Chemistry – Page 28 – David Bradley

Mighty Neat Diabetes Target

mitoneet protein

In this week’s SpectroscopyNOW column, I cover a wide range of subjects with the usual hint of spectroscopy, informatics, and crystallography. First up is a study on a unique protein, MitoNEET.

The protein was previously identified as a putative site for the activity of diabetes drugs known as thiazolidinediones, or which Actos is an example. The determination of the protein’s three-dimensional crystal structure coupled with bioinformatics information demonstrates that it is a clear target for small molecules. The mode of action was previously linked to an entirely different protein, according to biophysical chemist Patricia Jennings and physicist Mark Paddock, and their colleagues at the University of California at San Diego (UCSD) and Stanford Synchrotron Radiation Laboratory and the Hebrew University of Jerusalem, Israel.

“This is the first time that a protein like this has ever been found,” explains Paddock, “It is a brand new structure, a unique beast, which makes it an exciting target for structure-based drug design.” The structure shows two protomers intertwined to form a unique dimeric structure, explain the researchers, this constitutes a new fold not only among the 650 known Fe-S proteins structures but also among all known proteins.

Given that there is at least one clinically tested drug in this area it shouldn’t be too long before other novel compounds that can moderate insulin by interacting with MitoNEET are being investigated. However, it does highlight once again just how hit and miss the drug discovery process can be if the thiazolidinediones are not actually targeting the protein with which they were initially thought to interact.

Also in this week’s issue, more on the crab metabolite story from last week, copper blues and the toxic mouse, and Rod of Titania, the new superhero that could improve energy technologies and sunscreen simultaneously.

Culmination of Fulmination

Mercury fulminate

German chemists recently determined the crystal structure of a compound the alchemists knew as “Knallquecksilber”, but which goes by the formal name of mercury(II) fulminate. The compound is highly explosive, sensitive to heat and shock and its control in the form of a detonator material for dynamite gave Alfred Nobel his big break.

The new crystal structure corrects some previous mentions in the scientific literature, by revealing it to be an almost linear molecule. But, never mind the chemistry you can read more about that in the September issue of my Intute Spotlight. It is that name that intrigues me. Knallquecksilber.

Quite literally it means “bang quicksilver”, quicksilver being silvery mercury’s liquid alchemical name. Bang quicksilver hardly slips off the tongue, so a better translation might be exposive quicksilver, which isn’t quite so crisp and subtle as the German word, but close.

I had a chat with a German chemist friend about the etymology of this name and the lack of a subtle literal translation from the German into English. It’s common to quite a few German words, zeitgeist, meaning literally time-ghost or spirit of the times, being another favourite. My friend pointed out that knallen (verb) describes something exploding with a big bang, a
Knall, the crack of a whip or the banging of a door might be described using knallen in German, for instance.

But, he also pointed out that the English name for this salt itself – mercury fulminate – harbours an explosive origin. Fulmination, of course, being another word for a violent explosion and so perfectly apt for describing big bang quicksilver.

Periodic Table Names

Periodic table names, it’s an odd phrase, what does it mean? It obviously means something to dozens and dozens of visitors to ChemSpy.com who hit the site from the search engines looking for that exact phrase. I puzzled for ages trying to figure out what these visitors were after. Were they simply looking for different types of periodic table? There are lots of sites out there that discuss traditional, modified, circular, three-dimensional and some rather bizarre periodic tables (there are PTs for desserts and sexual positions, (NSFW) you may care to know).

Then I spotted a follow up search from a cluster of subsequent visitors, they were searching for not just “periodic table names” but “periodic table with names”. Then a query came in that was even more explicit – “periodic table with element names”. Duh! I thought to myself. They’re simply looking for a PT that not only has the elemental symbols but gives the full name of the element to which the symbol refers. Well, the answer to that query is easy – yes. Best among a big bunch has to be good friend Mark Winter’s site based out of Sheffield University WebElements.

So, there’s the answer. Unless you know otherwise…

More Periodic tables:

PT rings and more, PT of visualisation methods

Male-Female Crabs Split their Difference

Male-Female Crab

David Johnson and Robert Watson thought they had seen all there was to see in the Chesapeake Bay in almost three decades until they pulled out a crab from the way that had a male left half and a female right half. Now, that crab, acquired by Romuald Lipcius of the Virginia Institute of Marine Science at the College of William & Mary, has moved sideways into the world of natural metabolites where its gynandromorphic peculiarities have helped scientists, for the first time, discover that some molecules can be made only by one sex and not the other.

