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Expanded Genetic Code and Unnatural Amino Acids

#1
Yazata Offline
I was reading about this and thought that it was pretty extraordinary.

As most of you probably know, proteins are made of amino acids and some 20 amino acids are coded for by DNA and are found in (Earth) life.

What makes this a bit mysterious is the fact that there are far more amino acids than that, some 500 in total. So why are only this particular set of 20 coded for by DNA? Is it just fortuitous, an accident resulting from the original origin-of-life-events that just happened to produce a genetic coding mechanism for this particular 20? Has all of subsequent life built itself upon that narrow foundation?  

So the question arises, could synthetic DNA be engineered that codes for alternative amino acids that are not part of the favored 20? Would that DNA and the cells that contain it survive and sucessfully replicate?

And more speculatively, could expanding the genome's amino acid vocabulary give these synthetic organisms new properties?

I was just reading about work being done on these lines here:

http://schultz.scripps.edu/research.php

Peter Schultz writes:

"The genetic codes of every known organism specify the same 20 amino acid building blocks using triplet codons generated from A, G, C and T. These twenty amino acids contain a limited number of functional groups including acids, amides, alcohols, basic amines and thiols. Is this the ideal number or would additional amino acids allow the generation of proteins or even entire organisms with enhanced properties?...

...To this end, we have developed a methodology that allows one to genetically encode novel amino acids, beyond the common twenty, in both prokaryotic and eukaryotic organisms."


See also:

https://en.wikipedia.org/wiki/Expanded_genetic_code

https://en.wikipedia.org/wiki/Peter_G._Schultz

"This is accomplished by screening libraries of mutant amino acyl tRNA synthetases for mutants which charge nonsense-codon tRNAs with the desired unnatural amino acid.  The organism which expresses such a synthetase can then be genetically programmed to incorporate the unnatural amino acid into a desired protein in the usual way, with the nonsense codon now coding for the unnatural amino acid...

More than seventy unnatural amino acids have been genetically encoded in bacteria, yeast, and mammalian cells, including photoreactive, chemically reactive, fluorescent, spin-active, sulfated, pre-phosphorylated, and metal-binding amino acids. This technology allows chemists to probe, and change, the properties of proteins, in vitro or in vivo, by directing novel, lab-synthesized chemical moieties specifically into any chosen site of any protein of interest."
 

Don't be surprised if you see this work winning a Nobel prize sometime in the future.
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#2
Yazata Offline
More news on this today.

All DNA found in Earth organisms, from bacteria to human beings, has 4 bases: A,G,C and T. (Adenine, Guanine, Cytosine and Thymine.) Now the synthetic biology laboratory at the Scripps Research Institute referred to above has produced functional successfully reproducing bacteria with 6 DNA bases. The two new bases enable this artificially alien DNA to code for new amino acids that aren't part of the 20 normally found in Earth life.

The difference between this new development and the post immediately above, is that earlier work was incorporating the novel amino acids by engineering unnatural transfer RNAs. Now they have not only written the ability to produce them into the cell's DNA itself, they have done it by adding to DNA's chemical alphabet in a way that isn't seen anywhere else in Earth life.

Believe me, from a theoretical evolutionary molecular biological point of view, this is big. 

The MIT Technology Review opines:

"...the alien germs growing in San Diego already hint that our Earth biology isn't the only one possible. It suggests that if life did evolve elsewhere, it might have done so using very different molecules... life as we know it my not be the only solution, and may not be the best one."

https://www.technologyreview.com/s/60956...erational/

Another news story

https://cosmosmagazine.com/biology/four-...six-better

The lab's webpage

http://www.scripps.edu/romesberg/publica...l#Alphabet

The report is coming out in Nature, where the abstract says:

"Here we report the in vivo transcription of DNA containing dNaM and dTPT3 into mRNAs with two different unnatural codons and tRNAs with cognate unnatural anticodons, and their efficient decoding at the ribosome to direct the site-specific incorporation of natural or non-canonical amino acids into superfolder green fluorescent protein."

https://www.nature.com/articles/nature24659
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#3
C C Offline
In earlier work back in 2014, Romesberg at least mentioned safeguards for Franken-microbes. One gets the impression that these "aliens" don't merit the over-extravagant (or incredibly over-optimistic?) precautions of quarantining astronauts that landed on the Moon back in the 70s.

[...] the requirement to keep feeding the X and Y precursors to the bacteria is actually an important safeguard: If some of the bugs ever escape from the lab, they'll quickly revert to making natural four-letter DNA. On that point, Benner agrees. "The public is always asking, are you going to create a monster that’s going to escape and take over the world," he said. Benner thinks those fears are overblown, especially in this case. "If it gets out of the lab it's not going to go down to the San Diego zoo and start eating the penguins."

- - -
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#4
Yazata Offline
(Nov 30, 2017 05:36 AM)C C Wrote: In earlier work back in 2014, Romesberg at least mentioned safeguards for Franken-microbes. One gets the impression that these "aliens" don't merit the over-extravagant (or incredibly over-optimistic?) precautions of quarantining astronauts that landed on the Moon back in the 70s.

[...] the requirement to keep feeding the X and Y precursors to the bacteria is actually an important safeguard: If some of the bugs ever escape from the lab, they'll quickly revert to making natural four-letter DNA. On that point, Benner agrees. "The public is always asking, are you going to create a monster that’s going to escape and take over the world," he said. Benner thinks those fears are overblown, especially in this case. "If it gets out of the lab it's not going to go down to the San Diego zoo and start eating the penguins."

- - -

I was worrying about that too.

I can imagine a science-fiction scenario where amplifying the DNA code with new base pairs and incorporating new amino acids in addition to the usual 20 gives organisms new properties. And imagine that these new properties give these organisms strong selective advantage over the rest of Earth biochemistry. Then imagine some of them getting loose into the environment where they can reproduce and... evolve.

If they find some way (internal synthesis?) of providing themselves with X and Y bases and non-standard aminos, conceivably they might eventually... replace... our kind of life, by biochemically competing it into extinction just by being more efficient.
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