A new chemical process makes it easier to synthesize amino acids not found in nature
Every protein in your body is made of the same 20 building blocks called amino acids. But just because nature is stuck with a limited tool set doesn’t mean humans can’t expand it.
A study published in the journal Science on July 27 by a team including chemists from Pitt describes a powerful new way to create “unnatural” amino acids, which could be used in protein-based therapeutics and open new branches of organic chemistry.
“This is a completely new twist: new to nature and new to chemistry,” said Ping Liu, a professor of chemistry in the Kenneth B. Dietrich College of Arts and Sciences and corresponding author on the paper. “Telling an enzyme to create an unnatural amino acid conformation is unusual, and you have to do it through careful bioengineering.”
Change just one piece of a larger protein, and you can change what it looks like and what it does — so unnatural amino acids hold the promise of opening up new types of treatments such as antibiotics or immunosuppressants that use the proteins or their smaller cousins.
However, creating such molecules in the laboratory is a laborious, multi-step process: the pieces of amino acid that link together to form a protein chain must be protected, while researchers chemically transform the rest of the molecule. However, the reaction described in the new paper is simpler and more efficient, and provides chemists with an unprecedented level of control over how the groups of atoms in the resulting molecule are oriented.
It also uses a chemical tool, the PLP enzyme, in an unusual way. Enzymes are proteins that catalyze reactions, and usually, even when their functions are changed by bioengineering, all they can do is speed up known chemical processes that chemists can accomplish in other, albeit slower, ways. But when combined with a light-sensitive molecular catalyst, the enzyme involved in this new reaction can achieve much more.
“You could argue that bioengineered enzymes provide better efficiency than small molecule catalysts, but they catalyze the same reaction,” said Liu, pictured right. “But this is a completely new reaction. It simply didn’t exist before.”
Liu’s group uses computer simulations to figure out the complex dance that occurs in a chemical reaction at the level of atoms and electrons, adding the “why” to the “what” that the groups conducting the experiments discover. In this paper, Liu and Pitt postdoctoral researcher Binh Khanh Mai, pictured left, worked with a team of researchers at UC Santa Barbara led by Yang Yang — a collaboration that has been going strong since 2014, when Yang spent the summer in the lab. Liu as a researcher. Visiting graduate student.
Liu and Mai delve into the data provided by Yang’s group to understand how and why the reaction occurred, puzzling intermediate steps invisible to chemists. In one step, the duo took a particularly close look, as an electron has to travel an unusually long distance on its way between two molecules. “We had to do some careful modeling on how likely this would happen because this is a new step in nature, and it underpins the entire reaction mechanism,” Liu said.
These models are supported by enormous computing power. Liu cites the Pitt Center for Computing Research as key to the lab’s success, as the complex simulations the group runs to understand the intricacies of chemical reactions require time with sophisticated and powerful supercomputers.
However, there are still unanswered questions, and this paper is just the first step in a series of collaborations between the two teams. If they can better understand why the unusual reaction occurs, Liu’s team could unlock the ability to harness it in different contexts to create a wide range of chemical tools, new drugs, and more.
“You can think of how many different types of unnatural amino acids you can make, there are almost unlimited,” Liu said. “So can we use this insight to develop other new reactions as well?”
Stereoselective amino acid synthesis via synergistic photoradical and pyridoxal biocatalysis, Science