Introduction
Enzymes play a crucial role in biological processes, particularly in the digestion of proteins. Among them, chymotrypsin stands out as an essential digestive enzyme that operates through a sophisticated catalytic mechanism. In this article, we will explore how chymotrypsin facilitates the breakdown of peptide bonds, emphasizing its structural factors and the interactions within its active site. This overview will also discuss the key roles played by specific amino acids in the catalytic triad and their significance in enzyme function.
What is Chymotrypsin?
Chymotrypsin is a serine protease, an enzyme that digests proteins by cleaving peptide bonds. Part of a broader class of serum proteases, chymotrypsin is particularly notable for its catalytic mechanism, which exemplifies how enzyme structure correlates with function. Here, we will outline the characteristics of chymotrypsin and the components involved in its catalytic process.
Key Characteristics of Chymotrypsin
- Family: Serine proteases
- Function: Breaks peptide bonds in proteins
- Active Site Structure: Contains a catalytic triad
- Amino Acid Residues: Primarily involves serine, histidine, and aspartate
The Active Site of Chymotrypsin
The active site of chymotrypsin is integral to its function, composed mainly of a catalytic triad formed by three crucial amino acids: Serine 195, Histidine 57, and Aspartate 102. Although these residues are spaced apart in the primary structure, they are perfectly aligned in the active site due to the enzyme's tertiary folding. Their specific roles are as follows:
Roles of Amino Acids in the Catalytic Triad
- Serine 195: Acts as the nucleophile, attacking the carbonyl carbon of the substrate.
- Histidine 57: Functions as a base catalyst to deprotonate serine, and later acts as an acid catalyst during the hydrolysis phase.
- Aspartate 102: Stabilizes histidine through hydrogen bonding, facilitating its role in the catalytic process.
The Catalytic Mechanism of Chymotrypsin
The catalytic mechanism of chymotrypsin involves a two-step reaction process characterized by the formation of a covalent bond between the enzyme and its substrate. Let's delve into these steps in detail.
Step 1: Formation of the Tetrahedral Intermediate
- Substrate Binding: The peptide substrate binds to the active site, positioning the peptide bond to be cleaved (the scissile bond).
- Histidine as a Base Catalyst: Histidine extracts a proton from serine, forming a new nitrogen-hydrogen bond.
- Nucleophilic Attack: The oxygen of serine forms a covalent bond with the carbonyl carbon of the substrate, resulting in an unstable tetrahedral intermediate.
- Transition State: This tetrahedral intermediate represents a transition state that is energetically unfavorable, prompting the reaction to proceed.
Step 2: Breakdown of the Peptide Bond
- Histidine as an Acid Catalyst: The protonated histidine donates a proton to the nitrogen of the scissile bond, leading to the breaking of the peptide bond and the release of the C-terminal fragment of the substrate.
- Covalent Intermediate: The remaining peptide is now covalently attached to the serine residue.
- Enzyme Regeneration: The enzyme returns to its initial state, ready to bind another substrate molecule.
Summary of Reaction Steps
- Tetrahedral Intermediate Formation
- Peptide Bond Breakdown
- Release of Peptide Fragments
The Role of Water in Chymotrypsin's Mechanism
The second phase of the catalytic cycle of chymotrypsin involves the use of water as a nucleophile, replacing the substrate's original amine group. Here’s how this second phase proceeds:
- Histidine Extracts Proton from Water: Histidine acts again as a base catalyst, extracting a proton from water.
- Water as a Nucleophile: The now negatively charged oxygen from water attacks the carbonyl carbon of the attached peptide, creating another tetrahedral intermediate.
- Completion of Hydrolysis: The nitrogen-hydrogen bond in the tetrahedral structure breaks, allowing the enzyme to regenerate, completing the reaction cycle.
- Final Products: This mechanism yields the N-terminal fragment and releases the serine-bound peptide.
Conclusion
Chymotrypsin exemplifies the intricate relationship between enzyme structure and function. Through its carefully arranged catalytic triad, the enzyme harnesses the properties of serine, histidine, and aspartate to catalyze peptide bond hydrolysis effectively. By analyzing this mechanism, we appreciate the marvelous efficiency of enzymes in biochemical processes. In future studies, we will further explore how chymotrypsin stabilizes transition state intermediates and the implications for its function in digestion.
