase. THIS IS THE RATE LIMITING STEP.
The 7-a-hydroxycholesterol is then converted into 7-a-hydroxy-4-cholestene-3-one by a dehydrogenase, isomerase and NAD is needed. This step involves moving the double bond from the B to the A ring and oxidizing the OH group to C=O
This last compound is then converted into cholic acid and chenodeoxycholic acid.
What enzyme do we control when we control bile synthesis? What can we control it with?
7-a-hydroxylase which starts the conversion of cholesterol into bile acids.
Cholesterol is a positive stimulus for this enzyme and bile acids are a negative feedback.
How do we convert cholic acid to primary bile acids? Which primary bile acid is more common?
What happens if we shift this balance?
Using CoASH and ATP, we attach the CoA to the COOH group on cholic acid. Then with either glycine or taurine, we attach the aa to this same area kicking off the CoA. We now have primary bile acids like taurocholic acid or glycocholic acid.
(Note, you can do this with chenodeoxycholic acid too).
Glycocholic acid is 75% and Taurocholic acid is 25%.
You develop gall stones.
What time of bond exists between taurine/glycine and cholic acid? Why is this important?
What other compound has an amide bond between a fat and an aa?
An AMIDE bond
Bacteria can break this bond to help with excretion.
Ceramide - serine and palmitic acid or additional fatty acid added.
What is a secondary bile acid?
Bacteria remove OH groups on primary bile acids and amide linkage to form secondary bile acid.
How do you form cholestanol and coprosterol? Can you absorb these?
Bacteria reduce the double bond of the B ring of cholesterol to allow for excretion.
These compounds are not reabsorbable bile acids.
What are the functions of bile acids?
Accelerate action of p.lipase
Aid in emulsification
Help absorb ADEK vitamins
Keep cholesterol in solution allowing excretion.
Bile acid excretion stimulates intestinal motility
Major route of cholesterol removal from the body.
What are the 3 drugs for lowering cholesterol and how do they work?
1) Statin drugs block HMG-CoA reductase preventing the formation of cholesterol
2) Cholestyramine blocks reabsorption of bile acids thereby stimulating 7-a-hydroxylase to make more and use up cholesterol.
3) Vitorin also blocks bile acid reabsorption.
How do you absorb diet cholesterol?
Cholesterol esters are broken down by esterases into cholesterol and ffa's and both are absorbed.
What is the main way we absorb TGL's?
P. lipase cuts fatty acids off either side of the TGL and yields a monoglyceride and 2 fatty acids. These are then absorbed.
How do we absorb phospholipids?
Prophospholipase is released from the pancreas and trypsin activates it. This then cuts off the middle fatty acid to yield lysophospholipid which is absorbed.
What are the 2 ways to separate lipoproteins in the lab? What is the order the elute in both cases?
Top to bottom: Chylomicrons, VLDLs, IDLs, LDLs, HDLs
Source to end: Chylomicrons, LDLs, VLDLs and HDLs
What are the main compositions for the lipoproteins and what are their alternate names?
HDL (a-lipoproteins) mostly protein (their fat is phospholipid)
LDL (B-lipoproteins) mostly cholesterol
VLDL (preB-lipoproteins) mostly TGL's
Chylomicrons mostly TGL's
What apolipoprotein is specific to chylomicrons?
What is the disease called if you are missing it?
A betalipoproteinemia
What are endogenous and exogenous lipoproteins?
Endogenous - VLDL's
Exogenous - Chylomicrons
What enzyme is needed to convert a VLDL into an IDL?
What about converting IDL into LDL?
Lipoprotein lipase to remove TGL's from the VLDL
LCAT to transfer the cholesterol ester from HDL to IDL to form LDL. In the process cholesterol is given to the HDL.
What are the important apolipoproteins, where are they found and what is their function?
A-1 on HDLs and VLDLs. It 'A'ctivates LCAT
B-48 on chylomicrons. Needed for synthesis in intestines.
B-100 on LDLs, IDLs and VLDLs. 'B'inds to liver for remnant uptake.
C-1 is found on chylomicrons and VLDLs. Activates LCAT like A-1
C-11 is found on chylomicrons and VLDL's. Activation lipoprotein lipase.
E found on VLDLs, IDLs and chylomicrons. Also for liver recognition.
Discuss LDL receptor control in tissues
LDL binds to receptor.
Is taken up by cell by receptor mediated endocytosis
The cholesterol ester inside is broken down into free cholesterol and fatty acids.
This free cholesterol inhibits HMG-CoA reductase and also binds to ER to reduce LDL receptor synthesis.
The free cholesterol is then esterified with ACAT to be stored.
4 reasons why HDLs are good for you
1) Speed the formation of LDL's by cholesterol ester transfer with IDLs. This allows quicker storage of cholesterol.
2) They remove TGL's from chylomicrons quickly to leave the cholesterol rich remnant which is taken up by the liver.
3) They tranfer ApoCII and E to VLDLs and chylomicrons to cause faster activation of lipoprotein lipase and quicker uptake of remnants.
4) They take cholesterol from dead tissue and membranes back to the liver for excretion.
What is elevated in Type I hyperlipoproteinemia? What is the problem? Treatment?
It is a genetic deficiency in lipoprotein lipase so chylomicrons and serum TGL's are elevated. There is minor cholesterol elevation.
Reduce dietary fats
What is elevated in Type IIa hyperlipoproteinemia? What is the problem? Treatment?
IIa is an LDL receptor deficiency. Increased LDLs and cholesterol in the serum.
Statins, resins and diet.
What is elevated in Type IIb hyperlipoproteinemia? What is the problem? Treatment?
