Lake Erie Chemophobia: A Tale of Two Anatoxins

At first, I thought it might be an April Fools' prank in poor taste, but then I read the latest PNAS -

Looks like Lake Erie wants to hurt you.

OK, not the lake itself, but the potentially toxic concentrations of cyanobacteria formed in recent record algal blooms. Yesterday, a multi-institution group of ecologists and environmental engineers reported a 'perfect storm' of runoff fertilizer, warm weather, and quiet waters in the lake that led to a marked increase in 2011 cyanobacteria populations. In fact, there appear to have been two blooms - the first Microcystia, and the second Anabena, two bacterial baddies* associated with liver and neurotoxicity. Scary stuff!

Well, the press coverage stemming from the study hasn't calmed fears. Here's a sampling from NSF, Huffington Post, and Discover. The HuffPo title really runs the chemophobia angle:
"Lake Erie Blooms Expected to Continue, Threatening Ecosystem, People." (!!!)
They dress the presser up for the occasion, with words like noxious, toxic, ugly, hazard, and problem. Discover writes 'toxic' three times, without pointing out what the toxins are! Even the normally staid NSF jumps on the bandwagon, referring to a mysterious 'liver toxin.'

What types of toxins are we talking about? Actually, that's a bone of contention here: the researchers only mention two, microcystin and anatoxin. Those turn out to be confusing terms, since the generic names cover >80 types of different microcystins, and at least two anatoxins [A(s) and A, right]. One assumes that the scariest anatoxin (Anatoxin-A, or 'Very Fast Death Factor'), operates here, which certainly warrants concern.

But, sans information, there's a panicked sense to the releases not grounded in the published text. Both Discover and HuffPo indicate "~200x concentration" of "toxic stuff" in the cyanobacteria-enriched water. Do the researchers actually say this? Let's go to the PNAS (emphasis mine):

"Surface toxin concentrations could have reached over 4,500 μg/L in early August assuming all Microcystis and microcystin formed a surface scum 10 cm in thickness. The World Health Organization guideline for microcystin in recreational waters is 20 μg/L..."

This statement relies on multiple qualifiers and conditionals. Where's your skepticism, science writers? Yes, things were bad in Lake Erie in 2011, but to spit this couched statement back as fact does a real disservice.

Worst part? Of the three media, only Discover actually links back to the actual study. Sigh.

*Boy, I love science: the Purdue blue-green algae fact sheet I linked to for Anabena indicates that ecologists nickname the major detected species (Anabena, Aphanizomenon, Microcystia) Annie, Fannie, and Mike!

This Just In - File Under "Huge Marine Polyethers"

K. brevisculata
Source: Te Ara - Encyclopedia of New Zealand
Maggy Wassilieff

There's a new red tide in town: Karenia brevisulcata, a dinoflagellate first discovered in New Zealand in 1998. This ocean denizen was pegged for a wave of fish kills and human illnesses, which cued curious natural products chemists to have a peek at their toxin profile. The scientists noted that several of the cell extracts had molecular masses well above 2000 - large polyether territory - and were lethal to lab mice.


Et voilà! Say hello to brevisulcenal-F, their first solved structure from the algal cells. This toxin, tipping the scales at 2076 amu (M + Na), sets a record in its own right: it has seventeen contiguous 6- and 7-membered rings, A-Q, the most yet identified in a single marine ladder toxin (I can almost hear Mori, Nicolaou, Hirama, and Crimmins sharpening their swords, ready for action!).

Brevisulcenal-F spectrum and structure overlay
Source: JACS and M. Satake, U. of Tokyo

But how big is big? This new natural product certainly contends, but still doesn't approach two of the 850-lb gorillas in the room: palytoxin (PTX) and maitotoxin (MTX). First synthesized from PTX-COOH by Kishi in 1994, palytoxin, a soft-coral isolate from Hawaii, weighs in at 2680 amu. Although not specifically a ladder polyether, it was for decades considered the largest known non-peptide natural product. But PTX pales still in comparison to the largest known non-peptide np, maitotoxin, which totals 3422 amu, with 32 total ether rings. Isolated from Tahitian fish in 1976, maitotoxin eluded full structural characterization until the mid-1990s.

I'm glad my NMRs don't look like maitotoxin.
Source: Murata, JACS 1994

Where are these huge marine toxins coming from, exactly? Nakanishi advanced a polyepoxide cascade theory as early as 1985, which suggested that long, polyunsaturated terpenes (olefin biopolymers) were being somehow oxidized by the microorganisms, then cyclized into long ether "ladders," like a falling stack of dominos. It took another 20 years for experimental confirmation, but new cascade research by Jamison and others has shown that this might indeed be the case.