Second Route to Cysteine

BIOCHEMISTRY

An alternative biosynthetic pathway for making the cysteine-loaded transfer 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 Sll 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. Sll'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, Sll points out. The archaea Sll 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. Selenocysteine-requiring organisms are believed to use a similar pathway 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 of Virginia 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 Sll and Joseph A. Krzycki of Ohio State University independently discovered a pyrrolysine-tRNA ligase. Now, the Sll 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."