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Prenylcysteine lyase (PCLase) catalyzes the cleavage of prenylcysteine (a protein modification) to form an isoprenoid aldehyde and the freed cysteine residue on the protein target. The FAD is non-covalently bound to PCLase. Not many mechanistic studies have been done looking at the reactions of the flavin, but the proposed mechanism is shown below.
This type of reaction is also called a 1,2-nucleophilic addition. The stereochemistry of this type of nucleophilic attack is not an issue, when both alkyl substituents are dissimilar and there are not any other controlling issues such as chelation with a Lewis acid, the reaction product is a racemate. Addition reactions of this type are numerous.
Neutral nucleophilic reactions with solvents such as alcohols and water are named solvolysis. Nucleophiles may take part in nucleophilic substitution, whereby a nucleophile becomes attracted to a full or partial positive charge, and nucleophilic addition. Nucleophilicity is closely related to basicity.
Acyl compounds react with nucleophiles via an addition mechanism: the nucleophile attacks the carbonyl carbon, forming a tetrahedral intermediate. This reaction can be accelerated by acidic conditions, which make the carbonyl more electrophilic , or basic conditions, which provide a more anionic and therefore more reactive nucleophile.
The nucleophilic lysine residue is commonly targeted site in protein bioconjugation, typically through amine-reactive N-hydroxysuccinimidyl (NHS) esters. [3] To obtain optimal number of deprotonated lysine residues, the pH of the aqueous solution must be below the pKa of the lysine ammonium group, which is around 10.5, so the typical pH of the reaction is about 8 and 9.
An acid-base-nucleophile triad is a common motif for generating a nucleophilic residue for covalent catalysis. The residues form a charge-relay network to polarise and activate the nucleophile, which attacks the substrate , forming a covalent intermediate which is then hydrolysed to release the product and regenerate free enzyme.
Targeted covalent inhibitors (TCIs) or Targeted covalent drugs are rationally designed inhibitors that bind and then bond to their target proteins.These inhibitors possess a bond-forming functional group of low chemical reactivity that, following binding to the target protein, is positioned to react rapidly with a proximate nucleophilic residue at the target site to form a bond.
This covalent addition of AMP to a hydroxyl side chain of the protein is a post-translational modification. [4] Adenylylation involves a phosphodiester bond between a hydroxyl group of the molecule undergoing adenylylation, and the phosphate group of the adenosine monophosphate nucleotide (i.e. adenylic acid).