Re: explain how and why histidine is widely used as a catalytic residue

hi Andrew,

I'd be surprised if you are really unable to find information about serine or cysteine proteases online or in a textbook. The catalytic triad of serine proteases is a classic case study in biochemistry. That said, I recall learning the mechanism in every year of my biochemistry course and I only fully understood it during a discussion in my Honours year oral examination!

To understand the role of any amino acid residue in an enzyme mechanism, you need to appreciate the chemical properties of amino acids. This is why in a biochemistry course, you are taught the 20 "standard" amino acids, their structures and their properties. The properties of histidine are summarised on this Wikipedia page: Histidine. It contains a cyclic ring structure built around 2 nitrogen atoms and 3 carbon atoms. The ring gives histidine some aromatic character - like the amino acids phenylalanine or tyrosine. From organic chemistry, you should recall that the electrons in aromatic rings are "delocalised" - that is, the rings tends to withdraw electrons from atoms bonded to the ring and concentrate them around the ring. One of the nitrogen atoms in the histidine ring has a free lone pair and so is electron-donating - that is to say, it is slightly basic in character. These chemical properties determine how histidine acts as a catalytic residue.

Take a look at the Wikipedia article on serine proteases. I'm sure that you have seen similar articles elsewhere. The article tells us that the -OH group of the serine residue in the catalytic triad is responsible for the initial reaction with the peptide bond in the protease substrate.

I mentioned earlier my final biochemistry examination. I was asked the question: "Would you expect serine to be a particularly reactive residue?" Given that serine is not so different to an alcohol such as ethanol in structure, I answered "no". My examiner then asked "so what do you think is increasing its reactivity?" The penny finally dropped and I realised the answer was - the histidine! The concentration of electrons on the histidine allows it to accept the proton from the serine -OH, making the serine a nucleophile that can attack the peptide bond. In serine proteases, the negative character of the aspartate acts on the histidine to increase the efficiency of this process - hence the catalytic triad.

Basically (forgive the pun) then, histidine is a useful catalytic residue because it increases the reactivity of surrounding residues. This is just one way in which it can act and I'm sure that you can now search the web with some apropriate search terms to find more information. I think the key thing is not to get confused by the details when trying to understand enzyme mechanisms and not to treat them all as separate pieces of knowledge that you have to memorise. If you have a good understanding of the chemical properties of amino acids in proteins, you will be well placed to have a good guess at how any enzyme mechanism works.