Cholesterol Flashcards
1
Q
what is the starting point for cholesterol synthesis (source of all the carbons)
A
acetyl CoA
2
Q
where does most cholestrol come from
A
it is made in vivo
3
Q
why is cholestrol so hard to regulate
What might be the best way to regulate it
A
it is mostly made in vivo, with little contributions from the diet.
best way to regulate might be to eat less = less acetyl CoA
4
Q
what is a main synthetic product of cholesterol
A
steroid hormones
5
Q
how is most cholesterol excreted
A
through bile acids via the intestines
6
Q
cholesteryl esters are used to what
A
store and transport cholesterol
7
Q
what is the activated precursor of cholesterol
A
isopentenyl pyrophosphate
8
Q
what is the main regulatory step of cholesterol synthesis
A
HMG CoA reductase rxn
9
Q
what generates acetyl CoA
A
food is converted to Acetyl CoA which can be made into choelesterol
10
Q
how many carbons are in cholesterol? where do they come from
A
27, all from acetyl CoA
11
Q
how many six-membered rings and how many five membered rings are in cholesterol?
A
3 six membered rings and 1 five membered rings
12
Q
how many carbons does the hydrocarbon side chain have? what carbon is it attached to?
A
8 carbons: attached to carbon 17
13
Q
what do red dots in diagram indicate?
A
red dots in diagram show where COO- from acetate go to
14
Q
what is removed to make steroid hormones
A
hydrocarbon sidechain
15
Q
what is cholesterol made from
A
isoprenes; 5 carbon units
16
Q
how many hydroxyls are in cholesterol and at what position? what is the resulting property of the molecule
A
only one at carbon 3: (3-hydroxy)
it is very hydrophobic
17
Q
where is the only double bond
A
between C5 and C6: called delta-5
18
Q
how many double bonds do isoprenes have
A
2; one at each end
19
Q
cholesterol can be used to make what vitamin
A
vitamin D
20
Q
isopentenyl pyrophosphate has many products it can form
A
vitamin A, vitamin E, vitamin K, rubber, carotenoids, plant hormones, abscisic acid and gibberellic acid, rubber, phytol chain or chlorophyll, dolichols, quinone electron carriers: ubiquinone, plastoquinone, isoprene
21
Q
On the first diagram what products can become acetyl CoA
A
-Starch glycogen and sucrose can all converge to become glucose
– Alanine glucose and serine can all converge to become pyruvate
-Pyruvate can become a seal coat way
-Phospholipids and triacylglycerol’s can be broken down to fatty acids which can then be converted to a acetyl CoA
Phenylalanine and isoleucine are two amino acids that can be converted to acetyl CoA
22
Q
Starting from acetyl CoA, name what molecules it must be converted to an sequential order to become cholesterol
A
Acetyl CoA is converted to acetoacetyl-CoA which is then converted to mevalonate and that is converted to isopentenyl pyrophosphate which is converted to cholesterol
23
Q
According to the diagram what are the possible fates for cholesterol
A
It may become steroid hormone which is the main synthetic product
-It may be converted to bile acids which is the main way in which it is excreted.
– It may become cholesteryl esters which is a form that is used for storage and transport
24
Q
What is the main regulatory step of Cholesterol synthesis
A
The main regulatory step is the reduction catalyzed by HMG CoA way reductase from acetoacetyl-CoA to mevalonate
25
Describe the structure of isoprene
- Four carbon chain with a fifth carbon or methyl group sticking out of the second carbon in the chain
- there is a double bond on either end of the molecule and there are no other Atoms other than carbon and hydrogens
26
What is another name for isopentenyl pyrophosphate?
Activated isoprene
27
How many carbons does squalene have?
How many are removed when it is converted to cholesterol
30 Carbons.
Three carbons are removed when squalene is converted to cholesterol
28
What is the first reaction of cholesterol synthesis?
Two molecules of acetyl CoA are reacted to make acetoacetyl-CoA.
– Enzyme: thiolase
– CoA – SH is released
29
In cholesterol synthesis what is acetoacetyl-CoA reacted with? what product is made?
