A paleobiochemistry post! I think.

[Note: this was going to be a post on obscure bizarre sponge biosynthetic pathways. They're bizarre all right, and obscure has never stopped me before, but the subject (sponges) isn't easy to fit into any paleo record. The following discussion is an old workhorse of mine, freely adapted from Karl Bloch's Blondes in Venetian Paintings, a book filled with many good things.]

The most common sugar on Earth is probably glucose, also known as blood sugar or grape sugar. It's found in blood and grapes, and pretty much everything else with a metabolism. It's ubiquitous in living organisms as an energy source.

A molecule of glucose has six carbon atoms, twelve hydrogen atoms, and six oxygen atoms. That's proportionately the equivalent of one molecule of water (H2O) for every carbon atom. Perhaps you've seen the Mr. Wizard clip where the good wizard dumps sugar into the aggressive dessicant sulfuric acid, leaving behind steaming carbon foam. Hence carbo-hydrate.

In glucose, in water solution, five carbon atoms and one oxygen atom of the glucose molecule are often arranged into a hexagonal ring. It's not a flat ring, but staggered, a little like a lawn chair. Each carbon atom in the ring is connected to two other atoms not in the ring: a small hydrogen atom and a larger carbon or oxygen atom. Each carbon atom in the ring also has two slots for further bonding: an equatorial position, like a cup-holder, or an axial position, like a parasol.

This is important, because in glucose, all the larger atoms avoid the axial position, in favor of the equatorial position. As a result, glucose the most chemically stable of the six-carbon sugars. (Picture the parasols on the lawn chair crashing against each other and tipping it over.) This stability is likely why glucose was selected by evolution to be a ubiquitous energy source in the first place, several billion years ago.

There's an odd exception. Insects, while they use glucose in their metabolisms (everything does), use a different sugar in their blood hemolymph, called trehalose.

Trehalose is a disaccharide: two sugar molecules connected together. In this case, both sugar molecules are glucose, the footrest of one lawn chair connected to the footrest of the other. This, incidentally, keeps the rings of the lawn chairs from unravelling and reacting with other molecules. Even the comparatively stable glucose will unravel and react with things over time; it's why diabetics are more prone to blindness and kidney failure. But trehalose won't. It can't.

Trehalose is also an excellent cryoprotectant and protectant against dryness. Physically, it seems to mimic the structure of the network of water molecules in their liquid phase. (Yes, liquid water has structure! it's always in flux, but there are consistent loose interactions between water molecules. It's like a rave.) The water molecules link themselves to the oxygens on the equatorial cup-holder positions on the the trehalose molecule. Even a small concentration of trehalose will maintain this loose network.

Vertebrates can't synthesize trehalose. Insects can and do, sometimes in large quantities, and its concentration in hemolymph is correlated with an insect's ability to survive cold or other extreme conditions. The honeybee, whose thermal regulation is taken care of by the hive, does not produce trehalose; the mountain stone weta, which lives in the dry cold of New Zealand, produces the equivalent of one hundred times human blood sugar levels in trehalose.

This use of trehalose as a shared metabolic innovation among the insects strongly implies that it's basal. This in turn suggests that the insect lineage arose under conditions where a protectant against extreme cold or dryness was necessary -- the late Ordovician glaciations come to mind, even though the first documented insect dates from the Devonian. How trehalose metabolism is regulated in the insects is still a mystery.

Finally, trehalose was rediscovered in an effort to chemically characterize Biblical manna. Yeah, that's right: manna from heaven? Bug juice.

Comments

[Will Baird]

Very kewl, Carlos. Not the one I was hoping for - cyad being poisonous to mammals and its implications - but even so this is damned kewl. I didn't know about anything about trehalose at all. I like the hypothesis about when it might have arisen and why. is there anything testable about it? y'know to try to verify it?

[claudia]

1) I've never heard of the Bloch book. Should I have?

2) I knew about trehalose in general terms, via the route you'd expect: Hibernating insects are a major food source for overwintering birds. That sounds simple and obvious, but it plays out in some really complicated ways.

Are insects really the only animal lineage that synthesizes trehalose? Because there are others that could make use of it.

