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 molecules 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 Structural and Molecular Biology.

The scientists, led by Scripps Research Associate Professor Xiang-Lei Yang, focused on a molecule called human tryptophanyl色氨酰基-tRNA转核糖核酸 synthetase合成酶 (TrpRS), finding that it contains a "functional 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 inhibit the formation of new blood vessels—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 Enzyme, Two Functions

For some time, scientists have known that the aminoacyl tRNA synthetase family is composed of 20 ancient enzymes 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 dual 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 collaboration 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 stimulate the growth of blood vessels.

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

Soon afterward, 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 vessel formation.

Since that time, there has been considerable therapeutic 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 artery disease. Likewise, the TrpRS fragment's anti-angiogenic effects could help patients reduce undesirable 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 tumor 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.