What enzyme is used?
What is released?
Acetoacetyl-CoA is reacted with acetyl CoA to make beta – hydroxy – Beta – methylglutaryl CoA. (HMG – CoA)
Enzyme: HMG – CoA synthase
Released: CoA – SH
30
How many acetyl – Coa form acetoacetyl-CoA
2
31
What is a third Acetyl CoA reacted with to make HMG – CoA
Acetylacetyl CoA via the enzyme HMG-CoA synthase
32
What is HMG – CoA reacted with to make what product?
What enzyme is used?
What is released?
It is reacted with two NADPH molecules and two protons to make Mevalonate
Enzyme: HMG – CoA reductase
Released: NADP+ and CoA– SH
33
What type of reaction happens in the rate limiting step of cholesterol synthesis
The carboxy carbon is reduced: electrons from two NADPH molecules are added and CoA-SH is released
34
What is production of mevalonate inhibited by?
What kind of inhibition occurs?
What differences are there between the Statin drugs?
It is competitively inhibited by Statins
Statins have different our groups in two different places labeled R1 and R2
35
Name the four Statin drugs
Compactin
Simvastatin (zocor)
Pravastatin (Pravachol)
Lovastatin (Mevavor)
36
How is mevalonate converted to Delta three – Isopentenyl pyrophosphate?
What enzyme is used?
-Mevalonate is phosphorylated sequentially on C5 to form pyrophosphate
– Then phosphorylation at C3 occurs and is followed by immediate decarboxylation at C-1 and subsequent removal of the phosphate on C3 follows that.
37
What are the two activated isoprenes?
Delta three – isopentenyl pyrophosphate and dimethylallyl pyrophosphate
38
How many carbons do each of the precursors of cholesterol have?
Acetyl – CoA has two carbons and 1 Carbonyl carbon
Acetoacetyl – CoA has four carbons and 2 carbonyl carbon's
H MG – CoA has a five carbon chain with a six carbon on the third carbon in the chain; it also has a hydroxyl group on the third carbon; Hey carboxyl group on one end and a thio carboxyl group on the other (with CoA )
Mevalonate has a five carbon chain with a methyl group on the third carbon, hydroxyl group on the third carbon, and another hydroxyl group on the fifth carbon; there is no coA in this molecule
IsoPentenyl pyrophosphate has a four carbon chain with a methyl group on the second carbon and a double bond between C1 and C2; the diphosphate group is attached to the fourth Carbon.
Dimethylallyl pyrophosphate has a four carbon chain with a methyl group on the C2 and a double bond between C2 and C3; the pyrophosphate is attached to the fourth carbon
39
How is squalene made from activated isoprenes?
How many steps?
There are three steps
1. Geranyl pyrophosphate is made by fusing two activated isoprenes
2. A third isoprene is added to Geranyl pyrophosphate to make Farnesyl pyrophosphate
3. Two Farnesyl pyrophosphates fuse to form squalene Using NADPH
40
What is squalene reacted with to make its product?
What is this product?
What enzyme is used?
Squalene is reacted with NADPH and a proton as well as with O2 to make squalene – 2, 3 – epoxid
Enzyme: squalene monooxygenase
Released: H2O and NADP+
41
In animals, what is squalene– 2, 3 – epoxide made into?
What enzyme is use?
It is made into Lanosterol
Enzyme: cyclase
42
What three outcomes are possible from squalene – 2, 3 – epoxide?
-in plants it can be converted to stigmasterol the a multistep reaction
– And fungi it can be converted to ergosterol
-in animals it is converted to cholesterol eventually by way of Lanosterol
43
What enzyme is used to make cholesrol into Cholesteryl ester within the cell
What is cholesterol reacted with?
What is released?