3) Question: If trehalose is more stable than glucose, what's the downside? You might expect to see it in more lineages, doing more stuff. Is it too stable, or hard to synthesize? Toxic?

Doug M.

[Carlos]

Thanks, Will! Wasn't sure which one you wanted, and the cycad toxicity one completely slipped my mind.

Trehalose synthesis in insects uses a specific enzyme (trehalose-6-phosphate synthase, a rather uninformative enzyme name) which is of course coded for in the DNA. Comparative genetic studies could probably say something interesting about it.

The synthesis uses glucose-6-phosphate -- phosphate is used in carbohydrate metabolism to activate a compound -- and uracil-diphosphate-glucose. It's the same uracil that's in RNA. When you have an RNA base attached to something, it's a strong sign that it's not only activated, but metabolically partitioned. The most common one is adenine: e.g., adenine triphosphate (ATP), ubiquitous in metabolism. Uracil compounds are comparatively rare.

Doug, it's slightly energetically expensive to produce trehalose from two glucose molecules, and it's slightly energetically expensive to break it down to glucose again. So there is a disadvantage.

Also, compared to glucose, trehalose doesn't have any convenient chemical hooks. It's a little like the difference between diesel and gasoline. In fact, glucose would show toxicity at some concentrations where trehalose is found.

But most probably, the synthetic reaction is somewhat difficult to reach in enzyme space. To use the jargon, it's a 1,1 linkage between glucose molecules. Most of the really common biological ones are 1,4 -- cellulose, glycogen, starch -- with starch having a few 1,6 branches.

Trehalose is found in some other invertebrate lineages, like the tardigrades, and in (of course) fungi. But it's not found in many organisms where one might expect it. And in vertebrates, not at all.

There aren't many popular books on classical biochemistry. Bloch's is one.

[Doug M.]

"it's slightly energetically expensive to produce trehalose from two glucose molecules, and it's slightly energetically expensive to break it down to glucose again. So there is a disadvantage."

That makes sense. However, googling brings up this:

"Trehalose is the major carbohydrate energy storage molecule used by insects for flight. One possible reason for this is that the double glycosidic linkage of trehalose, when acted upon by an insect trehalase, releases two molecules of glucose, which is required for the rapid energy requirements of flight. This is double the efficiency of glucose release from the storage polymer starch, for which cleavage of one glycosidic linkage releases only one glucose molecule."

Huh. If that's right, it's a really fascinating example of preadaptation (and yes, I like that term just fine).

"Insect trehalase" -- apparently we vertebrates have our own trehalase, which is why we can eat things that contain trehalose: insects. And mushrooms, if we're so inclined. I wonder if trehalase is lost in vertebrate lineages that never encounter trehalose; obligate carnivores, say, or toothy cetaceans.

Apparently it's also being investigated as a treatment for Huntingtons; trehalose impedes certain types of protein accumulation, and that's exactly what causes Huntington's.

(How did we live before google? How??)

Doug M.

[Carlos]

Um. That's true, but somewhat off-point. Consider: what disaccharide doesn't produce two monosaccharides on cleavage? I mean, it's definitional. Sucrose, maltose, lactose. And starch wouldn't be the comparandum in animals; glycogen would be.

Anyhow, in insects, the trehalose precursors are formed from the breakdown of glycogen. Any sugars in the diet first have to be incorporated into glycogen storage, via the insect's fat body organ -- roughly equivalent to the vertebrate liver -- and then released for trehalose formation. So it's not obviously a quick release mechanism.

Little is known about insect trehelAse regulation, how the enzymes which break down trehalose into glucose are controlled. The mammalian trehalases, incidentally, are on the villi of the small intestine and in the kidney, and appear to be unregulated. Pure digestion.

[Noel Maurer]

Doug: fairly easily.

Maybe if they get around to finishing that Google Book thing, then that will change. But right now, well, the internets don't provide all that much more useful knowledge (or even, more surprisingly, data) than what you already have in a good office library.

Of course, this doesn't apply if you are polymathic way beyond the norm.

Which you are. But I'm not, and neither, sadly, are most people. So it's nice, and I miss being able to immediately pull up sports records and the like, but I'm loth to exaggerate.

Of course, I'd never have learned about insects' nature antifreeze in the pre-Internets day.