ACE Inhibitors Flashcards
What does ACE stand for
Angiotensin-converting enzyme
Why was it difficult to isolate ACE?
- Membrane bound
- Did not know structure of the enzyme
Which tissues can ACE be found in
- Kidneys
- Liver
- Gut
- Lung epithelium
What are the similarities between ACE and carboxypeptidase?
- Both proteases
- Zn2++ metalloprotease
- Both have S1’ binding pocket
- Arg145
What are the differences between ACE and carboxypeptidase?
- S1 binding pocket in ACE
- Distance between Arg145 and zn++ due to split dipeptide in ACE
- Carboxypeptidase S1’ prefers aromatic
- L-benzylsuccinic acid is an inhibitor to carboxypeptidase
Describe the carboxypeptidase binding pocket in detail
- Zinc metalloprotease to stabilize T.S
- Arg-145 forms ionic bond to terminal carboxylate group to stabilize reactant/product
- Hydrophobic S1’ pocket has binding preference for aromatic rings
Describe the ACE binding pocket in detail.
- zinc ion to stabilize T.S
- Arg145 for reactant/product stabilization
- Zinc and Arg likely to be further apart since dipeptide is split
- Hydrophobic S1’ and S1 pocket
What are the similarities and differences between the ACE and the carboxypeptidase binding pocket
Similar
- Zinc
- Arg-145
- Have S1’ hydrophobic binding pocket
Different
- # of S1 pockets
- Zinc and Arg likely to be further apart since dipeptide is split in ACE
What are the roles of the following in the ACE binding site: Arg145, Zn++, S1 and S1’ binding pockets?
- Arg145 forms ionic bond to terminal carboxylate group, stabilizing the reactants. Also stabilizing the product.
- Zinc stabilizes the T.S by polarising the negative O in the carbonyl group. Also stabilizes the product
- Hydrophobic S1’ pocket that holds substrate in place.
Describe how L-Benzenesuccinic acid acts as an inhibitor drug for carboxypeptidase
- L-Benzylsuccinic acid mimics binding interactions of both products, but within the same molecule
- Binds strongly but cannot be hydrolysed
- Inhibits the enzyme for as long as it is bound
What is the relationship between Enalapril and Enalaprilat? Why is Enalaprilat in the pill given to the
patient, and why not Enalapril?
- Ester form of enalaprilat
- Increases absorption in the gut
The long process of find an ACE inhibitor started with succinyl proline. Why succinyl proline?
- Similar to teprotide -proline portion (found in venom and shown to inhibit ACE) teprotide susceptible to digestive enzymes/ orally inactive.
- Zinc and Arg likely to be further apart since dipeptide is split, SO
Analogous inhibitor should be longer by one amino acid
Use a succinyl-substituted amino acid
Please describe in detail the journey from succinyl proline to SQ13297 to Captoril.
- Methyl substituent added to form additional hydrophobic interactions with S1’ pocket - extension strategy
- Stereochemistry is important for activity (the R enantiomer of Captopril shows 100 fold less activity)
- Carboxylate group replaced with a thiol group to form stronger interactions with the zinc ion
Captopril first non-peptide ACE inhibitor to be marketed
Why is sulphur a better binding group than carboxylate?
Sulfur is larger than O, the e- are farther from the nucleus and less tightly held by the nucleus. Want Zinc ++
Please describe in detail how the drawbacks associated with the reintroduction of the COOH group were
overcome (please describe the journey from Captopril through I, II, III, IV, V and Enalaprilat).
subst. grows to fit into S1 binding pocket to make up for poor binding of COOH.
