With H5N1 avian influenza gradually making its way across the world, a lot of people are preparing for the worst. It’s still not clear if this strain of the flu will ‘evolve the ability to spread between people,’ but if this happens, we’re in for some serious problems:

The current syntheses of oseltamivir (a.k.a. Tamiflu) fall ‘short of the ideal for several reasons: (1) the starting point in the synthesis is either (-)-shikimic or (-)-quinic acid, which are complex relatively expensive and of limited availability, and (2) two steps involve potentially hazardous and explosive azide-containing intermediates.’

But two new syntheses of oseltamivir/Tamiflu were reported in JACS earlier this week: one is by Yeung et al. and the other is by Fukuta et al.

Although the synthesis from Corey’s group is much shorter, both syntheses avoid using either (-)-shikimic or (-)-quinic acid as starting materials: Corey’s synthesis starts with 1,3-butadiene and trifluoroethyl acrylate and Shibasaki’s synthesis starts with the asymmetric ring-opening reaction of a meso-aziridine with TMSN3. If these syntheses could be scaled up and optimized further, it might be possible to reduce the cost of oseltamivir/Tamiflu and pharmaceutical companies (or paranoid graduate students) could make plenty of the compound, which could be stockpiled and used if a human pandemic occurs.

The only catch: oseltamivir-resistant virus has already been reported in Vietnam…

Joshua

Joshua Finkelstein (Associate Editor, Nature)

The National Academy of Sciences and the American Academy of Arts & Sciences have announced their new members: ‘72 new members and 18 foreign associates from 16 countries’ for the NAS (including David Baker, Eric Heller, and Nobel Laureate Harold Kroto) and ‘175 new Fellows and 20 new Foreign Honorary Members’ for the AAAS (including Dale Boger, Amos Smith III, and Timothy Swager).

This announcement comes only a few weeks after Howard Hughes Medical Institute released the names of their new ‘million-dollar professors’ (including Catherine Drennan, Scott Strobel, and Richard Zare).

On behalf of everyone at Nature, congratulations!

Joshua

Joshua Finkelstein (Associate Editor, Nature)

As if New Yorkers like myself didn’t already have enough to worry about, the local news last week helpfully informed us of another threat: the potential for a major hurricane to hit New York City.

Most scientists believe that increased emissions of greenhouse gases have contributed heavily to global warming, which has in turn been responsible for the increase in the number and strength of Atlantic hurricanes. Hurricanes do not usually hit states above North Carolina with great force because the ocean temperature must be at least 80°F (27°C) for a hurricane to maintain its destructive momentum. But with global warming causing an increase of ocean temperatures worldwide, the potential for a major hurricane to reach New York and other coastal areas in the northeast is growing.

I looked up a few facts and figures, which unfortunately seemed to confirm the news report.

After Miami and New Orleans, New York is considered the third most likely city for a major hurricane disaster (and of course we all remember what happened to Miami and New Orleans in 2005!).

The United States Landfalling Hurricane Project reports that there is an approximately 26% chance that New York City or Long Island will be hit with a Category 3+ hurricane in the next 50 years.

If a Category 3 hurricane hits NYC, the storm surge will flood the Brooklyn-Battery tunnel and cause extensive flooding of the subways.

The NYC Office of Emergency Management has posted maps of hurricane evacuation zones for all of the New York boroughs. I was somewhat dismayed to find that my apartment in Brooklyn is in the green zone, which means it is in trouble if a Category 3 ever heads my way (luckily, I live on the third floor of a four-story house). However, the NPG office is in even more danger in the yellow zone in Manhattan, meaning that it is at risk from a Category 2 storm surge!

Allison Doerr (Assistant Editor, Nature Methods)

In today’s issue of Science, there’s a nice review on protein dynamics by Mittermaier & Kay and a paper on the dynamics and function of a peptidyl carrier protein domain of tyrocidine A synthetase. In their review, Mittermaier & Kay wrote:

Recent methodological advancements in NMR have extended our ability to characterize protein dynamics and promise to shed new light on the mechanisms by which these molecules function … NMR spectroscopy is uniquely suited to study many of these dynamic processes, because site-specific information can be obtained for motions that span many time scales, from rapid bond librations (picoseconds) to events that take seconds.

