At which nucleophilic site is serine most likely to be acylated by penicillin in the enzyme-substrate complex?

• A. The carboxyl group of the side chain (–COOH)
• B. The amino group of the backbone (–NH\(_2\))
• C. The hydroxyl group of the side chain (–OH) at the \(eta\)-carbon
• D. The hydrogen atom of the \(eta\)-carbon

Answer: (C)

Verified step by step guidance

1. Step 1: Understand the context of the problem. Penicillin acts as an irreversible inhibitor by acylating specific nucleophilic sites in enzymes, particularly those involved in bacterial cell wall synthesis. The nucleophilic site must be reactive enough to interact with penicillin's β-lactam ring.
2. Step 2: Identify the functional groups in serine. Serine contains a hydroxyl group (–OH) on its side chain, a carboxyl group (–COOH), and an amino group (–NH\(_2\)) in its backbone. Additionally, the hydrogen atom on the β-carbon is present but is not nucleophilic.
3. Step 3: Evaluate the nucleophilicity of each functional group. The hydroxyl group (–OH) is highly nucleophilic due to the lone pairs of electrons on the oxygen atom, making it a prime candidate for acylation. The carboxyl group (–COOH) and amino group (–NH\(_2\)) are less likely to be acylated in this context because they are not positioned for direct interaction with penicillin's β-lactam ring.
4. Step 4: Consider the steric and chemical accessibility of the hydroxyl group. The hydroxyl group on the side chain of serine is located at the β-carbon, making it accessible for interaction with penicillin. This accessibility is crucial for the acylation reaction to occur.
5. Step 5: Conclude that the hydroxyl group (–OH) at the β-carbon of serine is the most likely nucleophilic site to be acylated by penicillin in the enzyme-substrate complex. This aligns with the mechanism of action of penicillin as an inhibitor.