The male-female crab is a unique example of the blue crabs. It turns out that the males of this species produce a natural metabolite that is absent in females. This suggests that some complex biochemistry is underway that is activated only in males. Robert Kleps of the University of Illinois at Chicago and colleagues have isolated this small molecule and identified it as 2-aminoethylphosphonic acid (AEP), an uncommon but well-documented natural metabolite.

We used low-field NMR using phosphorus-31, to observe the small molecule, explains Kleps. He points out that science tends to get lost in the rush for higher field NMR running hydrogen-1 and carbon-13 on 100 kilodalton proteins. However, he adds that, “Even low-field NMR spectroscopists can make interesting discoveries. I’m very happy to have stumbled over this metabolite, while doing basic research on invertebrate metabolism.”

So, why might the existence of a metabolite in the males of this blue crab species and not the females have any bearing on our everyday lives? Well, there are well known differences between the sexes in people, such as disease susceptibility, anatomy and drug metabolism. Kleps points out that these differences might in fact be due to the presence or absence of a crucial metabolite.

Now that the existence of a sex-specific metabolite has been found for one animal the search is on for others, including ones that might exist in people.

For more details on the NMR study check out my column on SpectroscopyNOW.com, the research paper itself is available in Plos One.

You can hear a description of the crab from Lipcius here and listen to Kleps’ podcast

ChemModLab Enters ChemSpider Web

A new project that combines work from two distinct cheminformatics groups will form a new system for the delivery of modeling and identification of commercially available compounds for biological testing.

The North Carolina State University Exploratory Center for Cheminformatics Research group, developed ChemModLab to compute quantitative structure-activity relationship (QSAR) models and this will be pulled together with the almost 18million structures currently in the ChemSpider database. These structures are sourced from the scientific literature, chemistry database providers and commercial chemical vendors and screening library providers.

“This data collection provides an ideal basis for combing the QSAR capabilities of ChemModLab with the compound collection and indexing of ChemSpider to allow identification of virtual hit compounds via in silico screening, says ChemSpider boss Antony Williams.

Googling InchiKeys

What it is to be an InChI – at once unique and representative of so much and yet meandering and potentially far too long. Now, IUPAC has launched a new version – InChIKey – a condensed version of the InChI chemical identifier that will be a fixed 25-characters long.

This new format will make searching for molecules on the web much simpler by preventing unpredictable breaks that happen with the conventional seemingly endless InChI strings for some of the more complex compounds. It will thus facilitate a web-based InChI lookup service and allow InChI to be stored in fixed length database fields and so make chemical structure database indexing far easier. One of the most important aspects of this new approach to the InChI is that it will allow verification of InChI strings across networks. Imagine the woe, for instance, if the tail of your Viagra InChI were cropped short in transmission…

IUPAC admits that there is a finite, but very small probability of finding two structures with the same InChIKey. The odds are of the order of billions to one against, but chemists are making more and more new substances as we speak so you never know when there might be a data collision. It is very, very unlikely, however.

The new release can be downloaded from the IUPAC web site (www.iupac.org/inchi). What effect this will have on my passwords for chemists idea, I simply don’t know!

Post-Labor Day SpectroscopyNOW

Earth's core

My latest science news round-up for SpectroscopyNOW.com is now live:

The problem of the core – Understanding how the bulk iron at the earth’s core is packed together and with what other lighter elements is critical to revealing the origins and evolution of the earth and precisely how it generates its magnetic field.

Fluorinated agents at the ready Intrusive biopsies for people with cancer could be sidestepped thanks to the development of fluorine-containing contrast agents by David Parker and colleagues at Durham University.

Baby light – Near-infrared light could allow researchers to see activity within the infant brain even while the tot wriggles and giggles.

High-field NMR morphs caffeine structure – High-field NMR has overcome the problem of spectral ambiguity in nitrogen-rich compounds, thanks to efforts by Canadian scientists. The team has studied two anhydrous polymorphs of the stimulant, caffeine, and has found that, despite extensive disorder, both caffeine polymorphs reveal the characteristic structural signatures of crystalline compounds.

Diamonds out of Hades – Raman spectroscopy could turn the history of the early Earth upside down and hint that conditions were suitable for life as little as 250 million years after its formation, pushing back the so-called Hadean era several hundred million years.

Sweet nanoreactor – A one-pot chemical reaction system based on nanoscopic capsules embedded in a polymer membrane has been devised by researchers in The Netherlands. The nanoreactor system allows cascade reactions to be carried out that would otherwise require multiple distinct reaction steps with time-consuming and wasteful separation and purification stages.

