The rate of s‐cis/s‐trans isomerization in angiotensin II is at least 70‐fold greater than in His‐Pro and is not rate limiting in receptor binding

Abstract

The dipeptide L-histidyl-L-proline interconverts between the s-cis and s-trans rotational isomers of the amide bond with an average rate constant of 2.0 ks-' at 22.5O. This rate is independent of pH throughout the pH range 5.5-8.5 as determined by pH jump from low pH with potentiometric recording of the slow approach to equilibrium pH, and by integration of the histidine C-2 and C 4 proton n.m.r. resonances as a function of time following pD jump from low pD. From the temperature dependence of the n.m.r. experiments this interconversion has an Arrhenius activation energy of 20 kcal . mol-' and a free energy of activation of 21 kcal . mol-' , similar to other simple acyl-and aminoacylprolines. The octapeptide angiotensin I1 containing L-histidyl-L-proline at position 6-7 interconverts at least 70-fold faster than the free dipeptide. This rate is too fast to be rate limiting in the binding of angiotensin I1 to its receptor in rat adrenal cortex.Key words: angiotensin 11; angiotensin I1 isomerization rate; histidylproline; proline; proton n.m.r.; scislptrans isomerism. 1440367-8377/82/070144-05 $02.00/0 0 1982 Munksgaard, Copenhagen

Intramolecular Hydrogen Bond-Controlled Prolyl Amide Isomerization in Glucosyl 3(S)-Hydroxy-5-hydroxymethylproline Hybrids: A Computational Study

“…The bond distance is approximately 1.9 Å. This hydrogen bond was found in prolyl amide trans conformers (10,16,23,30,37,56; Table S2, Supporting Information), which contribute about 7% of the total distribution. The second type of hydrogen bond exists between the prolyl C δhydroxymethyl group and the prolyl N-terminal carbonyl oxygen (C δ sCH 2 sOH • • • OdCsN, see Figure 3b) and is found in cis conformers only.…”

“…These are relevant because the prolyl N -terminal cis / trans isomerization rate and equilibrium ratios of specific proline analogues are helpful in detecting and monitoring the local structure and environment of proline. Some examples include C-3-, C-4, and C δ -substituted prolines, − silaproline, azaprolines, , fused bicyclic proline, − pseudoprolines, − proline analogues with different ring sizes, ,, fused glucose-proline analogues, and 4-hydroxyprolines and 4-fluoroprolines. , Recently, we have reported on the synthesis of spirocyclic glucose-3( S )-hydroxy-5( S )-hydroxymethyl)proline hybrid (Ac-Glc3( S )-5( S )-(CH 2 OH)HypH-OMe, 1 ) and glucose-3( S )-hydroxy-5( R )-hydroxymethyl)proline hybrid (Ac-Glc3( S )-5( R )-(CH 2 OH)HypH-OMe, 2 ) (Scheme ). , Peptide mimics 1 and 2 differ in the stereochemistry at the hydroxymethyl substitutent at the C-5-position of the pyrrolidine ring which is strategically located to form a hydrogen bond to the cis N-terminal carbonyl group in proline (Scheme ). The thermodynamics and kinetics of the prolyl amide cis−trans isomerization in compounds 1 and 2 were investigated in detail with a large variety of different techniques .…”

“…These are relevant because the prolyl N-terminal cis/trans isomerization rate and equilibrium ratios of specific proline analogues are helpful in detecting and monitoring the local structure and environment of proline. Some examples include C-3-, C-4, and C δ -substituted prolines, [15][16][17][18] silaproline, 19 azaprolines, 20,21 fused bicyclic proline, [22][23][24][25][26] pseudoprolines, [27][28][29] proline analogues with different ring sizes, 27,30,31 fused glucose-proline analogues, 32 and 4-hydroxyprolines and 4-fluoroprolines. 33,34 Recently, we have reported on the synthesis of spirocyclic glucose-3(S)-hydroxy-5(S)-hydroxymethyl)proline hybrid (Ac-Glc3(S)-5(S)-(CH 2 OH)-HypH-OMe, 1) and glucose-3(S)-hydroxy-5(R)-hydroxymethyl)proline hybrid (Ac-Glc3(S)-5(R)-(CH 2 OH)HypH-OMe, 2) (Scheme 1).…”