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Wed Aug 24, 2016, 11:49 PM

Elucidating the structures of powerful fish toxins from algal blooms.

While I tend to focus my growing environmental paranoia on the accelerating and on going destruction of the planetary atmosphere, we are making huge "progress" (Thinkprogress) at destroying the other fluid phase that is responsible for life on this planet, specifically surface water bodies, even one very, very, very, very large surface water body, our planetary oceans.

Of course, the interaction of these two phases makes some of the destruction interrelated, for instance, the acidification of the oceans because of the release of the dangerous fossil fuel waste carbon dioxide into our favorite waste dump, the atmosphere, or the release of vast quantities of the highly neurotoxic element mercury from coal (and to a lesser extent dangerous natural gas) burning while we all wait, like Godot, for the grand Greenpeace inspired so called "renewable energy" nirvana that never comes.

Another mechanism by which we are destroying the oceans is by eutrophication, which is the result of the release of vast quantities of fixed nitrogen, ammoniacal compounds, nitrates and related compounds and mobilized phosphorous. This important effect has, for one example, destroyed huge swathes of increasingly destroyed Gulf of Mexico near the mouth of the Mississippi River because of our need for corn for um, food, and of course, the all important goal of serving our most important master and God, the automobile, which requires us to produce huge amounts of "renewable" ethanol, even as we hem and haw into the even more absurd "electric car" era.

I feel wonderful, all "renewally." You can be very popular if you're "renewally," but unpopular if you question this assumption about the form of energy abandoned in the early 19th century because most people lived short, miserable lives of dire poverty.

We're, um, rich today, at least the top billion or so of us.

Eutrophication's mechanism involves the explosive growth of algae, and often, besides depleting oxygen in waters, this algae generates highly toxic "natural" compounds.

We love "natural" stuff on this planet, to the point we're willing to kill ourselves.

A recent event along these lines was the microcystin poisoning of the water supply of several major Ohio cities two years ago because of an algae bloom, resulting in the shutting of the water supply of Toledo.

The toxin that shut off Toledo’s water? The feds don’t make you test for it.

Microcystin is a very interesting complex compound.

All this comes to mind because I happened to stumble upon a very interesting and fun paper in the primary scientific literature concerning a algal ichthyotoxins, Prymnesins.

The paper is interesting to analytical chemists, because of the wonderful 2D and 3D NMR experiments performed on a remarkably high field instrument operating at 800 MHz in a 18.7 Tesla magnetic field.

When I was a kid, I was real excited when I could get access to a 300 MHz instrument. Kids today have it wonderful, or would have it wonderful, if we hadn't done so much to kill their planet for them because we were so certain that wind and solar "could" provide all of their energy after we're all dead and they're living in a nirvana we never actually constructed, but were absolutely certain they would construct, unless of course, they're all wiped out because we were, um, wrong.

That's their problem, not ours.

I'm no longer an NMR kind of guy by the way; I'm more of a mass spec kind of guy, and there's some very nice high resolution mass spec work in this paper on the structural elucidation.

Here's a graphic with the structure of prymnesins superimposed over a 1D NMR and 3D NMR spectra:

This is an incredibly complex molecule, and apparently, the biochemical synthesis doesn't involve all that much sugar chemistry, despite the fused pyranosyl rings hydroxy functionalized rings. I'm inspired to look up the biosynthetic references just for fun. Those triple bonds on the side chain are relatively rare in biomolecules, which makes them also interesting.

Here's an excerpt from the introduction:

Blooms of ichthyotoxic (fish-killing) microalgae are a recurring phenomenon in coastal and river waters, with huge impacts on wild fish stocks as well as caged fish. Such blooms have detrimental economical consequences for the local communities, fish farmers, and recreational and commercial fishers. An algal species that has been associated with massive fish kills in at least 14 countries is the haptophyte Prymnesium parvum (the golden alga).(1) In recent years, problems with P. parvum have spread to all southern states in the USA,(2) where it has become endemic in several river systems, with estimated economic losses higher than $10 million.(3) Consequently, programs have been initiated in countries such as the USA, Norway, and Denmark in order to assess the ecological and economic impacts of P. parvum blooms and to develop management options for controlling fish kills.(4) The possible ichthyotoxic components of P. parvum have been extensively studied,(5) but due to their complex structures and low abundance, it was not until 1996 that Igarashi et al.(6) successfully isolated and elucidated the structure of the two large polyether ladder-frame compounds, prymnesin-1 and -2. Later, the relative configuration of the prymnesins was revised by the Yasumoto group using synthetic models.(7-10) Despite the numerous P. parvum blooms that have occurred during the last two decades, prymnesin-2 has only once been tentatively detected again by liquid chromatography combined with high-resolution mass spectrometry (LC-HRMS).(11) Other groups have isolated and suggested “golden algae toxins” and fatty acid amides(12-14) as the principle toxins of P. parvum. However, we have recently shown that these compounds are not ichthyotoxic at ecologically relevant concentrations.(15) On the basis of these latter findings, our attention was drawn toward the prymnesins. We hypothesized that the reason that so few groups have been able to detect the original prymnesins could be that the structural diversity of prymnesin-type compounds is larger than previously realized.

