Pericyclases

A collaboration between the Tang, Houk and Garg labs at the University of California, Los Angeles, led by a team of postdoctoral scholars and graduate students, discovered and characterized a family of natural enzymes called the pericyclases.

Enzymes are proteins found naturally in cells, facilitating and speeding up chemical reactions within the cell. Pericyclases catalyse a special class of organic reactions called pericyclic reactions – where the reactants form a cyclical structure before forming products. These reactions are commonplace in laboratory synthesis of small molecules (i.e. commodity chemicals or pharmaceuticals) and are often considered ‘abiological’ or ‘invented’ by synthetic chemists.

The team’s discovery means that we now know that nature uses this chemistry, revealing an entire “toolbox” of enzymes that catalyse reactions previously not known. This fundamentally shifts our knowledge on how nature constructs complex molecules that are essential for life, opening up new opportunities in chemical synthesis.

By combining enzyme discovery, mutational studies, X-ray crystallography, quantum mechanics, molecular dynamics, and synthetic chemistry, the 18 members of our team, located in the US, China, Japan, and Spain, have revealed previously unknown secrets of nature.

Professors Yi Tang and Ken Houk

Using an interdisciplinary approach combining genetics, biochemistry, structural biology and computational science, the team have studied these pericyclases to understand how the enzymes evolved and the mechanisms behind the catalysis.

This fundamental understanding means the team can modify the enzymes to alter and therefore control what reaction is catalysed. This increases the potential of these enzymes in synthetic chemistry even further, and provides proof-of-concept that enzymes can be artificially modified in the lab for new applications.

Q&A with Pericyclases

What does good research culture mean to you?

Yi Tang: Freedom to explore. With this project in particular, we had no idea that such enzymes were even there so you can’t be afraid to try different things. We found a class of enzyme that is hidden and was overlooked in previous publications relating to this molecule. Testing conventional wisdom is important in scientific research.
 Good scientific culture is also grant funding agencies, especially government research agencies, being willing to support such fundamental research, as the application of these enzymes is fairly far away. The willingness and support of the National Institute of Health is key to enabling our work.

What advice would you give to a young person considering a career in chemistry?

Yi Tang: My advice is to appreciate that chemistry has a glorious history and there’s been so much discovery, especially since the early 1900s. You should appreciate and respect the science, learn from the giants and ask questions. Just when you think you’ve done well on a chemistry test, it doesn’t mean you know anything about chemistry, so continue to absorb like a sponge because there is so much to learn.

What advice would you give to a young person considering a career in chemistry?

Masao Ohashi: Don’t be afraid of challenging things – even if other people think that it is stupid. If you believe something is important, just don’t be afraid to challenge, as this is needed for breakthroughs and discovering new things.

What does good research culture mean to you?

Cooper Jamieson: For me, a good work environment means being able to chat casually with colleagues and mentors. With this project, working with Masao and Professors Tang and Houk, I remember going to Masao’s office on my second day and we’d chat about this project for hours – discussing science and also other things. That was a wonderful way to get started and get ideas flowing about where we want to go next. It’s a fun and accessible way to work at UCLA and I’m really grateful for that. 

What advice would you give to a young person considering a career in chemistry?

Cooper Jamieson: I didn’t come to chemistry from a very ‘traditional’ path, I came to chemistry through art because I wanted to ask questions and figure out the answer to those questions. I think anyone who is asking questions will do well in chemistry, so I would just tell people to keep asking questions.

What's the importance of collaboration in the chemical sciences?

Kendall Houk: The role of collaboration is essential. I’m one of the world’s most prolific publishers – we had 60 papers published last year – and all but a few of these are collaborative. We work with people all over the world, exchanging scientific information to make the kind of discoveries that can only be made by collaboration. For example, I can’t do an x-ray crystal structure – but that’s what Professor Zhou did. I can’t isolate an enzyme – that’s Professor Tang. I can’t synthesise molecules – that’s Professor Garg. Any one of us could do research by ourselves, but the impact is far more limited compared to the amazing, more global discoveries that can be made by this type of collaboration.

Why is chemistry important?

Kendall Houk: Chemistry is everywhere and everything we do is controlled by chemistry. Our life is based on chemical reactions functioning properly through enzymatic reactions. All of our building materials and food is chemistry. If we want to solve problems like the climate crisis, we have to use knowledge of chemistry to figure out green fuels and ways to remove pollutants. Anything that you really imagine you’d like to have in the future is chemistry, so fundamental discoveries in chemistry are going to drive our society in the future and sustain life as we know it.

What advice would you give to a young person considering a career in chemistry?

Kendall Houk: I give advice to students that they’re going to work on things that haven’t even been discovered yet. For example, when I was a PhD, there weren’t any real computers, but now we have computers that are a billion times faster and that’s all I do. When I started as a graduate student, there was no field of pericyclase reactions. Now, this team is the number one team in the world for understanding these reactions so I’m working on and excelling in something that didn’t even exist when I was a student. I think that’s going to be true of everybody.