HHMI Professors on changing the culture of science education

13 HHMI Professors, including Brandeis’s Irving Epstein, wrote a recent editorial in the journal Science calling for a reexamination of priorities between research and teaching at research universities. The seven initiatives they call for:

  1. Educate faculty about research on learning.
  2. Create awards and named professorships that provide research support for outstanding teachers.
  3. Require excellence in teaching for promotion.
  4. Create teaching discussion groups.
  5. Create cross-disciplinary programs in college-level learning.
  6. Provide ongoing support for effective science teaching.
  7. Engage chairs, deans, and presidents.

Strong stuff — will we respond to this challenge?

Phantasmidine, a Nicotinic Receptor Agonist from Ecuadoran Poison Frogs

IIn 1992, the lab of the late John Daly at NIH reported the isolation of epibatidine (1) from the skin of an Ecuadorian poison frog.  In addition to being a toxin, epibatidine has potent analgesic activity. Subsequent studies showed that this activity resulted from interaction with acetylcholine nicotinic receptors (nAChRs) with binding to some of the receptors at sub nanomolar levels.  The binding to several different types of nAChRs may be responsible for its non-selective activity.

In 2010, the Daly group reported the isolation and tentative structure determination of the epibatidine congener phantasmidine (2) from a total sample of only 20 micrograms. Preliminary biological studies with the limited material available indicated that phantasmidine (2) differs from epibatidine (1) by being selective for β4-containing nicotinic receptors, suggesting that phantasmidine might fill a niche for characterization of these receptors. However, the limited natural material available precluded detailed pharmacological analysis and definitive structure determination.

In their recent paper in Organic Letters entitled the Synthesis of Phantasmidine, the Snider lab at Brandeis reported a short and efficient synthesis of phantasmidine that confirmed the tentative structure and makes ample material readily available for further biological evaluation, which is currently in progress.  To prepare the tetracyclic framework, they invented a new tandem intramolecular aldol reaction-nucleophilic aromatic substitution reaction to form both five membered rings in a single reaction.   Treatment of keto amide 3 with sodium hydroxide gave aldol adduct 4 which cyclized to lactam 5.  Reduction of the lactam completed a practical synthesis of phantasmidine (2).

Spring-loading the active site of cytochrome P450

Enzymes differ from other catalysts in the exceptional substrate selectivity they exhibit.  However, the active sites of related enzymes are often very similar, even though different substrates are acted upon (for example in the superfamily of cytochrome P450s).  How does a given enzyme preferentially bind a particular substrate?  In a new paper appearing in the jounal Metallomics, Chemistry grad student Marina Dang and Profs. Susan Sondej Pochapsky and Thomas Pochapsky use nuclear magnetic resonance (NMR) to identify a helical structure remote from the active site of the enzyme cytochrome P450cam that is responsive to changes in substrate.  They propose that this helix can adjust the position of residues that contact substrate in the enzyme active site, much like the spring that holds batteries in place against electrical contacts in a flashlight.

Back to class

2010 Beckman Scholar Philip Braunstein ’12 discusses his research project in the Hedstrom lab at the last class meeting of Organic Chemistry CHEM 25a. Training the scholars in communicating science and improving the visibility of undergraduate research are key components of the Beckman Scholars program.

Photographs by Nathaniel Freedman

Can a “chemical rope” help treat ALS?

In this week’s issue of PNAS, Brandeis postdoc Jared Auclair and Chemistry grad student Kristin Boggio, together with Professors Greg Petsko, Dagmar Ringe, and Jeffrey Agar discuss Strategies for stabilizing superoxide dismutase (SOD1), the protein destabilized in the most common form of familial amyotrophic lateral sclerosis. Working from the hypothesis that the mechanism of the toxicity involves dimer destabilization and dissociation as an early step in SOD1 aggregation, they looked for mechanisms to stabilize SOD1 using chemical cross-linking. Cross-linking the dimer using 2 adjacent cysteine residues results in substantial stabilization of relevant SOD1 mutants.

A "Chemical rope" stabilizes SOD1 protein. Mutations that destabilize SOD1 in motor neurons are associated with familial ALS

Read more about Prof. Agar, this research, and its potential for this technique in the treatment of ALS at Brandeis NOW

Life is a Ponzi Scheme (and more)

Greg Petsko, Gyula and Katica Tauber Professor of Biochemistry & Chemistry, has been writing a monthly column in the journal Genome Biology since its inception 10 years ago. To honor the journal’s 10th anniversary, these columns have now been released as an e-book.

These columns are wide-ranging and rarely fail to amuse and inform. Some examples:

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