The paper, which is right now open access is here:

Chemodiversity of Ladder-Frame Prymnesin Polyethers in Prymnesium parvum

We're killing ourselves, but if nothing else, there's some very interesting aspects to the way we're going about it. Life is wonderful, if short.

If anything about the destruction of the oceans disturbs you, don't worry, be happy. The Tesla car company has just announced it has a 100 kwh battery for its stupid electric car that all of our millionaires and billionaires can drive around in to smugly show the peons they are "saving" the planet by being responsible millionaires and billionaires.

Have a nice day tomorrow.

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Response to NNadir (Original post)

Thu Aug 25, 2016, 12:15 AM

1. *Slightly* reminescent of brevitoxin ... only slightly ...

Made me wonder, could both be from a common precursor ? Or one a degradation product of the other ? Problem is, I see only one methyl group in prymnesin, so that won't work. Maybe the only similarity is possible epoxidation/cyclization of intermediates.

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Response to eppur_se_muova (Reply #1)

Thu Aug 25, 2016, 12:28 AM

2. According to the text's references, which I have not as yet collected or read...

...the biosynthesis proceeds in a stepwise series of methylations resulting from acetate condensation and, presumably, decarboxylation steps.

Whether this involves an unsaturated fatty acid intermediate, I cannot say. I'll put up a comment if I get around to getting the references and have time to leaf through them.

If I just looked at the molecule and had to make an unsophisticated guess, I would have imagined carbohydrate biochemistry might have been involved because of all the hydroxy functions, but that would be, apparently naive.

Thanks for your interesting comment.

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Response to eppur_se_muova (Reply #1)

Thu Aug 25, 2016, 11:01 PM

3. I collected a few of the references in the paper relevant to biosynthesis...

...of polyketides.

The mechanism for brevotoxin that you showed from the Wikipedia reference to Brevetoxin via epoxidation would seem to make sense, especially owing to the susceptibility of epoxides to stereocontrol, as demonstrated in the lab by Sharpless and leading to his Nobel Prize.

The unsaturated acid would of course, be available, from acetate.

[sup]13[/sup]C labeling experiments seem to demonstrate that in fact most of the carbons in the related fused ring system of yessotoxin are, in fact, derived from acetate. Yessotoxin, also a dinoflagellate product has more methyl functionalities than prymnesin, 10 to be precise, all of which originate in acetate except for one that is apparently derived from a methionine methyl group in the mechanism that sometimes allows for branching.

Tetrahedron 67 (2011) 877-880

There's a very nice review article on the subject of biosynthetic pathways for these "ladder ether" systems: Nat. Prod. Rep., 2014,31, 1101-1137

I've only gone far enough into these papers to say I've been there, which involves looking at the pictures and reading through a little bit - excerpts - of the text. If you don't have immediate access to the papers, PM me and I'll be happy to send you copies of the papers.

Support for the chain epoxide ring opening cascade is found from the fact that [sup]18[/sup]O labeling experiments show that the internal oxygens in these systems do not for the most part derive from acetate. It appears that they are from oxygen gas.

This is interesting in the sense that one of the effects of algal blooms is, of course, oxygen depletion of the water. However, the mechanism by which this oxygen depletion takes place involved the decay of dead organisms decaying during oxidation by aerobic organisms in the regions below the blooms. There is localized oxygen from photosynthesis probably in the live bloom itself.

It's interesting that relatively simple mechanisms can lead to such complexity. These are interesting organisms that we've been promoting in our unyielding efforts to kill the planet while we wait tirelessly for the grand renewable energy nirvana that never arrives.

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Response to NNadir (Reply #3)

Fri Aug 26, 2016, 01:27 PM

4. Thanks, but I'll just add these to the list of things I need to catch up on ...

if I ever manage to get a job in chemistry again. Which may not happen, for all I can tell.

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Response to eppur_se_muova (Reply #4)

Sat Aug 27, 2016, 04:15 AM

5. Speaking only for myself, if I only read the chemistry (and physics and math and history)...

...relevant to what I actually do at my job, I'd be missing a big part of my life, which is not to say that I don't love my job. I do. There are people alive today who might not be were it not for the tiny roles I played while collecting a pay check.

It's been a rough time for chemists, I think, though, particularly synthetic organic chemists, particularly with the move away in the pharmaceutical industry from small molecules, and of course, from the fact that one can pay a Ph.D. in China or India 1/4 of what American chemists used to make and still get the same results. Maybe that's changing. I hope it is.

I started out in synthetic organic chemistry but what I do now is purely involved in analytical chemistry, picograms and femtomoles. I'm glad I spent a lot of time thinking about analytical chemistry even though it wasn't what I was doing at the time. It opened doors for me.

I'd be lucky, very lucky, if I live 20 more years, but I want to go down learning as much as I can before time's up. It is, I think, the whole purpose of life, to see.

It's both beautiful and terrifying, those algal toxins, and it's both beautiful - very beautiful - and terrifying, life itself.

Have a nice weekend.

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