Scientists imbue cells with pathway to make own drugs



Only the bird species is known to naturally create an enzyme that can make an amino acid that isn't one of the 20 required to encode the majority of proteins, or a noncanonical amino acid.

Even if researchers are unsure of what the enzyme accomplishes for the bird, the fact that it exists—a discovery uncovered through computerized comparison of genome databases—shows that it is conceivable for the enzyme to function within the context of live cells.

However, they have a solid concept of what it might be able to achieve for us.

An amino acid called sulfotyrosine (sTyr), a mutant of the standard amino acid tyrosine, is a crucial building block for programming living cells to express therapeutic proteins, according to a new study by Rice University chemist Han Xiao, theoretical physicist Peter Wolynes, and their collaborators. It might enable cells to function as sensors that keep an eye on their surroundings and react with the appropriate treatment.

It is necessary to alter a cell's DNA in order to produce the transferase enzyme, sulfotransferase 1C1, that is present in the ibis' ability to synthesis sTyr and incorporate it into proteins. As a result, the production of sTyr, a crucial recognition moiety in a number of biomolecular interactions, is catalyzed.

The proof-of-concept work created mammalian cells that manufacture sTyr for the first time. The Xiao lab created cells in an experiment that improved the effectiveness of thrombin inhibitors, anticoagulants used to stop blood clotting.

The majority of our species are constructed out of 20 canonical building elements in nature, according to Xiao. "You must consider how to make a new building block if you wish to add one. We found a solution to that issue by asking the cell to create it.

"However, in order to recognize it, we need the translational machinery. Furthermore, a unique codon to encode this brand-new building component," he added. "We've met all three of these requirements with this study,"

To determine whether cells could be instructed to produce compounds with additional amino acids, Xiao was awarded a National Institutes of Health funding in 2019. The brand-new study shows the lab's rapid development.

Up until now, noncanonical amino acids were given to cells via chemical synthesis. The cell can accomplish the work far more effectively, according to Xiao, but finding a novel transferase enzyme with tyrosine pockets that can bind sulfate is necessary. Then, any number of catalysts could be built on the basis of that lock-and-key arrangement.

We can now completely alter a protein's structure and function thanks to this new method of protein modification, he claimed. "We demonstrated that adding an artificial building block to the medicine can significantly increase the drug's potency for our thrombin inhibitor models."

It was worth looking to see if nature had already developed a functional codon before them. Wolynes, co-director of the Center for Theoretical Biological Physics, was enlisted by Xiao for this task. Wolynes' lab examined genome databases and discovered sulfotransferase 1C1 in the ibis.

The Xiao lab developed a fully autonomous mammalian cell line that is capable of biosynthesizing sTyr and precisely inserting it into proteins using a mutant amber stop codon, a three-nucleotide combination of uracil, adenine, and guanine.

We were fortunate, Xiao added. "A sequence similarity study of genetic data revealed that the ibis is the only species carrying out this behavior. We next enquired as to if they could explain why this enzyme can recognize tyrosine but our human sulfotransferase cannot.

The AlphaFold2 artificial intelligence algorithm, created by Alphabet/DeepMind, Google's was used by the Wolynes team to forecast protein shapes.

A library of biosynthesized noncanonical amino acids will be created using a combination of bioinformatics and computationally accelerated screening, according to the researchers.

The paper's co-lead authors are graduate student Shikai Jin and former Rice research assistant Yuda Chen, who is now a postdoctoral scholar at the University of California, San Francisco. Mengxi Zhang, Kuan-Lin Wu, Yixian Wang, undergraduate student Anna Chung, and postdoctoral researchers Yu Hu, Shichao Wang, and ZeRu Tian are co-authors.

Rice University

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