Genetic code expansion and how we get to designer proteins

Genetic code expansion might be the coolest thing in Omics that you've never heard of.

Genetic code expansion and how we get to designer proteins
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DNA codes for messenger RNA (mRNA) which is then translated into protein.

And it's proteins that perform the majority of the functions in our cells!

They can serve as structural components, as molecular motors delivering cargo to various regions of the cell, and they can function as enzymes performing chemistry that would otherwise be impossible.

Proteins are created by ribosomes which read mRNA and stitch together amino acids to form the final protein sequence.

They do this by binding to mRNA and transfer RNAs (tRNAs) that are loaded with specific amino acids.

The sequence of the amino acids in a protein is determined by the mRNA sequence (codon) binding to a complementary tRNA (anticodon).

Proteins are made using 20 common amino acids but there are over 500 of them found in nature!

Many of those extra amino acids are just modified common amino acids, but this presents an interesting challenge:

What if we could expand the number of amino acids that can be coded for by DNA??

Doing this would allow us to engineer totally new proteins!

And this is the focus of an exciting area of synthetic biology referred to as ‘genetic code expansion.’

We can get to these designer proteins through a number of different biological hacks.

One of them is to change what the natural base pairs (NBPs) code for!

There are 4 DNA bases (A, T, C, G), these are read 3 at a time to code for proteins and this ‘triplet code’ is referred to as a codon. There are 64 potential codons and 20 common amino acids. Each amino acid is coded for by approximately 3 different codons.

But, we have the tools to change that!

Stop Codons - Are triplet codes that don’t code for any amino acids but serve to tell a ribosome to stop; however, we can make tRNAs that actually bind to the stop codons and cause a ribosome to insert whatever amino acid is attached to that stop-codon-binding-tRNA!

4 Base Codons - We can create tRNAs that use 4 base codons instead of 3 base codons (but this can get tricky in a living organism!)

Codon/tRNA Reprogramming - We can engineer a cell to incorporate a different amino acid on a specific tRNA.

But, hacking what the natural base pairs code for can have unintended consequences in the proteins we need to keep cells alive!

Thankfully, synthetic biologists have also been working to add unnatural base pairs (UBPs) to these systems and have been successful in creating organisms that can use 6! base pairs (A, T, C, G, X, and Y).

This means we can create our funky new proteins without affecting how other critical proteins are made, because we can make tRNAs that complement new triplet codes and recognize our unnatural X and Y bases.

Ultimately, this allows us to create new proteins that have desirable functions.

Genetic code expansion has important applications in academic research, protein and enzyme engineering, and therapeutic development.

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