ChemAxon Hits a Nerve

ChemAxon recently announced version 2 of its Instant JChem, a desktop application for working with chemical and
other data on local and remote databases. Version 2 adds forms and form building, relational data support, advanced query
building and multiuser access.

Instant JChem is a software application for all major operating systems which bundles ChemAxon’s Marvin and JChem enterprise cheminformatics toolkits with a local database engine to give an ‘out of the box’ solution for research informatics. Personal use is free, although if you want to go “enterprise” you will have to check out their price list.

Cacao caffeine myth – Chocolate Myths

TL:DR – Cocoa beans, and so chocolate, can contain a small amount of caffeine despite claims to the contrary.

Caffeine theobromine

A front page item on a social bookmarking site claimed that chocolate does not contain caffeine. The link was tied to an introductory paragraph that said: “There is a persistent urban legend that chocolate contains caffeine. It would seem that this rumor is based primarily on a confusion between two similar alkaloids: caffeine and theobromine. Theobromine is the active ingredient in chocolate and it occurs only in [the plant Theobroma cacao. The two stimulants are related and have similar structures.”

Yes, they most certainly do, theobromine (not in any way related to the element bromine by the way) and caffeine are almost the same chemical structure but in the caffeine molecule the hydrogen atom on a nitrogen atom in theobromine has been swapped for a methyl (CH₃) group. Why is this important? Well, the difference in chemical and biological activity of two molecules that can differ by a couple of hydrogens and a carbon is astounding. More on that later. What about the site’s claims that chocolate does not contain caffeine?

A quick search on PubMed plucked out several papers all of which have carried out analyses of chocolate to demonstrate that it does indeed contain caffeine. As just one example, in 2006, German researchers Stark, Bareuther, and Hofmann of the German Research Institute for Food Chemistry, in Garching, provided a molecular definition of the taste of roasted cocoa nibs (Theobroma cacao) by means of quantitative studies and sensory experiments. In their paper they state: “theobromine and caffeine…were among the key compounds contributing to the bitter taste of roasted cocoa.” Their tests were carried out using solvent extraction, gel permeation chromatography, and reversed-phase high-performance liquid chromatography (RP-HPLC) and corroborated earlier findings. The actual quantity of caffeine in chocolate is very small, especially compared with the amount of theobromine.

To quote the UK’s Institute of Food Research on the subject of caffeine in chocolate:

“Chocolate contains bio-active compounds, e.g. caffeine and theobromine. Caffeine is only present in small amounts in chocolate – in fact, one would have to eat about eight 100-gram bars of milk chocolate to consume the amount of caffeine present in a cup of coffee. Theobromine is related to caffeine, and is present in chocolate in much higher amounts, although it has relatively weak stimulant effects. It is possible that in combination, these and other potentially bio-active constituents do influence our liking for chocolate. At present, however, there is no direct evidence to support this.”

Caffeine is a bitter-tasting alkaloid, a natural product, a xanthine, found in several plant species, coffee, tea, and cacao. It is a stimulant, like its close chemical cousin, theobromine. There have been dozens of media articles, purportedly based on solid research, that send out mixed messages regarding the health effects of caffeine on people and whether or not we should expose our bodies to this stimulant.

A quick search of the web for cacao theobromine and caffeine reveals several sites warning of the toxicity of stimulants in chocolate, coffee and other products. But, an NIH page also appears that says something along the line of caffeine content need only be reported if levels are above a certain threshold.

Alchemical Happenings

As regular Sciencebase readers will know, I write a regular chemistry news round-up for ChemWeb under the plome-de-nume of The Alchemist. This is the latest incarnation of a column I first wrote for the original ChemWeb.com almost a decade ago. ChemWeb is now owned by chemical industry search engine chemindustry.com, which is fast developing the site into an indispensable resource for anyone working in the chemical sciences.

Anyway, here is a summary of the latest Alchemist chemistry news headlines.

This week, iron and chemical education skills are rewarded, while analytical and synthetic efforts finally pay off after almost four decades or work on a natural insecticide with the first total synthesis of the neem tree extract azadirachtin. The Alchemist also discovers that diamonds really are almost forever and nanoscopic polymer capsules can facilitate one-pot cascading biotransformations. Finally, a new range of fluorinated contrast agents for medical imaging could make cancer diagnostics stick and computational developments on actinide compounds could revolutionize our understanding of the chemistry of radioactive materials. That synthetic odyssey undertaken by Steve Ley and colleagues at Cambridge University to synthesise azadirachtin will feature in more detail here in a forthcoming post.