New chemical process makes it easier to craft amino acids that don't exist in nature

A study published in Science on July 27 by a team including Pitt chemists describes a powerful new way to create "unnatural" amino acids, which could find use in protein-based therapies and open up novel branches of organic chemistry.

"This is a completely new transformation: new to nature and new to chemistry," said Peng Liu, a professor of chemistry in the Kenneth P. Dietrich School of Arts and Sciences and a corresponding author on the paper. "Telling an enzyme to create an unnatural configuration of an amino acid is unusual, and you have to do it with careful bioengineering."

Change just one piece of a larger protein, and you can alter how it's shaped and what it does -- so unnatural amino acids hold promise for opening up new kinds of therapies like antibiotics or immunosuppressants that make use of proteins or their smaller cousins.

Creating such molecules in the lab, however, is an onerous, multistep process: The pieces of the amino acid that link to one another to form a protein chain have to be protected as researchers chemically transform the rest of the molecule. The reaction described in the new paper, however, is simpler and more efficient, and it offers chemists an unprecedented level of control over how groups of atoms are oriented in the resulting molecule.

It also employs a chemical tool, a PLP enzyme, in an unusual way. Enzymes are proteins that catalyze reactions -- typically, even when their functions are altered by bioengineering, all they can do is speed up known chemical processes that chemists could achieve in other, albeit slower ways. But paired with a light-sensitive molecular catalyst, the enzyme in this new reaction can achieve far more than that.

"You can argue that bioengineered enzymes provide better efficiency than small molecule catalysts, but they catalyze the same reaction," said Liu, pictured right. "But this is an entirely new reaction. It simply didn't exist before."

Liu's group uses computer simulations to figure out the intricate dance that happens in a chemical reaction on the level of atoms and electrons, adding the "why" to the "what" discovered by groups that conduct experiments. For 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's been going strong since 2014, when Yang spent a summer in Liu's lab as a visiting graduate student.