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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« EMBL Chemical BIology: Natural Product Multiheterocycles | Main | EMBL Chemical Biology: Discovering Catalysts »

September 27, 2012

EMBL Chemical Biology: Labeling Proteins

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Posted by Derek

Jason Chin of the MRC Molecular Biology lab in the UK has been talking here about protein labeling and genetic code expansion, an overview of the numerous papers his group has been publishing in this area over the last few years.

And he's just made what I think is a very worthwhile point. While talking about labeling proteins with very reactive alkyne-containing amino acids (for fluorescent "click" applications), he said that some people would look at this and say "Why bother - you can already label these things with GFP". But sticking an entire Green Fluorescent Protein onto an existing one is hardly a silent event. If you're going to think about these things the way a chemist would, you need to come in with something as small and unobtrusive as possible. And it also needs to be something that you can localize, which doesn't just mean "I know what protein it's on".

Chemists think - or had better think - at a higher magnification. What exact surface of the protein is this label on? What residues are next to it? What sort of binding pockets might it be interrogating? We need to treat proteins as molecules, and as molecules they have a lot of detail in them.

Comments (6) + TrackBacks (0) | Category: Chemical Biology


COMMENTS

1. Bauke on September 27, 2012 4:01 AM writes...

Excellent point Derek. To many findings are corroborated by label-effects. That's why we go fluorescent and organometallic ;-) No more house-sized labels on postcards!

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2. milkshake on September 27, 2012 10:34 AM writes...

I would be careful about incorporating terminal alkyne-substituted aminoacids (like propargyl and homopropargyl glycine) - these things could be ferociously toxic. Just last year a paper came out about mass poisoning in China that killed dozens of people, after picking supposedly edible mushrooms. The actual toxins were identified as propargyl-sidechain substituted alanine and serine. Another closely related plant toxin is called hypoglycin (has cyclopropyl and exo-methylene). There are many more examples of a creepy and sometimes viciously toxic simple aminoacids (N-methylaminoalanine, N-oxaloylaminoalanine, canaline and canavaline)

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3. Derek Lowe on September 27, 2012 12:12 PM writes...

#2, Milkshake

I had a chance to ask David Tirrell that very question after reading your comment. He says that since they're hijacking the protein synthesis machinery, it's not like the organisms are being exposed to a lot of free alkynyl amino acid, but they can push the incorporation levels in the proteins surprisingly high before seeing signs of trouble. Is the target of the mushroom toxins known? Excitatory amino acid ion channels?

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4. milkshake on September 27, 2012 2:33 PM writes...

Derek, I think it was this paper: Angewandte 51(10), 2368-70 (2012). DOI: 10.1002/anie.201106502, Homopopargyl alanine and its hydroxy analog. The poisonng was correlated with heart rhabdomyolysis and hypoglycaemia. From the close structural similarity with hypoglycine (an irreversible isovaleryl-CoA inhibitor and blocker of beta oxidation) they speculate that these acetylenic aminoacids screw up lipid metabolism in muscles.

Another remarkably simple creepy aminoacid is mimosine (aka leucenol) - toxic as hell, causing G1 cell arrest. I almost put it into my molecule once, as a tyrosine mimic building block.

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5. gippgig on September 28, 2012 1:48 AM writes...

#3: The organisms do have to be exposed to a lot of free alkynyl amino acid so that the new aminoacyl-tRNA synthetase will charge the new tRNA with it.
#4: I would classify mimosine as a fairly complex amino acid (of the amino acids in the genetic code, only tryptophan could be considered more complex).

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6. gippgig on September 28, 2012 2:10 AM writes...

Oops, forgot pyrrolysine. Make that "amino acids in the standard genetic code".

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