Also a defective LDL receptor. Increased LDLs, VLDLs, serum cholesterol and TGLs
Statins, resins and diet.
What is elevated in Type III hyperlipoproteinemia? What is the problem? Treatment?
A block converting IDLs into LDLs. IDLs, serum cholesterol and TGLs are increased.
Reduce weight, fat and CHO intake
What is the deficiency in Type IV hyperlipoproteinemia? What is increased? Treatment?
Has no external symptoms
No deficiency, caused by American diet, DM and obesity.
VLDLs and serum TGLs are increased. Serum cholesterol is slightly increased.
Alcohol and CHO's increase VLDLs significantly.
Watch your diet
What is the deficiency in Type V hyperlipoproteinemia? What is increased? Treatment?
Secondary to DKA and nephrosis.
Increased VLDLs, chylomicrons and serum TGLs. Slight serum cholesterol increase.
Treatment not known
What are the 2 stages of atherosclerosis?
1) Formation of fatty streaks which is deposition in macrophages and smooth cells of the blood vessel.
2) Cholesterol esters, dermatin sulfate and platelets form calcified plaques which cause hardening of the arteries and clot formation.
What level of serum cholesterol predisposes you to an MI? What else does it predispose you to? What is the recommended level to stay below?
> 250mg/dl
Death from the 1st MI
What are the primary factors increasing your risk for MI? What about secondary factors?
Primary factors
Smoking, serum cholesterol and hypertension
Secondary factors
Decreased exercise, stress, diabetes, obesity, OCD
What 2 ratios are you interested in for your atherosclerosis risk?
Total cholesterol/HDL < 5
How do foam cells form?
Cholesterol deposits in the tunica intima of the artery. This cholesterol gets oxidized and is taken up by macrophages, these are foam cells.
T-cells can also secrete cytokines which attract smooth muscle cells to ingest the oxidized LDL and form foam cells.
Why do alcohol and statin drugs help with reduced atherosclerosis?
Alcohol and statin drugs are both antioxidants that prevent oxidation of the B ring double bond of cholesterol.
In addition, statins block HMG-CoA reductase lowering the de novo synthesis of cholesterol.
What is the new marker for heart disease? Where does it come from? Does it correlate with serum cholesterol?
C-reactive protein (CRP) comes from the liver in response to vascular cells releasing interleukin-6 after damage.
It does not correlate well with serum cholesterol
What are the new MI risk factors?
[chol] > 200mg/dl
HDL < 40mg/dl
CRP > 3mg/dl
What is the rate limiting step for the formation of prostaglandins?
Cyclooxygenase converting arachidonic acid (or other 20C fatty acids) into PGG2.
What are the 2 enzymes of the PGH synthase complex?
Cyclooxygenase converts arachidonic acid into PGG2.
Hydroperoxidase converts PGG2 into PGH2
Does aspirin block COXI or II better? How does it work?
It blocks COXI best but is also able to block COXII
Aspirin acetylates a serine residue in the active site of COXI. This is an irreversible chemical reaction.
What does tylenol block?
What enzymes do I use to make prostacyclin and thromboxane A2 from PGH2?
Prostacyclin synthase
Thromboxane synthase
Discuss how platelets aggregate? How does aspirin stop this?
Thrombin binds to the platelet and activates phospholipase A2.
This cuts arachidonic acid from PIP2 and COXI converts the arachidonic acid into PGG2 and then hydroperoxidase converts PGG2 into PGH2.
PGH2 is converted into thromboxane A2 by thromboxane synthase.
Thromboxane A2 causes platelets to become sticky.
Aspirin blocks the COXI step.
How does prostacyclin work? Where is it made and how?
PGI2 (prostacyclin) is made in the endothelium.
COXII converts arachidonic acid into PGG2 and then hydroperoxidase converts that into PGH2.
PGH2 is converted into PGI2 by prostacyclin synthase.
PGI2 binds to platelets and activates adenylate cyclase. This lowers cAMP which inhibits Phospholipase A2. No arachidonic acid, no thromboxane A2 preventing platelets from sticking.
Name 2 functions of thromboxane A2 and prostacyclin
TXA2 is a vasoconstrictor and platelet aggregator.
Prostacyclin is a vasodilator and causes platelets to repel.
How do I make leukotrienes?
Lipooxygenase converts arachidonic acid into either LTA4, LTB4 or LTC4. These are inflammatory mediators.
Lipooxygenase can also convert arachidonic acid into 5 or 10-HPETE - these are vasoconstrictors
What can I use to block leukotrienes?
Singulair blocks the action of leukotrienes.
What is saponification?
Using alkaline hydrolysis to break fatty esters into soap.
If the fat doesn't have any esters then it is non-saponifiable
What is the difference btw cis and trans fatty acids?
Cis lower the melting point because it creates a kink in the fatty acid.
What is the function of ∆3 cis-∆2 trans enoyl-CoA isomerase?
It is needed to break down unsaturated fatty acids because B-oxidation requires a trans double bond at the 2 position. The enzyme converts the cis double bond at the 3 position to the 2' trans double bond.
What does a deficiency in LCAT cause?
Low levels of serum cholesterol esters and lysolecithin.
High levels of serum cholesterol and lecithin.
How does a-ketoglutarate dehydrogenase differ from pyruvate dehydrogenase?
Pyruvate dehydrogenase has protein phosphatase activity
Why is oxygen still used when amytal is applied to mitochondria?
Amytal blocks complex I but complex II is still able to feed protons into Ubiquinone
What cofactor does acetyl-CoA carboxylase require?
How do you know how many methylene groups there are in a fatty acid?
There are 2 less than the carbon count unless it is unsaturated.
What cofactor does HMG-CoA reductase need?
NADPH to form mevalonic acid.