21st Amino Acid From E.coli Produced By Rice University Chemists
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21st Amino Acid From E.coli Produced By Rice University Chemists

The genetic code of Escherichia coli bacteria has been expanded successfully to produce a synthetic building block, a noncanonical amino acid by Rice University chemist Han Xiao and his team. Their study appears in Chem, the Cell Press journal.

The researchers say that the work is a step toward technologies that will allow the generation of novel proteins and organisms with a variety of useful functions.

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DNA’s building blocks are amino acids. Generally, to program the entire set of proteins necessary for life, organisms need only 20 of them. However, to see how a 21st amino acid would enable the design of “unnatural organisms” that serve specific purposes, the Norman Hackerman-Welch Young Investigator and an assistant professor of chemistry, Xiao started the study with the help of a $1.8 million National Institutes of Health grant.

In the new study, an amino acid that appears naturally in humans as a precursor to the neurotransmitter serotonin, and not in the bacteria E. coli, called 5-hydroxyl-tryptophan (5HTP) was produced by engineering the bacteria. A protein that fluoresces when the organism is under metabolic stress is produced by the bacteria prompted by the novel production of 5HTP.

Rice University researchers introduced noncanonical amino acid building blocks into proteins in living cells, pioneering a powerful tool for investigating and manipulating the structure and function of proteins. The resulting unnatural organism, a strain of Escherichia coli bacteria, is able to monitor low levels of oxidative stress. Credit: Xiao Lab/Rice University

Xiao said, “A lot of interdisciplinary techniques are required in the process. To create a strain that synthesizes and encodes a 21st noncanonical amino acid, and then uses it to produce the desired protein, we combined synthetic chemistry, synthetic biology, and metabolic engineering in this study.”

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A three-step process is involved in programming the autonomous unnatural bacteria: First, bioorthogonal translational machinery for the amino acid, 5HTP was created by researchers led by graduate student Yuda Chen. In the second step, they found and targeted a sequence in DNA or RNA that doesn’t produce a protein— blank codon and genetically edited it to encode 5HTP. Finally, they gave the bacteria the ability to produce 5HTP by grafting enzyme clusters from other species into E. coli.

Xiao said, “Isolated from the programmed bacteria, these 5HTP-containing proteins can be labeled further with other molecules or drugs. The strain itself being capable of serving as a living indicator for reactive oxygen species is shown here, and the detection limit is really low.”

More than 200 noncanonical amino acids have been reported to be created by researchers to date, however, most of them cannot be synthesized by their host organisms. Xiao said, “Rather than just dealing with cells in the lab, our vision is to be able to investigate medicinal or biological problems in living organisms by engineering whole cells with the 21st amino acid.”

He added, “The need to inject artificial building blocks into an organism is eliminated by moving this technology to the host species because they can synthesize and use it on their own and studying noncanonical amino acids at a higher, whole organism level will be made possible.”

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Xiao said that they hope they will be able to make their own therapeutic drugs if customized building blocks allow targeted cells, like those in tumors. Xiao and his team want to release better medicines they create in real-time by making the cells to detect disease and make drugs.

Co-authors of the paper include an assistant professor of chemistry at Boston College, Abhishek Chatterjee; Xinlei Fang, an undergraduate student Adam Cardenas, and visiting scholar; and Rice postdoctoral fellows Zeru Tian, Lushun Wang, and Juan Tang.

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21st Amino Acid From E.coli Produced By Rice University Chemists