NEWS OF THE WEEK

PRECURSOR To make cysteine-bound tRNAs, some archaea use SepRS to attach O-phosphoserine (red) to the cysteine tRNA (blue), then use SepCysS to convert thetRNA-bound precursor to cysteine (green).

Freire

B I O C H E M I S T R Y

SECOND ROUTE TO CYSTEINE Path may have served as model for adding amino acid to genetic code

A N ALTERNATIVE BIOSYN-

thetic pathway for making the cysteine-loaded trans­

fer RNAs (tRNAs) required to make most proteins may have been nature's jumping-off point for expanding the genetic code beyond the standard 20 amino acids, says Dieter Soil of Yale University.

To translate proteins containing the amino acid cysteine, organisms require cysteine-loaded tRNAs. Most organisms make these by at­taching premade cysteine to the tRNA. Soil's team has now re­vealed that some members of the class of microbes known as archaea

take a different path: They first at­tach a precursor amino acid to the tRNA, then convert it to cysteine (Science 2005,307,1969).

The new path is chemically analogous to the one organisms use to make the selenocysteine-loaded tRNAs required to insert selenocysteine, the 21st amino acid, into proteins, Soil points out. The archaea Soil studied use a ligase enzyme (SepRS) to make tRNA-bound O-phosphoserine and then use a second enzyme (SepCysS) to convert the tRNA-bound amino acid to cysteine. Se-lenocysteme-requiring organisms are believed to use a similar path­

way to make selenocysteine-bound tRNA via a serine-bound tRNA precursor. The parallels between these two pathways sug­gest that the cysteine path "may have been used originally to add selenocysteine to the genetic code," comments Robert H. White ofVirginia Polytechnic In­stitute & State University

Until recently, there were no known ligase enzymes capable of attaching an amino acid other than the standard 20 amino acids to a tRNA. That changed last year when Soil and Joseph A. Krzycki of Ohio State University indepen­dently discovered a pyrrolysine-tRNA ligase. Now, the Soil team's discovery of a second such enzyme (SepRS) makes it "seem more like­ly that yet more nonstandard amino acids might also prove to have dedicated aminoacyl-tRNA ligases," Krzycki comments. "If so, there are likely not just 22 geneti­cally encoded amino acids in the natural world. More await discov­ery"—AMAN DA YARN ELL

D R U G D E V E L O P M E N T

BETTER DRUGS FOR TUBERCULOSIS Drug discovery partnership aims to speed search for improved treatments

CO I N C I D I N G WITH WORLD

TB Day on March 24, the nonprofit Global Alliance

for TB Drug Development and GlaxoSmithKline (GSK) have an­nounced an agreement to develop new treatments for tuberculosis.

According to the TB Alliance, no newTB drugs have been intro­duced in decades. The current reg­imen involves taking several drugs for six to nine months. Toxic side effects are frequent, as are multi-drug-resistant TB strains. AIDS patients who are infected withTB often cannot take the TB drugs.

TB Alliance President Maria

C. Freire says that, given the 2 mil­lion TB deaths annually the proj­ect with GSK "gives us reason for optimism."The alliance also has a partnership with the Novartis In­stitute for Tropical Diseases.

David Pompliano, GSK's head of biology, says the project builds on efforts already under way at his company's Très Cantos, Spain, fa­cility, which is dedicated to dis­eases of the developing world. The project is also, as Pompliano says, "plugged into the drug discovery machine" at GSK to include high-throughput screening, bioinfor-matics, and target validation work.

Fifty full-time scientists in Spain, 25 of whom will be new hires, are to devote their atten­tion to TB drugs.

A drug lead currently undergo­ing optimization is in a novel class of antibiotics called pleuromu-tilins. "The goal is to have chemists modify the core pleuromutilin structure to optimize the anti­bacterial activity against TB," Pompliano says. "We have already made 500 analogs in this class."

GSK will also apply its com­pound library to the partnership. "What we are doing is going back to those compounds for which we know the molecular target and looking for anti-TB activity," Pompliano says. Another part of the program, now in the lead identification stage, targets two enzymes specific to Mycobacteri­um tuberculosis.

The agreement stipulates that any resulting medicines will be "af­fordable and accessible to those most in need."—VIVIEN MARX

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