Angiotensin Converting Enzyme Inhibitors Flashcards
The key component of this process is—————— which is a peptide hormone with potent——————- properties.
angiotensin II, vasoconstrictive
Angiotensin II also promotes the release of another hormone called———— from the adrenal cortex.
aldosterone: Aldosterone promotes increased fluid retention in the kidneys—another factor that increases blood pressure because of increased blood volume.
Problems of hypertension occur when the RAAS cascade becomes too active, and so a number of antihypertensive agents have been designed which block the cascade at various points:
Angiotensin-converting enzyme (ACE) Inhibitors
• Angiotensin II receptor antagonists (ARB)
• Aldosterone inhibitors
• Renin inhibitors
————— is a key component of the biosynthetic pathway that generates the hormone————.
Angiotensin-converting enzyme (ACE) , angiotensin II.
The pathway involves the conversion of——- to ———catalysed by the enzyme ——— , followed by the conversion of——- to — -, catalysed by ——.
angiotensinogen, angiotensin I , renin
angiotensin I to angiotensin II, ACE
Angiotensin II : drugs that block the synthesis or actions of this hormone can act as ——-.
1-potent vasoconstrictor
2-increases blood pressure
antihypertensives
Why is the peptidase renin released?
1-As a result of the decreased blood perfusion to the juxtaglomerulus
2- Sympathetic Stimulation
3- decreased levels of salt
ACE
1-membrane-bound enzyme which has been difficult to isolate and study.
2-t is a member of a group of enzymes called the zinc metalloproteinases and catalyses the hydrolysis of a dipeptide fragment from the end of a decapeptide called angiotensin I to give the octapeptide angiotensin II.
Although the enzyme ACE could not be isolated, the design of ACE inhibitors was helped by studying the structure and mechanism of another zinc metalloproteinase that could—an enzyme called (carboxypeptidase).
1- Is cytosolic and easier to isolate
2- This enzyme splits the terminal amino acid from a peptide chain and is inhibited by L-benzylsuccinic acid .
What is the structure of L-Benzylsuccinic acid?
- 4 carbons + 2 carboxylic acids on the terminal end + benzene ring.
- Design is based on hydrolysis of products arising from enzymatic reaction.
- Benzyl group occupies the S1 pocket, carboxylate ion is present to form an ionic interaction with Arg-145
- 2nd carboxylate acts as a ligand to the zinc ion, mimicking the carboxylate ion of the other hydrolysis product.
-CANT BE HYDROLYSED AS THERE IS NO PEPTIDE BOND PRESENT SO THE ENZYME IS INHIBITED FOR AS LONG AS THE COMPOUND STAYS ATTACHED
What makes thiol (-SH) a better substituent than carboxylic acid CA?
1- non ionizable
2- more hydrophobic
3- can make stronger coordinate interactions with zinc making it better in oral absorption and giving it a high affinity
What does the active site of carboxypeptidase include that’s crucial for its binding?
Charged arginine unit and a zinc ion.
Carboxylic acid is bound ionically to the arginine unit while the carbonyl group of terminal peptide is bound to zinc ion
How does the S1 hydrophobic pocket affect binding?
It accepts the side chain of amino acid.
Aromatic rings bind strongly to the pocket raising specificity of enzyme towards a peptide substrate containing an aromatic amino acid at the C-terminus
How is hydrolysis of the terminal peptide bond affected by zinc ion?
-plays a role in the mechanism by polarizing the carbonyl group and making the amide group more susceptible to hydrolysis.
Teprotide (ACE inhibitors)
1-nonapeptide was isolated from venom of viper
2- Amino acid proline at C-terminal
3- A reasonably potent inhibitor but susceptible to digestive enzymes and is orally inactive
4- succinyl proline was the end result
5-SP was found to be weak but specific inhibitor of ACE and it was proposed that both carboxylate groups were ionized, one interacting with the arginine group and one with zinc ion
