Tuesday, July 31, 2012

New Rainbow of Synthetic Firefly 'Fire'

I love deep answers to seemingly simple questions, like why grass looks green (emission spectra), or what causes "metal" smell (hand oils). I also enjoy rational drug design, the process where a hit becomes a lead through a series of well-thought and "why not?" changes. Finally, everyone likes flashy colors, especially natural ones.

Well, what if a recent paper met all three criteria? And had a catchy abstract graphic, to boot?

Look no further than the latest Angewandte Highlight, out now in the Early View section. Prof. Wei Guo and his students sum up progress towards synthetic luciferins, which are capable of bioluminescence just like the yellow-green D-luciferin many of us remember from childhood firefly collections (I'm hardly the first blogger to mention synthetic luciferins, btw. See Scheme 1 in the paper for a general luciferase reaction).

Credit: Guo et. al., ACIEE Early View
Regarding design, the chemical ground rules have been known since the late '60s:

1. Don't mess around too much with the phenol group. It prefers to be -OH or -NHR.
2. Heteroatom swaps in the two heterocyclic rings are mostly OK.
3. Don't cleave the carboxylate, or you'll turn out the light!

With these simple statements in mind, chemists have brought forth a slew of new luciferins over the past decade. The take-home message? Depending on the substitution pattern, luciferase lights up over a broad range, from deep in the red (>600 nm) up to bright blue (around 460 nm). Researchers use the new luminescers as probes, guest-starring in cellular assays sometimes reserved for the mighty GFP.

A few things caught me by surprise. First, how such tiny structural manipulations could produce such large changes to the observed bioluminescence - an S-for-Se swap gains 50 nm (red shift) whereas an S-for-N-Me buys you 100 nm...in the opposite direction! (blue shift) Second, I had no idea that there was a mutant version of luciferase - ULTRA-GLO - that not only permits high-throughput analysis, but also increases the observed light 3- to 6-fold, like a wild molecular highlighter.

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