Acyl-CoA-Cholesterol Acyl Transferase (ACAT)
it is reacted with FA-CoA
released: CoA-SH
44
What is cholesterol reacted with to make cholesteryl ester in HDL?
what enzyme is used?
what is the other product?
it is reacted with Phosphatidylcholine (lecithin) to make cholesteryl ester and Lysolecithin
enzyme: Lecithin-Cholesterol Acyl Transferase (LCAT)
45
How much cholesterol is made de Novo per day
1 g
46
How much cholesterol do we consume per day?
0.3 g
47
What are the plasma levels of cholesterol maintained mainly by de novo synthesis
150 to 200 mg/dL
48
What are the four main mechanisms of cholesterol regulation
1. HMG – CoA reductase:
– Main biosynthetic control
– Phosphorylation decreases activity
– Level of enzyme is also regulated
2. -Acyl-CoA :cholesterol acyltransferase, ACAT
3. LDL/HDL ratios
4. Excretion of bile acids
49
What are the regulators of HMG – coenzyme a reductase?
Activators: insulin
Inhibitors:
- glucagon
- intracellular cholesterol (Stimulates proteolysis of HMG – CoA reductase )
50
Name Regulators for ACAT
Activator: Intracellular cholesterol
51
What is ACAT
Acyl- CoA cholesterol acyltransferase
52
What regulates receptor mediated endocytosis of cholesterol (LDL Cholesterol)
Intracellular cholesterol via proteolysis of HMG – CoA reductase
53
How is LDL-cholesterol Taken up by the cell?
By receptor mediated Endocytosis
54
What path does Cholesterol take in the body?
Deliver releases cholesterol through bio acids in the intestine and as LDL through the blood stream.
– Cholymicrons enter capillaries after being absorbed.
– Lipoprotein lipase breaks up cholymicrons and VLDL to Produce free fatty acids (This happens in capillaries of mammary, muscle, or adipose tissue)
- VLDL remnants are sent to the liver or are converted to LDL to be sent either to the liver or extrahepatic tissue.
- Cholymicron remnants are sent to the liver
- extrahepatic tissue makes HDL from precursors coming from the liver and intestine. Produced HDL's are sent to the liver.
55
Why does Cholesterol need to be associated with proteins in order to be transported?
Because it is hydrophobic
56
What differentiates different lipoprotein complexes
Their unique sets of Apoproteins and different ratios of lipid to protein resulting in particles of varying density
57
What is important about each form of lipoprotein complex?
Each plays a particular role in cholesterol transport and control
58
Which lipoprotein carries the most cholesterol by percent wt.
LDL's carry 8 percent free cholesterol and 37% cholesteryl esters
VLDL's have 7% free cholesterol and 12% cholesteryl esters
HDL have to percent free cholesterol and 15% cholesteryl esters
Chylomicrons have 1% free cholesterol and 3% cholesteryl esters
59
What percent of lipoproteins is made out of protein
HDL has the highest percentage with 55%
LDL has the second highest with 23%
VLDL has 10%
Chylomicrons have 2%
60
What percent of triacylglycerol it's do lipoproteins have
Chylomicrons have 85% triacylglycerol's
VLDL has 50% chylomicron
LDL has 10% chylomicron
HDL has 4% chylomicrons
61
What are the important Apolipoproteins
- ApoB 100: has a molecular weight of 513,000 and associates with BL DL, LDL and binds to LDL receptor.
- ApoA-1 associate with HDL and date activate LCA T; interacts with ABC transporter
MW: 28,331
ApoA 2 : associates with HDL MW 17,380, respectively
62
What Apoproteins bind associate with HDL?
ApoD and ApoA 1 and 2 Are exclusively associated with HDL
ApoA 3 associates with HDL but is also in chylomicrons
ApoC 2 and 3 Associated with HDL but also with chylomicrons and VLDL
ApoC 1 Associates with HDL and VLDL
ApoE associates with HDL, VL DL, chylomicron
63
Described LDL particle receptor mediated endocytosis
LDL particle with cholesteryl esters inside associates with an LDL receptor through a POB – 100
LDL particles Is taken in, receptor molecules disassociate and the lysosome degrades the endosome with the LDL particle inside
64
What Apoproteins are recognized by the LDL receptor?
