METHYLTRANSFERASES

Tavishi

I love being able to understand the minutia of how an enzyme or tiny little protein works, and how that echoes into greater pathological conditions. Currently, the class (module is what we call it here) that we are working through at school is Inheritance, Genetics, and Evolution. This is great and really scratches my microbiology itch.

One of my favorite classes of enzymes are methyltransferases, which are enzymes which add methyl groups to things. A methyl group is literally four atoms, but the addition of a few extra methyl groups can literally cause cancer. Methyl groups consist of a central carbon atom bound to three hydrogen atoms. Now, carbon has four sort of binding spots, and that fourth one is where whatever is getting methylated goes.

Methyltransferases are classified based off of structure and function.

Based off structure, methyltransferases can be grouped into five classes. There is some discourse over how to specifically classify methyltransferases, but I prefer this grouping method.

Class I methyltransferases are defined by a Rossman fold, which generally consists of 3 beta sheets and 3 alpha helices alternating. In the case of class I methyltransferases, there are 4 alpha helices and 3 beta sheets (alpha 1, beta 1, alpha 2, beta 2, alpha 3, beta 3, alpha 4). Attached to β1 and  β2 is the SAM.

(Beta sheets and alpha helices are two secondary structures of proteins. Essentially, the initial structure that the strands of amino acids form based off the properties.)

The SAM, or S-adenosylmethionine, is what has the methyl group that will be transferred by methyltransferases.

Class I methyltransferases methylate DNA, and thus, need structures to hold the DNA. The  β1 group has an acidic region, which lets it hold onto a methionine. Then, there's a little triad of glycines, which helps grab onto the adenosines in nucleotides of DNA.

yellow is SAM, blue is alpha helices, green is beta sheets.

Class II methyltransferases interact with cobalamin, or vitamin B12. Fun fact: I know a SAM with cobalamin deficiency (it's why his hair is gray at the ripe age of 17), and unfortunately, my tarantula. These enzymes are part of a larger scheme: methionine synthases. I don't like these enzymes, so they get no further attention. We are proud cobalt haters in this household.

Anyways, class III methyltransferases are dimeric, with each monomer consisting of a beta sheet followed by a few alpha helices. At the center of these monomers are where what gets methylated (substrate) goes. These enzymes also have a SAM that gives methyl groups out.

There are two more classes of methyltransferases. Class IV methyltransferases consist of a beta sheet and five of its alpha helix friends, which form a little loop with one of the beta sheet strands and one of the alpha helices that ties up the SAM. The knot sorta tightens when the SAM loses its methyl to the methylated substrate, becoming SAH.

Class IV methyltransferases frequently methylate tRNAs.

can you tell i love alpha fold.

There are also class V methyltransferases which are maybe one of the more relevant methyltransferases. These methylate the lysine residues on histone proteins, which affects gene expression (will circle back to this!).

These methyltransferases have 3 domains: SET domain, pre-SET domain, and post-SET domain. What's important is the SET domain. This is the primary structural characteristic of class V methyltransferases, and is where most of the beta sheets are. These proteins consist of four alpha helices wrapped in beta sheets. Near the c-terminus of the alpha helices is the SAM group, which again, is what stores the methyl group for methyltransferases. When methylating, histones bind near the n-terminus, and sort of go underneath (directionality here is weird?) to get to the actual methyl on the SAM.

Protein structures make my brain hurt in a good way. Please do NOT take me as an authority on any of this, or really, most of what I write about; I'm just a yapper who has too much fun at school.

The two most important functions of methyltransferases is DNA methylation.

DNA methylation generally represses transcription of DNA; essentially, it prevents certain DNA sequences from being expressed. Methyltransferases generally add a methyl group to the nucleotide cytosine, but they also do modify adenine as well. No other nucleotides are particularly known for being methylated.

What's unique about DNA methylation is that it is a form of epigenetic modification; that means that the DNA itself isn't being modified, but rather, it's just being "tagged" differently. Think of it as the difference between putting a sticky note on a wall, and writing on the wall in sharpie.

When DNA is methylated, there are three groups of proteins that recognize the new 5-methylcytosine taking the place of cytosine: zinc fingers, MBDs, and UHRF proteins. Of these, MBDs are most notorious.

involvement in lotsa different pathways!

DNA methylation is implicated in so many different pathways, from development of the central nervous system to even the biochemical basis for learned fear (insane btw.) That concludes my weekly yapping! Let me know if anyone wants a specific topic for next week's post...