Although I’m sure X-ray crystallography will still be widely used to determine the three dimensional structures of proteins in the future, I think we’ll start to hear more about the utility of NMR spectroscopy, especially since there are a number of NIH-funded structural genomics centers that are using NMR spectroscopy to solve protein structures, there are new labeling methods that may make it possible to use NMR to solve the structures of larger proteins, and there are exciting demonstrations of how solid-state NMR can be used to probe the structure and function of membrane proteins.

NMR can also be used to find important biologically active small-molecules/potential drugs – for example, Oltersdorf et al. used NMR to find and optimize a new anti-cancer compound and Forino et al. used a “fragment-based approach” to find a new inhibitor of the lethal factor metalloproteinase from Bacillus anthracis.

Of course, many of these experiments can’t be done on an aging NMR spectrometer. In a recent Nature paper, Dorothee Kern’s group used a Varian 800-MHz spectrometer to examine the dynamics of the prolyl cis–trans isomerase cyclophilin A. 800-MHz spectrometers will need to get a lot cheaper before many laboratories can afford to use them routinely…

Joshua

Joshua Finkelstein (Associate Editor, Nature)

If you’re a regular reader of Chemical & Engineering News or the BBC News website, you’ve probably already heard about an exciting paper in yesterday’s issue of Nature by Ro et al.

The authors were able to re-engineer S. cerevisiae to produce fairly large amounts of artemisinic acid, a precursor to the anti-malarial drug artemisinin (up to 100 mg per liter of culture). The authors used a novel cytochrome P450 monooxygenase from A. annua to perform a three-step oxidation of amorpha-4,11-diene to artemisinic acid, which can be chemically converted to artemisinin. Malaria kills more than one million people each year, and artemisinin is a highly effective, but costly, treatment. If this process could be scaled up and optimized, the authors “”https://www.nature.com/nature/journal/v440/n7086/suppinfo/nature04640.html">project that artemisinin or its derivatives could be produced at costs significantly below current prices, thereby lowering the cost of an artemisinin combination therapy by a significant amount."

This work was funded by a $42.6 million grant from the Bill & Melinda Gates Foundation, which was was awarded to the California Institute of Quantitative Biomedical Research at University of California, Berkeley, Amyris Biotechnologies, and the Institute for OneWorld Health (a non-profit pharmaceutical company). It’s an interesting collaboration:

If you want to learn more about the work, Jay Keasling was interviewed on this week’s podcast and there’s a news story in the April 13th issue of Nature by Narelle Towie.

Joshua

Joshua Finkelstein (Associate Editor, Nature)

OK – I know this is going to sound strange, but I really love looking at electron density… Most structural papers have a few figure panels showing some electron density (usually the active site residues), but atomic resolution structures are rare and it’s just so satisfying to see little globes of density around each atom (rather than a big blob that could represent one of several rotomers…)

If you love electron density too, there’s a recent paper from Nature Chemical Biology that might interest you: Lyubimov et al. “obtained five sets of X-ray diffraction data at atomic resolution (0.92–0.99 [Angstroms]) over a broad pH range (4.5, 5.2, 5.8, 7.3 and 9.0).” And Figures 1, 2, and 4 are beautiful… (If you don’t currently subscribe to that journal, the paper’s graphical abstract has a taste of what you’re missing…)

This isn’t the first atomic resolution X-ray crystal structure of a protein – there’s also a 1.0 Angstrom structure of cutinase from Longhi et al., a 0.78 Angstrom structure of subtilisin from Kuhn et al., a 0.95 Angstrom structure of a pancreatic elastase/N-acetyl-Asn-Pro-Ile-CO2H complex from Katona et al., a a series of atomic resolution structures of RNase A from Berisio et al., and a 0.95 Angstrom structure of cholesterol oxidase from Lario et al.

Lyubimov et al. remind us that "[i]n 1936, Mirsky and Pauling wrote, ‘The importance of the hydrogen bond in protein structure can hardly be overemphasized’" – I’m sure that Mirsky and Pauling would be really interested to read the aforementioned papers, as we are now able to examine the role of hydrogen atoms in enzymatic catalysis for fairly large proteins (cholesterol oxidase is 56 kDa, for example).

Hopefully this field will continue to grow and we’ll see more atomic resolution structures in the RCSB Protein DataBank – I don’t know about you, but I’d love to see a 0.9 Angstrom structure of the ribozyme in action…

Joshua

Joshua Finkelstein (Associate Editor, Nature)