LDL particles are primarily taking in through the LDL receptor which recognizes protein apoprotein B apo protein E
65
what 2 bile acids are primarily synthesized int the liver
chenodeoxycholic acid & cholic acid
66
how much of bile acids are conjugated?
via what?
Most bile acids (98%) are conjugated via an amide bond to either glycine or taurine
67
Are only conjugated Bile acids secreted into the gall bladder and intestine?
Both free and conjugated bile acids are secreted into the gall bladder and intestine
68
what happens to Biles acids after they are excreted?
Conjugated bile acids are converted into the free form in the intestine
69
what do bacteria do to bile acids?
name some of the products
Bacteria convert the primary bile acids to dozens of secondary bile acids including
7-deoxycholate and lithocholate
70
What do bile acids do in the intestine?
in what form do they do this?
how much is reabsorbed?
In the gut primary and secondary bile acids emulsify fat, 95% are reabsorbed and return to the liver.
71
What happens to Bile acids in the liver?
In the liver, the primary and secondary bile acids are reconjugated to glycine or taurine and resecreted.
72
what percentage of bile acids are excreted?
what percentage of all excreted cholesterol does this account for?
10% is excreted as what?
5% of primary and secondary bile acids are excreted.
- Main excretory pathway for cholesterol (90%)
- 10% is excreted as steroid hormones and their derivatives
73
What happens to bile acid in each compartment?
Cholesterol is converted to primary BA CoA
Primary bile acid CoA is converted to either bile acid or conjugated bile acid
It is excreted into the gallbladder and remains in that form
When it enters the intestine conjugated bile acid , it becomes bile acid
-then it is reacted to become bowel acid lipid complexes
- 5% is excreted and then 95% return to the liver
74
What is the first reaction in bile acid synthesis?
Cholesterol is reacted with NADP H and one proton as well as Oxygen to make 7-hydroxy cholesterol
Enzyme: 7 alpha – hydroxylase
75
What is 7 – hydroxy cholesterol converted to?
It can either be converted to Cholyl– CoA or to chenodeoxycholyl-CoA
There are several steps. (Don't worry what they are)
Both reactions use NADPH and a proton as well as oxygen and two molecules of CoA -SH are used to make Cholyl – CoA
released: propionoyl-CoA
76
What are the differences between the conjugated bile acids
What are the names of the bile acids?
Glycocholic acid and taurocholic acid
- NH-CH2-COOH
- NH-CH2-CH2-SO3H
77
Why are bile acids toxic
Because they are acidic
78
How much control in bile acid synthesis
Bile acid synthesis is under excruciating control
-7-hydroxycjolesterol is major control point
79
What are androgens and glucocorticoids made from
What else are cholesterol derivatives involved in?
Secondary cholesterol
Cholesterol derivatives are used in the messenger system
80
what are the major control points of bile acid synthesis
LXR-alpha (Liver X Receptor) :
- activator: Cholesterol
- inhibitor: 7-Hydroxylase by
1. increase BA production which activates LCA (Lithocholic acid), JNK (Jun N-terminal kinase) and FXR (Farnesoid X Receptor) activity
2. LCA (Lithocholic acid) increases PXR (Pregnane X Receptor) activity which inhibits 7-hydroxylase
3. JNK (Jun N-terminal kinase) inhibits 7-hydroxylase
4. - FXR (Farnesoid X Receptor) activate SHP which inhibits LXR-alpha (Liver X Receptor) which is activator of 7- hydroxylase
LRH: Liver Receptor Homolog
81
What in the intestines promotes bile acid excretion?
Some foods bind to bile acids
Oatmeal (soluble fiber) lowers cholesterol
Chia seeds also reduce cholestol by increasing bile acid secretion
82
Give the bile acid control regulators name and abreviations
```
FXR: Farnesoid X Receptor
LXR: Liver X Receptor
PXR: Pregnane X Receptor
JNK: Jun N-terminal kinase
LRH: Liver Receptor Homolog
SHP (name not on slide)
```
LCA: (Lithocholic acid), in intestines
BA in intestines
