All life exists only on one side of the mirror. More professionally, the biomolecules that make up the organism - DNA, RNA and protein - are all "chiral". Their building blocks have two possible mirror shapes, but in each case life chooses only one.
Recently, in the journal Science , researchers reported that they have made great progress in exploring the other side of the mirror. They redesigned a workhorse enzyme that synthesizes RNA to form the mirror form .
Then, they used the enzyme to build all the RNA needed to make ribosome , the cellular machine responsible for building proteins. Other ingredients still need to be added, but once completed, mirrored ribosomes may be able to produce proteins that can serve as new drugs and diagnostic methods and cannot be easily broken down in the body.
It also laid the foundation for a more ambitious goal: to create mirror life, which has inspired scientists' imagination since Louis Pasteur (Louis Pasteur ) in 1848.
"This is an important step in rebuilding the dogma of the center of molecular biology in a mirrored world," said , Emeritus Professor of Chemistry at the University of Chicago, Stephen Kent .
This dogma refers to the standard operating procedure of life : genetic code (usually DNA) is transcribed into the corresponding RNA sequence, which is then translated into a protein that performs most of the basic chemical reactions in the cell. A delicate and complex molecular machine made of proteins, or in the case of ribosomes, a combination of proteins and RNA performs each step. Each molecule involved in
produces chiral products. Chemists have long been able to synthesize the opposite DNA, RNA and proteins. But they have never been able to put all the pieces together to create mirrored life, not even enough pieces to see if this conceit is possible.
Synthetic biologist Zhu Ting, a West Lake University in Hangzhou, China, has been working towards this vision for many years. In Zhu's view, the first step is to make mirrored ribosomes—the factory can make many other mirrored parts. This is not a trivial matter. The ribosome is a molecular behemoth composed of three large RNA fragments, consisting of a total of about 2900 nucleotide building blocks and 54 proteins.
"The most challenging part is making long ribosomal RNA," said Zhu Ting . Chemists can synthesize fragments up to about 70 nucleotides and stitch them together. However, in order for the three longer ribosomal RNA fragments to appear in mirror form, they needed a molecular machine that could remove them - polymerase .
016, Zhu Ting and colleagues tried this task for the first time, synthesizing a mirror version of polymerase from the virus. Polymerase produces mirrored RNA, but it is slow and error-prone.
In the current study, Zhu Ting and graduate students Xu Yuan began to synthesize a mirror version of the main enzyme, which is used in the global molecular biology laboratory to synthesize the growth RNA chain, namely T7 RNA polymerase . It is a huge 883 amino acid protein that goes far beyond the limits of traditional chemical synthesis.
But analysis of T7s X-ray crystal structure shows that this enzyme may be divided into three parts, each of which is stitched from short fragments. So they synthesized these three parts - one has 363 amino acids , the second has 238 amino acids, and the third has 282 amino acids.
In solution, the fragments naturally fold into appropriate 3D shapes and assemble into working T7. "Putting proteins of this size together is a tough effort," said chemist Jonathan Sczepanski, a Texas A&M University College Station.
Then the researchers put the polymerase into the work. They assembled mirror genes encoding three long RNA fragments the team hoped to make; then mirrored T7 RNA polymerase to read the code and transcribe it into ribosomal RNA.
results provide an attractive glimpse of the power of mirror molecules. The researchers show that mirror RNAs formed by polymerases are much more stable than the normal versions produced by conventional T7 because they are not affected by naturally occurring RNA chewing enzymes that almost inevitably contaminate these experiments and quickly destroy normal RNA.
The same anti-degradation ability "may open the door for brand new diagnostics and other applications," including new drugs, said Northwestern University chemist and ribosome expert Michael Jewett. For example, Zhu Ting and Xu Yuan also use their mirror enzyme to create stable RNA sensors, called riboswitches, that can be used to detect diseases-related molecules, as well as stable long RNAs that can be used to store digital data.
Other researchers have shown that mirrored versions of short-chain DNA and RNA called aptamers can act as effective drug candidates, evading degradation enzymes and immune systems, thus destroying most traditional aptamer candidates.
However, the broader use of this stability is not as simple as creating mirror copies of existing drugs, as these compounds, such as false gloves, will no longer match the chirality of their intended targets in vivo. Instead, researchers may have to screen a large number of mirror candidates to find effective drugs.
but Jewett and others say the new work may help this effort as it lays the foundation for the manufacturing of functional mirrored ribosomes. These can make it easier for pharmaceutical companies to create mirrored amino acid strings or peptides, Jewett said. Since peptides are extracted from 20 amino acid building blocks, rather than just the four nucleic acids that make up the aptamer, they offer greater chemical diversity and potentially better drug candidates.
Now, Zhu Ting and her team need to make the remaining components of mirrored ribosomes. The three RNA fragments they synthesized account for about two-thirds of the total mass of the ribosome. What remains are 54 ribosomal proteins and several that work in conjunction with ribosomes, all of which are smaller and therefore may be easier to synthesize. Then the question is whether the complete parts kit will assemble into ribosomes.
Even if they do, the resulting molecular machines may still not work properly, Harvard George Church (George Church) warned that he is leading one of the few research groups in the world dedicated to the method of mirroring life.
In order to produce protein in large quantities, the ribosomes must work with an additional set of auxiliary proteins. To play a role in living cells , Church believes it is necessary to rewrite the genetic code of the organism so that engineered ribosomes can recognize all these proteins, especially the 20 proteins that transport amino acids to build new proteins. The group of Church is studying this issue. “It’s very challenging,” he said.
But if everything is combined, researchers and life may eventually be able to enter a world of mirrors.
