Question

What are the roles of each member of the SHD catalytic triad? How does the mechanism work?

This is a question I'm self-answering for others' reference! :)

Answer 1

THE SHD CATALYTIC TRIAD

The SHD catalytic triad, as its name suggests, consists of the amino acids (AAs) serine, histidine, and aspartate, whose one-letter codes are S, H, and D, respectively.

This kind of triad exists, for example, within the enzyme trypsin, which can be found in the pancreas, first synthesized as an inactive precursor (so it doesn't do its job until it is needed).

TRYPSIN CUTS SPECIFIC PEPTIDE BONDS

The idea with trypsin is that it's supposed to hydrolyze specific peptide bonds, where the peptide bond in question follows a specific `R` group in the AA sequence that is large and `\mathbf(("+"))`. This is an example of charge complementarity.

The highlighted bond is the peptide bond that is hydrolyzed during the enzymatic activity upon finding the highlighted `R` group.

AMINO ACID ROLES

Serine in this triad would make a great nucleophile, if not for its having a proton. Having it deprotonated would really help. To accomplish this, we need to accomplish something to the effect of lowering the pKa of serine so that it wants to donate its proton away.

Histidine becomes a desirable solution by being an activator to serine. Since histidine's pKa is about 6.04, and neutral serine's pKa is about 15.9, it would be unlikely on its own for this to happen, though...

However, aspartate has a pKa of about 3.90, and a negative charge, so as a hydrophilic compound, it wants to be an acid so that both histidine and aspartate form an H-bonding interaction.

Aspartate's desire for histidine's proton prompts histidine to raise its pKa to keep its upper-right proton, balancing out the pKa difference between histidine and serine, promoting the deprotonation of serine to form an H-bonding interaction.

As an additional bonus, aspartate also orients histidine so that its freely-rotating methylene bridge is kept in place. Nice!

Together, these work within trypsin, for example, to catalyze the hydrolysis/cleavage of specific peptide bonds of other proteins.

WHAT'S THE MECHANISM THOUGH?

Well, it's this big diagram here:

1. Histidine steals a proton from serine, activating it.
2. Serine is now able to attack the carbonyl carbon, binding in a tetrahedral complex.
3. The complex is stabilized by a backbone `"NH"` from a nearby glycine, as well as that of the same serine. Histidine is oriented by aspartate. The tetrahedral complex collapses to cleave the peptide bond, and the resultant `"NH"` steals a proton away from histidine.
4. Histidine can grab a proton from water, as its pKa is still raised (making it a weaker acid) after being stabilized by aspartate.
5. Hydroxide is a great nucleophile which can then attack the carbonyl carbon for a second nucleophilic attack.
6. The tetrahedral complex, again stabilized by the backbone `"NH"` on the glycine and the same serine, can then collapse, cleaving the serine right off and grabbing a proton off of histidine as before.
7. We end with a carboxylic acid, the result of the hydrolysis of a peptide bond.