Researchers at The Scripps思科利普斯 Research Institute have solved a 10-year-old mystery of how a single protein from an ancient family of enzymes酶类，酵素 can have two completely distinct roles in the body. In addition to除……之外 providing guidance for understanding other molecules⁴ in the family, the research supplies a theoretical underpinning支柱，基础 for the protein's possible use for combating diseases including cancer and macular degeneration黄斑变性. The research was published in the December 13, 2009 advance, online issue of the high-impact journal Nature Structural⁶ and Molecular⁷ Biology.

The scientists, led by Scripps Research Associate Professor Xiang-Lei Yang, focused on a molecule³ called human tryptophanyl色氨酰基-tRNA转核糖核酸 synthetase合成酶 (TrpRS), finding that it contains a "functional⁸ switch" that enables it to perform two different functions. In one of its forms, the molecule acts to facilitate促进，帮助 protein synthesis蛋白质合成. In the second form, the same molecule works to inhibit⁹ the formation of new blood vessels¹¹—an effect that, if successfully harnessed, could be medically useful.

"I'm very excited about these findings," said Yang. "This piece of work provides a very deep mechanistic understanding. It has really shown that the activity of this tRNA synthetase is of biological significance and that it's a good example of the many, many different functions that have been found with the tRNA synthetase family."

One Enzyme¹, Two Functions

For some time, scientists have known that the aminoacyl tRNA synthetase family is composed of 20 ancient enzymes² that attach the correct amino氨基 acid to a tRNA as the first step in the synthesis of proteins.

The mystery of the protein family's dual¹² functionality, however, was born about a decade ago, with the publication of a 1999 paper in the journal Science by Paul Schimmel, who is Ernest and Jean Hahn Professor of Molecular Biology and Chemistry and a member of The Skaggs Institute for Chemical Biology at Scripps Research, in collaboration¹³ with合作 a member of his lab at that time, Keisuke Wakasugi.

In the 1999 paper, Wakasugi and Schimmel showed that a member of the human aminoacyl-tRNA synthetase family, tyrosyl-tRNA synthetase (TyrRS), did more than adding the amino acid tyrosine酪氨酸 to a protein chain during protein synthesis. In addition, a fragment of the protein could function to attract immune cells and to stimulate¹⁴ the growth of blood vessels.

The findings were met with astonishment¹⁵ and some skepticism怀疑论 in the scientific community.

Soon afterward¹⁶, however, the Schimmel lab showed that another member of the family, TrpRS, also had a dual function. In addition to its role adding the amino acid tryptophan to a protein chain during protein synthesis, a fragment of TrpRS could inhibit new blood vessel¹⁰ formation.

Since that time, there has been considerable therapeutic¹⁷ interest in TyrRS, TrpRS, and other members of the aminoacyl-tRNA synthetase family. As a pro-angiogenic factor, the TyrRS fragment could be useful in diseases where growth of blood vessels is desirable, such as in some forms of heart disease or peripheral外围的，次要的 artery¹⁹ disease. Likewise, the TrpRS fragment's anti-angiogenic effects could help patients reduce undesirable²⁰ blood vessel growth in diseases such as cancer and a great many eye diseases that lead to catastrophic vision loss.

In fact, fragments of TrpRS were used as part of a study led by Scripps Research Professor Martin Friedlander that successfully halted the progression in animal models of highly vascular血管的 brain tumor²² and neovascular eye disease (PNAS 2007 104:967-972).

Despite the interest in tRNA synthetases, however, no one has been able to figure out exactly how they perform their different roles—until now.