Leaving groups protonation

Since concerted bond breaking and leaving group protonation was found to be considerably favored over a stepwise mechanism in the first part of the reaction, the analogous concerted pathway was also modeled here. Simulation of the first step showed that the protein environment cannot stabilize a negative ligand in the active site outside the phosphate binding loop, which would also be the case for a stepwise proton transfer to Asp 129 and a subsequent in-line attack of a hydroxide ion. 

Elimination is however greatly enhanced under conditions which transform this hydroxy group into a good leaving group (protonation, acylation, phosphorylation. . . ) or conditions which can result in a change of the conformation of the macrocycle (acidic medium, cations, heat.. . ). One of the mildest methods for generating the trienone (47) involved treatment of pristinamycin 11 with AT-methylanilinium trifluoroacetate in THF [111]. 

Proton transfer Loss of a leaving group Proton transfer... 

Proton transfers-----Loss of a leaving group----- Proton transfer... 

Aspartic proteases form a group of proteolytic enzymes that catalyze peptide bond cleavage by acid-base catalysis and activation of a water molecule for nucleophilic attack on the amide carbon. Crystal structures of mammalian and fungal enzymes are known. In pepsin, the best studied aspartic protease, catalysis proceeds by water activation and leaving group protonation. Both involve an aspartate, which explains the low pH optimum of around 4. The two aspartic acid residues are situated around a hydrophobic deft that can accommodate seven amino acids (the S4-S3 subsites). The active site is covered by a flexible flap, which contributes to SI subsite specificity. 

PROTON TRANSFER < NUCLEOPHILIC ATTACK PROTON TRANSFER PROTON TRANSFER < LOSS OF A LEAVING GROUP PROTON TRANSFER... 

---