we're continuing our studies in chapter six on how enzymes work and in this lesson we want to review the catalytic
mechanism of the digestive enzyme kimot Trion it's a good example for us to consider because in the course of its
reaction we'll see actually several examples of different types of catalysts it's part of a large family of serum
proteases a proteas is simply an enzyme that digests protein that is it breaks pepti Bond the catalytic mechanism
always involves a Serene residue hence the name in this case we have Illustrated the catalytic Triad that's
part of the active site and that's pictured in the ball and stick model on the lower right here so we have a
sparate 102 histadine 57 and Serene 195 the numbers indicate their position in within the primary structure and so
And yet when the enzyme adopts its final tertiary fold these amino acid residues are perfectly positioned within the
active site not only must they be within the active site but they must be at the right positions in in order to carry out
function it's not important you remember these numbers but you do need to know each of these residues and what their
roles are in the catalytic mechanism Serene provides the nucleophile there our oxygen atom histadine is going to
act as a base Catalyst to activate the Serene residue later it will be an acid Catalyst and aspartate is play more of a
supportive role it's helping to stabilize the histadine in the course of its reaction overall the reaction
mechanism is one of calent catalysis remember that involves a two-step reaction where the enzyme actually forms
a coal bond with its substrate so let's follow that reaction sequence here we have the catalytic
Triad in blue in the active site our Cove valent Catalyst our Serene residue histadine our base Catalyst and here's
aspartate it's stabilizing the histadine by means of that hydrogen bond so that's our catalytic Triad you want to notice
the roles of each of these amino acids as we go through now here's the substrate our peptide and the bond be
broken is the red line here so here's the amine group and the carbonal group as a part of that peptide bond we call
the bond to be broken the sisle bond just as scissors are used to cut things so the sisle bond is the bond to be cut
that's the r subc and here's the inter terminal part R subn so in other words our peptide bond is somewhere within
Catalyst to extract a proton from Serene so here's our electron Rich nitrogen atom it's going to extract a proton and
form a new bond with hydrogen as it does so it that hydrogen will break its bond with oxygen and that allows the oxygen
atom to form a new bond with carbon so here we have the resolved structure from the previous slide nitrogen has
formed a new bond with that hydrogen atom it now carries a positive charge because it was a
proton we've broken the bond between oxygen and hydrogen but it does form a hydrogen bond and that's the dashed line
here the oxygen on the Serene has formed a new coent bond with the carbonal carbon and notice that carbonal carbon
now is a tetrahedral intermediate notice it's also one of those unstable carb anions so this is our unstable
tetrahedral intermediate and that's pictured as our first energy Hill up here our unstable tetrahedral transition
state intermediate X1 double dagger in the next step of the reaction the histadine is now going to act as an
acid Catalyst remember it has that proton it can donate only instead of giving it back to Serene it's going to
donate it to the nitrogen that's part of that ccle bond that we're going to break as it does so that nitrogen hydrogen
bond will break it will receive back its electron and again be neutral and will form a new bond between the nitrogen and
the peptide bond and that hydrogen atom in that case in order for the nitrogen to form that bond with hydrogen it must
break its bond with carbon and so once we've done so we will break that peptide bond notice that when this
reaction sequence ends we will have added a hydrogen atom to that peptide bond we will thereby when we break this
Bond release the C terminal part of our peptide and form a new amine Terminus on that portion of the
peptide so here's the resolved structure we've actually accomplished our goal of Breaking the Bond and we've Rel least
the C terminal portion of our peptide but now we have the rest of our peptide cently attached to our Serene residue so
if we look at our reaction diagram this is the hill between the valley between our two Hills
we form that Cove valent Bond so we've accomplished our goal of breaking the peptide bond the histadine is back into
its original form but now we have a Cove valent Intermediate A Cove valent attachment between the enzyme and the
substrate and remember we have to resolve the structure before we're finished and so that's what we're going
to do in The Next Step the next series of steps are simply a repeat of exactly what we just seen it's just that the
nucleophile is different so again we have histadine acting as a base Catalyst only now our nucleophile is water and so
histadine is going to extract a proton from water it'll form a new nitrogen hydrogen bond here and and that will
here so this is exactly like step one on our earlier slide after we've done so now we have a
new nitrogen hydrogen bond here again that histadine is carrying that positive charge remember it's stabilized by this
histadine hydrogen bond over here and now we have a an a carbon oxygen bond with our tide here and so now we have a
new tetrahedral intermediate that carbonal carbon is now again a tetrahedral intermediate an unstable
carb annion this is our second energy Hill here X2 double dagger and so we must resolve the
structure we do so in this case now histadine can now donate that proton back to Serene and so we have
accomplished our goal of breaking the peptide bond and the active site looks just like it did when we began so the
enzyme has been regenerated and here's the inter terminal portion of our peptide which will release so you'll
notice that in the first case we added a hydrogen atom to the nitrogen of the sisle bond and in this case we added o
to the carbon of the sisle bond so overall we simply added water to the bond it was hydrolized that is liced by
these transition state intermediates those carbonal carbon tetrahedral intermediates and we'll see
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