Covalent Catalysis - Online Tutor, Practice Problems & Exam Prep

Covalent catalysis involves the formation of a transient covalent bond between an enzyme and a substrate, creating an intermediate molecule that accelerates the reaction rate compared to uncatalyzed reactions. Enzymes utilize nucleophilic amino acids to attack electrophilic centers in substrates. This process, exemplified by enzymes like chymotrypsin, demonstrates that despite additional steps, the overall reaction remains faster. Understanding this mechanism is crucial for grasping enzyme kinetics and the role of enzymes in biochemical pathways.

Covalent Catalysis

So at this point, we already know that there are 4 major types of enzyme catalysis, and we have already covered the first three, which are general acid-base catalysis, electrostatic catalysis, and metal ion catalysis. In this video, we're going to cover the 4th and final one, which is covalent catalysis. Covalent catalysis is when a transient temporary covalent bond forms between the enzyme and the substrate to form an intermediate molecule. Even though an extra intermediate molecule is produced and there's a longer pathway, there's still an overall increased reaction rate in comparison to the uncatalyzed rate.

Typically, the way that covalent catalysis works is that enzymes can use amino acids that act as nucleophiles, which, recall from your previous organic chemistry courses, are just atoms or molecules that have extra electron density that they can donate. These nucleophilic amino acids that the enzymes have can attack substrates, which would be the electrophilic centers, which are of nucleophiles. They have less electron density. It's really important to note that any covalent bonds that form with the enzyme must eventually be broken in order to restore the original enzyme, because remember enzymes are not going to be consumed by the reaction.

Below, in our example, we're going to take a look at covalent catalysis. Notice here we have an uncatalyzed reaction at the top, and this reaction is showing a substrate, which has components A and B that are covalently attached to each other. Notice that at the end, we have converted the substrate into the products where they are no longer covalently attached. This reaction is just a hydrolysis reaction.

Below, you can see the mechanism for this reaction, or an example of the mechanism for this reaction. Notice we're showing the enzyme catalyzed reaction. Again, this enzyme is going to be performing covalent catalysis. The substrate is exactly the same, and the products are also exactly the same. The only difference is that there's an enzyme involved. You can see that our enzyme can have an amino acid that acts as a nucleophile. Here it's acting as a nucleophile and attacking this carbonyl group. Ultimately, even though there's an additional step here, the overall rate of this enzyme-catalyzed reaction is still faster than the uncatalyzed reaction.

Moving forward, we're going to be able to see some examples of enzymes that utilize covalent catalysis, such as chymotrypsin. But for now, this concludes our lesson on covalent catalysis, and I'll see you guys in our next video.

An enzyme has two key catalytic residues, Glu 35 (pK_a= 5.9) and Asp 52 (pK_a= 4.5). Which of the following is likely true about the mechanism for this enzyme if the optimum pH = 5.2?

• A. Glu 35 is more likely a nucleophile than Asp 52.
• B. Glu 35 is more likely a general acid than Asp 52.
• C. Both a and b are true.
• D. a, b & c are false.

Which of the following mechanisms is not used by enzymes for catalysis?

a) General Acid-base catalysis. 

b) Induced fit of enzyme to transition state. 

c) Destabilizing the transition state. 

d) Providing complementary electrostatics.

e) Binding of metal ions.

f) Specific Acid-Base Catalysis

g) a & c.

h) c & f

i) b, c & f

• A. General Acid-base catalysis.
• B. Induced fit of enzyme to transition state.
• C. Destabilizing the transition state.
• D. Providing complementary electrostatics.
• E. Binding of metal ions.
• F. Specific Acid-Base Catalysis
• G. a & c
• H. c & f
• I. b, c & f

Which catalytic mechanism uses an electrophilic cofactor to stabilize a negative charge on an intermediate?

• A. Acid-base catalysis.
• B. Electrostatic catalysis.
• C. Covalent catalysis.
• D. Metal ion catalysis.

Which of the following catalytic mechanisms proceeds via noncovalent interactions?

• A. Acid-base catalysis.
• B. Electrostatic catalysis.
• C. Covalent catalysis.
• D. Metal ion catalysis.
• E. b and d.
• F. a, b & d.

Suppose that the covalent catalytic mechanism of an enzyme depends on a single active site amino acid (Cys), whose pKa = 8.3. A mutation in a nearby amino acid residue of the enzyme only slightly alters the microenvironment so that the pKa of the Cys residue increases to 10.3. Would this mutation cause the enzyme-catalyzed reaction rate to increase or decrease? Explain.

• A. Reaction rate increases.
• B. Reaction rate decreases.

Here’s what students ask on this topic:

What is covalent catalysis in enzymes?

Covalent catalysis in enzymes involves the formation of a transient covalent bond between the enzyme and the substrate, creating an intermediate molecule. This intermediate accelerates the reaction rate compared to uncatalyzed reactions. Enzymes use nucleophilic amino acids to attack electrophilic centers in substrates. Despite the additional steps involved, the overall reaction rate is faster. This mechanism is crucial for understanding enzyme kinetics and the role of enzymes in biochemical pathways.

How does covalent catalysis increase reaction rates?

Covalent catalysis increases reaction rates by forming a transient covalent bond between the enzyme and the substrate, creating an intermediate that stabilizes the transition state. This stabilization lowers the activation energy required for the reaction, making it proceed faster than the uncatalyzed reaction. Even though additional steps are involved, the overall pathway is more efficient, leading to an increased reaction rate.

What are some examples of enzymes that use covalent catalysis?

Examples of enzymes that use covalent catalysis include chymotrypsin, trypsin, and other serine proteases. These enzymes utilize nucleophilic amino acids, such as serine, to form transient covalent bonds with their substrates. This mechanism helps in the efficient breakdown of peptide bonds in proteins, demonstrating the importance of covalent catalysis in biochemical processes.

What role do nucleophilic amino acids play in covalent catalysis?

Nucleophilic amino acids play a crucial role in covalent catalysis by attacking electrophilic centers in substrates. These amino acids, such as serine, cysteine, and lysine, have extra electron density that they can donate to form a transient covalent bond with the substrate. This intermediate stabilizes the transition state, lowering the activation energy and increasing the reaction rate.

Why must covalent bonds formed in covalent catalysis eventually be broken?

Covalent bonds formed in covalent catalysis must eventually be broken to restore the original enzyme. Enzymes are not consumed in the reactions they catalyze; they must be regenerated to participate in subsequent reactions. Breaking the covalent bond ensures that the enzyme returns to its original state, ready to catalyze another reaction cycle.