Bird’s enzyme points to new therapies

Newswise – Houston – (September 19, 2022) – Thank you for Nader crested ibis For a clue that could one day help our bodies make better medicines.

The bird species is the only one known to naturally produce an enzyme capable of generating a nonessential substance Amino acid; That is, not one out of 20 is necessary for the coding of most proteins.

Its existence — a discovery made by computationally comparing genome databases — proves that it is possible for this enzyme to function in the context of living cells, even if scientists don’t know what it does to birds.

But they have a pretty good idea of ​​what it can do for us.

A new study by a Rice University chemist Han Xiaotheoretical physics Peter Wolins and their colleagues show that amino acids, Sulfotyrosine (sTyr), a standard amino acid mutant tyrosine, is an essential building block for reprogramming living cells that express therapeutic proteins. It could allow cells to act as sensors that monitor their environments and respond with treatment.

Mimicking the ability of ibis to synthesize sTyr and incorporate it into proteins requires modification of the cell’s DNA using a mutant. codon This in turn makes transporter An enzyme, sulfotransferase 1C1, found in birds. This stimulates the generation of sTyr, an essential part for recognizing a variety of biomolecular interactions.

A proof-of-concept study produced for the first time mammalian cells that make sTyr. In one experiment, Xiao’s laboratory made cells that boosted the potency of thrombin inhibitorsAnticoagulants used to prevent blood clotting.

The study appears in Nature Connections.

“In nature, most of our species is made up of 20 basic building blocks,” Xiao said. “If you want to add an extra building block, you have to think about how to make it. We solved this problem: we can ask the hive to make it.

“But then we have to have the translation mechanism to recognize it. And a special code to encode this new building block.” “Through this study, we fulfilled all three of these requirements.”

Xiao received a grant from the National Institutes of Health in 2019 to see if cells could be so Programmed to make items that contain extra amino acids. The new study demonstrates the lab’s exciting progress.

Until now, scientists had been introducing chemically synthesized non-canonical amino acids into cells. Getting a cell to do the work is much more efficient, Xiao said, but that requires discovering a new cell transporter An enzyme with tyrosine pockets that can bind sulfates. This lock and key combination can then be used as the basis for a variety of triggers.

“Now, with this new strategy to modify proteins, we can completely change the structure and function of the protein,” he said. “For our models of thrombin inhibitors, we have shown that putting an abnormal building block into the drug can make the drug more effective.”

It was worth a look to see if nature beat them to a useful codon. Therefore, he enlisted Xiao Wulins, co-director of Center for Theoretical Biophysicswhose lab compared genome databases and found 1C1 sulfotransferase in ibis.

Use a mutant Xiao laboratory amber saver codona triple-nucleotide group of uracil, adenine and guanine, to encode the required sulfotransferase, resulting in a completely independent mammalian cell line capable of synthesizing sTyr and incorporating it with great precision into proteins.

“We got lucky,” Xiao said. The ibis is the only species to do this, which was discovered through a sequence similarity search for genomic information. Next, we asked if they could see why this enzyme recognizes tyrosine, while human sulfotransferase cannot. “

Wolynes team works Alpha Fold 2an artificial intelligence program developed by Alphabet / Google deep mind that predict the structures of proteins.

The researchers expect to use a combination of bioinformatics and computational enhanced screening to produce a library of biosynthetic non-canonical amino acids.

Former Rice Research Associate Yoda Chen, now a postdoctoral researcher at the University of California, San Francisco, and graduate student Shikai Jin are lead authors of the paper. Co-authors are graduate students Mengxi Zhang, Kuan-Lin Wu, and Yixian Wang; Undergraduate Anna Chong, and postdoctoral researchers Yu Hu, Wang Zhichao, and Tian Ziru.

Xiao is the young researcher Norman Hackerman-Welch and Assistant Professor of Chemistry, Bioengineering and Biosciences, and a CPRIT Investigator in Cancer Research. Wolins is Professor of Science at the Dr. Pollard Welch Foundation and Professor of Chemistry, Biosciences, Physics, and Astronomy at Rice.

The Cancer Prevention and Research Institute of Texas (RR170014), the National Institutes of Health (R35-GM133706, R21-CA255894 and R01-AI165079), the Robert A. Welch Foundation (C-1970), the US Department of Defense (W81XWH)-21-1-0789 ), the John S. Dunn Foundation Award for Collaborative Research, the Hamill Innovation Award, and Support for the Center for Theoretical Biophysics (2019745) supported by the National Science Foundation.