Flashcards in Biochem Week 2 Deck (56):
Cholesterol is an important precursor to what three compounds?
1) bile salts/acids
3) precursor to vitamin D
Name the 5 sex chromosomes that cholesterol is a precursor to
progesterone, estrogens, testosterone, cortisol, aldosterone
True/False: Humans have about 1000 grams of cholesterol, mostly in membranes
FALSE 100 grams
it is mostly in membranes doe
True/False: Gallstones can be over 80% cholesterol
______ allow for effective treatment for high cholesterol and were developed in the 1990s
True/False: Cholesterol makes membranes more fluid
False, makes them more rigid
True/False: The hydroxyl group on cholesterol interacts with surfaces of membrane
Myelin membranes are especially ___ in cholesterol
Describe the polarity of cholesterol
Cholesterol is very apolar [hydrophobic]
it interacts well with apolar alkyl groups in membranes
How many rings does cholesterol have?
What functional groups does it have and at what positions?
Does it contain any double bonds or side chains?
How many carbons in total?
hydroxyl at position 3
methyl groups at 18 and 19
double bond between c5 and c6
8 carbon side chain
27 total carbons
Concentration of cholesterol in the blood is about twice that of ____ but both are about ____ mM
Most of the cholesterol in the blood is in what form? How is it carried?
carried in the form of lipoproteins
What two compounds can be added to produce cholesterol esters from cholesterol?
What enzymes are involved?
acyl-CoA cholesterol acyl transferase (ACAT)
lecithin cholesterol acyl transferase (LCAT)
Describe the major details of cholesterol biosynthesis
acetyl-coa is converted to mevalonate which is converted to isoprene
from there, 6 5carbon intermediates are used to form a 30 carbon molecule called squalene which is converted to 27 carbon molecule cholesterol through 5 add'l steps
Humans synthesize about 1/2 of cholesterol we have from ______ which can come from ______ or ______ and must get to ______
acetyl-CoA, carbohydrates, fatty acids, cytoplasm
What is needed in the cytoplasm to make cholesterol (2 compounds)
What are the two sources of acetyl coa?
beta oxidation of fatty acids
How is acetyl coa transported into the cytoplasm from the mitochondrial matrix?
it is used in the citrate synthesis reaction [oxaloacetate + acetyl Coa --> citrate]
citrate is then transported to the cytoplasm where the reverse reaction occurs and an acetyl coa is produced
The __________ is a major source of NADPH [shunt]
pentose phosphate pathway
In the cytoplasm, citrate is converted to oxaloacetate, producing ______ which is then converted to malate. Malate is converted to pyruvate by _______ [important enzyme]
acetyl coa; malic enzyme
2 AcetylCoA in cytoplasm join to form _________ which join with another acetylCoA to make ________ in a reaction catalyzed by _________
acetoacetylCoA, HMG CoA, HMG CoA synthase
What is the destiny of Hmg CoA made in cytosol? in mitochondrial matrix?
in cytosol, goes to cholesterol
in mito matrix, goes to ketone bodies
What is the key regulated step in cholesterol biosynthesis? [and in almost every regulatory mechanism known in biochemistry]
HMG CoA + 2NADPH + 2H+ --> mevalonate + CoA + 2NADP+
CATALYZED BY HMG COA REDUCTASE
There are several ways that HMG-COA reductase is inhibited. _______ of the enzyme, for example, decreases its activity
There are several ways that HMG-COA reductase is inhibited. The rate of translation of the enzyme is inhibited by __________ and _________
non-sterol metabolites, dietary cholesterol
There are several ways that HMG-COA reductase is inhibited. An increase in ______ increases the rate of HMG-CoA reductase degradation
There are several ways that HMG-COA reductase is inhibited. Describe the relationship between sterol regulatory element binding proteins (SREBPs) and this inhibition.
SREBPs are transcription factors that bind to the sterol regulatory element DNA sequence.
When there are low levels of sterols, the SREBPs are cleaved and translocated to the nucleus where they bind to specific sterol regulatory element DNA sequences thus upregulating enzymes involved in sterol synthesis
However, sterols inhibit the cleavage of SREBPs and thus reduce synthesis of add'l sterols.
