Key result
TOAC(1)-Ang I and TOAC(3)-Ang I were cleaved by ACE, whereas analogues with TOAC at positions 8 and 9 were not, likely due to steric hindrance.
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The study demonstrates that TOAC substitution at positions 8 and 9 of Angiotensin I prevents cleavage by ACE due to steric hindrance, while substitutions at positions 1 and 3 allow enzymatic activity.
The angiotensin I-converting enzyme (ACE) converts the decapeptide angiotensin I (Ang I) into angiotensin II by releasing the C-terminal dipeptide. A novel approach combining enzymatic and electron paramagnetic resonance (EPR) studies was developed to determine the enzyme effect on Ang I containing the paramagnetic 2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid (TOAC) at positions 1, 3, 8, and 9. Biological assays indicated that TOAC(1)-Ang I maintained partly the Ang I activity, and that only this derivative and the TOAC(3)-Ang I were cleaved by ACE. Quenching of Tyr(4) fluorescence by TOAC decreased with increasing distance between both residues, suggesting an overall partially extended structure. However, the local bend known to be imposed by the substituted diglycine TOAC is probably responsible for steric hindrance, not allowing the analogues containing TOAC at positions 8 and 9 to act as substrates. In some cases, although substrates and products differ by only two residues, the difference between their EPR spectral lineshapes allows monitoring the enzymatic reaction as a function of time.
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Teixeira et al. (2007) studied this question. Angiotensin I analogues containing TOAC was evaluated on Enzymatic cleavage by ACE. TOAC(1)-Ang I and TOAC(3)-Ang I were cleaved by ACE, whereas analogues with TOAC at positions 8 and 9 were not, likely due to steric hindrance.
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