Lecture 4 Prep for Exam 1 Flashcards
In what form are triglycerides stored in our body?
esters and glycerol
The gallbladder is basically the _____ factory of the body
salt
How do you convert something that is very lipophilic (such as cholesterol in this case) and make it very amphiphilic (such as cholic acid in this case)…
you make it more polar
Amphiphiles are both polar and nonpolar…what do they help aid in?
They are emulsifying agents (detergents) that aid in the digestion of lipids
Where is the main factory of proteins?
the liver…
What is occuring in the liver?
primary bile acids synthesis…cholesterol being converted into CA or CDCA (via the enzyme CYP7A1
After the bile acids are made in the liver, where are they stored?
gallbladder!…these bile acids must be ready on demand once you have something of fatty material
How many 6-membered rings does the steroid structure have? How many 5 membered rings does it have?
3 “6-membered” rings and 1 “5-membered” ring
What structure is this?
steriod!
How do we make amphiphilic material from lipophilic cholesterol?
First the hydroxylase is put at the 7th position due to NADPH being reduced to NADP+, then two things can happen to either produce Cholic Acid or Chenodeoxycholic acid…
For Cholic Acid: the 12-alpha hydroxylase will help with attaching hydroxyl group at the 12th position, there will be a reduction of the double bond in the 6 membered ring, and there will be a side chain oxidation and cleavage
For Chenodeoxycholic acid: there will be a reduction of the double bond in the 6 membered ring and there will be a side chain oxidation and cleavage (just no 12th position -OH addition)
explain oxidation and reduction: (in terms of gain/loss of oxygen, gain/loss of hydrogen, gain/loss of electrons)
Which is more polar?
cholic acid
If you want the best emulsifying agent you want them to be:
a) very lipophilic and very hydrophilic
b) very lipophilic and very hydrophilic
a) very lipophilic and very hydrophilic
Someone gives you a drug and says they want you to make it more water-soluble…how would you do this?
more water soluble=more hydrophilic
I would then ask if it is an acid, if yes, then I will add a base
If it is a base, then I would add an acid
Altogether you are getting the ionized form which is the water soluble form! Excreted more easily
(more ionization=more charge=more polarity)
Can you use thioesters or esters for chemical reactions?
Use thioesters (are less stable) and you can easily modify them…they are weaker than esters
Which is the nucleophile in the equation?
the amine group
Where does the amine attack?
The amine will attack the carbon of the thioester group because it is more lipophilic and will transform easily to yield the acetyl choA product
Because of the thioester reaction with amine that we understand, what basically occurs in the reaction?
The CoA-SH is replaced by either Taurine or glycine…in the thioester reaction with amine essentially the S was replaced with the NH…in the case of Cholyl-CoA with addition of Taurine or Glycine to yield Taurocholic acid or glycocholic acid
What is the main message showing us from this reaction?
We cannot directly react an amine with a carboxylic acid
You must take the carboxylic acid and put the acid first, activate it with acetyl coA, and then react it with the amine
What is the pkA of the two acids?
about 5
What is the pH of the stomach? What is the pH of the first part of the small intestine (the duodenum)? What about the pH of the lower part of the small intestine?
pH of stomach= about 2
pH of duodenum= about 4
pH of the lower part of the small intestine= about 7.4/8
Are these molecules in their protonated or their unprotonated form?
If you want these molecules to have better water solubility..you want them to be…
CO-! ionized=better water solubility
Can we adjust the ionizability of these bile salts in order to make it more water soluble?
The answer is yes, because look at the pKa now of these primary bile acids…
Are these molecules in their protonated or unprotonated form? Why are they better emulsifying agents for lipids?
These conjugated bile acids are mostly in their deprotonated form…they are more water soluble and thus, better emulsifying agents for lipids
What does to emulsify mean?
the process of combining two substances that normally don’t mix well together. To emulsify fats usually means to mix them with water-based liquids and a binding substance like bile salts…Emulsify fat means that you change the environment so the fat and water molecules can mix together more easily. Typically this requires you to add a compound, known as an emulsifier, which can serve as a bridge between the fat and water molecules.
Within the intestine, what can intestinal bacteria do to the stored bile acid groups?
it can partially dehydroxylate and remove glycine and taurine groups to then yield secondary bile acids: DCA (deoxycholic acid) and LCA (lithocholic acid)
Why is the best emulsifying agent taurocholic acid and not glycocholic acid?
B/c it has lower pKa so it is going to be higher ionized and you’ll get polar and nonpolar
How do you make an acid more acidic? By adding an electron withdrawing group or electron donating group?
by adding an electron withdrawing group
Are primary amines considered electron donating or withdrawing?
Primary amines are typically considered electron donating due to the lone pair of electrons on the nitrogen atom. These electrons are available for donation to other atoms in a chemical reaction
Are secondary and tertiary amines considered to be electron donating or withdrawing?
They are considered to be electron withdrawing due to the inductive effect. When the amine group takes part in resonance through its free electron pair, it donates electrons through conjugation.
Explain the mechanism that causes primary bile acids to become secondary bile acids
The removal of the -OH group in the 7th position of cholic acid and chenocholic acid
Explain enterohepatic circulation
What is the best emulsifying agent? Why?
Best is Taurocholic acid as it has a lot of OH-‘s making it very hydrophilic
What is the worst emulsifying agent? Why?
Worst is Lithocholic acid as it has no -OH’s making it very lipophilic
How does the drug-Cholestyramine-work in regard to lowering cholesterol levels?
Cholestyramine is a highly charged polymer…since it is highly charged it wants to form salt-bridges/electrostatic interactions with non charged species, therefore, when a molecule like cholic acid comes near, electrostatic interactions then are formed between the two groups. These interactions bind and sequester bile acids in the gut and prevent its reabsorption and forms insoluble complexes with bile acids in the intestine (excreted with feces)
When there are less bile acids in the feces this results in the conversion of more plasma cholesterol to bile acids in the liver (lowering cholesterol levels)
***IN THE PICTURE THE CHOLESTYRAMINE INTERACTS WITH BILE SALTS IN THE LIVER AND NOT IN THE GALL BLADDER (IGNORE BLUE ARROW)
Is this drug acidic or basic?
-there is no hydrogen bonding (not a hydrogen bond acceptor) and the amide is neutral (unlike if it were an amine)
acidic drug!!!
Why do we have to have the administration of statins be separated by at least four hours after cholestyramine?
Both Lipitor and cholestyramine will interact with each other and both will get into the feces without getting absorbed (neither will effectively bind to bile acids)…this is due to Lipitor also being an acidic drug and then interacting with cholestyramine…therefore, not only with Lipitor but any drug that is acidic and they want to switch over to cholestyramine…they will have to wait at least 4 hours before
How does drug toxicology occur in relation to the enterohepatic circulation?
Sometimes when a drug is metabolized, it will then become toxic…therefore, when the drug then is reabsorbed it will then cause damage to the liver due to it being toxic …many anticancer drugs face this issue
What are eicosanoids?
signaling molecules that are synthesized by oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) (all fatty acids are 20 carbon units in length)
What are the 3 main eicosnoids?
prostaglandins (PG), Leukotrienes (LT) and Thromboxanes (TX)
unsaturated means…
less hydrogens (double bonds)
saturated means…
more hydrogen bonds (no double bonds)