Sterol regulatory element binding proteins (SREBPs) belong the to the basic ______________ class of transcription factors
helix-loop-helix leucine zipper
Where are unactivated SREBPs found? Describe their movement under low sterol levels.
When inactive, attached to the ER and nuclear envelope.
Low sterol levels prompt movement to Golgi apparatus where they are cleaved by proteases. The protein then enters the nucleus where it increases transcription of target genes that inc synthesis of HMG-CoA reductase.
Describe why diet and exercise may not be effective in lowering cholesterol levels.
There is a direct feedback inhibition by cholesterol or cholesterol product on HMG-CoA reductase.
Therefore, the higher the cholesterol in your diet, the less you make.
AND the less cholesterol in your diet, the more you make.
Describe how statins work in reducing cholesterol levels
They are competitive inhibitors of HMG-CoA Reductase.
Two examples are Atorvastatin (Lipitor) and Lovastatin (Mevacor).
The top parts of the molecules look very similar.
What is a side effect of using statins?
Inhibiting HMG CoA reductase decreases ubiquinone (CoQ) production. 2-10% of people will have muscle pain. Little evidence that CoQ supplementation helps.
What is CoQ (ubiquinone)'s function in the cell?
It is a key intermediate in the electron transport chain
Describe the basics of how mevalonate is converted to squalene
Mevalonate goes to a C5 then a C10 and then a C15. Two C15s condense to a C30 which then goes to cholesterol (C27)
Squalene then goes through a series of steps to produce cholesterol with a single OH group. There are about 19 _______ steps in this sequence
True/False: We make about 1/2 of cholesterol in our bodies
Overall, acetyl CoA is converted to C5 ______ then three C5 intermediates condense to form C15 _____. Then two C15 intemermediates form the _______ squalene.
hemiterpenoids; sequiterpenoid; triterpenoid
Squalene is cyclized to a ____ membered ring structure. The C30 intermediate is modified to cholesterol in a series of over 30 enzymatic reactions. ______ play major role in modifying the C30 intermediate.
four, cytochrome p450
True/False: Much of cholesterol is made in liver
The major metabolic fate of cholesterol is conversion to ______ which occurs in the ______
bile acids, liver
Bile salts are stored in the ______ then transported to ______ and function to ________
gallbladder, small intestine, solubilize lipids
True/False: most of bile salts are reabsorbed and recycled
True/False: Cholesterol is present in bile acids in large amounts
false, small amounts
What happens when gallbladder is removed in terms of bile acids?
Bile acids go directly into the small intestine
95% of biliary secretion undergoes portal venous return to _____. Overall, biliary secretion is recycled about _____
hepatocytes; 4-12 cycles per day
True/False: Liver synthesizes about 0.2 to 0.6 gms of cholesterol per day, and roughly twice that amount is excreted
false, equal amount excreted
What is the key difference between a bile salt and cholesterol?
Bile salts are polar forms of cholesterol
They have shorter side chain! C5 instead of C8!
What are the four common bile acids? What is the most common?
1) cholic acid
2) deoxycholic acid
3) chenodeoxycholic acid (41%)
4) lithocholic acid
Bile acids have ______ groups. In addition, they may have more ____ groups than cholesterol.
carboxyl (COOH), OH
What two compounds are added to bile acids to make them more soluble?
glycine [produces glycocholic acid]
taurine [produces taurocholic acid]
these conjugates have pKa of 1-4
non-conjugates have pka of 7.0
pH of duodenum is 3-5
Bile salts are planar _____
Describe the role of bile salts
Bile salts are emulsifying agents that facilitate dietary fat digestion in the small intestine. They are synthesized in the liver from cholesterol.
The bile acid cholic acid or ____ is produced from cholesterol in a series of reactions. Two of these reactions are ______ catalyzed by _____ enzymes.
cholate, cytochrome p450 enzymes
From cholic acid, the bile salt _______ is produced when cholyl-CoA reacts with glycine to form an ______ bond linkage
What is cholestyramine?
What are its side effects?
It is a compound that is not absorbed and attracts bile salts which bind to its positive charge. This removes bile salts from the body and thus less are recycled. The liver has to use more cholesterol to make more bile salts, and thus lowers cholesterol.
Side fx are diarrhea and discomfort.