The keys to unlocking the chemistry behind complex biological problems

Enzymes are biological catalysts. They are able to greatly accelerate various reactions that would otherwise have been very slow at normal temperature, without being consumed themselves. Lynn Kamerlin’s research team is particularly interested in what happens in one fundamental chemical reaction: phosphate ester hydrolysis.

This reaction is involved in a number of important processes in our cells, such as cellular signalling, energy conversion, and maintaining the integrity of our genetic material. On the surface, this looks like a very simple chemical reaction. However, despite decades of intensive experimental and computational studies, its precise mechanism remains controversial.

­“This is partly because there are several different mechanisms for phosphate hydrolysis, and it is impossible to distinguish them definitively and unambiguously using experimental methods alone,” explains Lynn Kamerlin, Professor at the Department of Cell and Molecular Biology at Uppsala Biomedical Centre.

Using a combination of theoretical physical organic chemistry and computational enzymology, the research team has succeeded in developing a comprehensive model for this type of reaction.

“I am very proud that we have succeeded in establishing the mechanisms for the extremely important chemical reaction. It is involved in so many processes in the cell – these molecules are the building blocks of life”, says Lynn Kamerlin.

One important task for the research team – and also for understanding the molecular evolution of enzyme superfamilies – is to map out the catalytic promiscuity of phosphotransferases, in order to understand how these enzymes can catalyse so many different substrates, with such different requirements for efficient catalysis. In addition, the development of new computational methods offers a new way to study enzyme selectivity, providing a better understanding of the drivers of enzyme function. It also offers important clues for how to manipulate enzymes, to create artificial, designed enzymes with significantly greater catalytic capacities than those that currently available.

“Enzymes are an important tool in both drug manufacturing and the production of fine chemicals. Enzymes that selectively catalyse industrially important reactions are of particular interest to us,” says Lynn Kamerlin, adding that biocatalysis is already everywhere around us, whether we are using enzymes as detergents or using yeast to raise bread.

She also mentions that her team are interested in a group of human-made toxins called organophosphates. These are primarily used as pesticides and nerve agents. However, they are also commonly used as plasticizers in plastics, as flame retardants, as anti-foaming agents and as additives in lubricants and hydraulic fluids.

In recent years, the global consumption of organophosphates has increased, and every year, hundreds of thousands of people are poisoned in accidents in agriculture and farming, for example. Numerous organisms have developed resistance to organophosphates. Several unrelated organisms carry enzymes that break the toxins down, in the same way that bacteria become resistant to antibiotics, and cancer cells to cytotoxins. Some organisms can develop resistance without even having been in contact with the chemicals.

Computer simulations are being used to study detoxifying enzymes that break down human-made toxins, and establish how they have evolved and how natural pesticide resistance arises.

“The objective is to understand their evolution at the molecular level. We hope to be able not only to create new enzymes to treat organophosphate poisoning, but also to use that knowledge in the future design of drugs to prevent the development of resistance in bacteria and cancer cells,” says Lynn Kamerlin.

Lynn Kamerlin wanted to be a scientist since she was a child, but she also has another career behind her as a pianist. She began playing the piano when she was four, and at her most active, practiced over 8 hours a day. These days she plays mostly at home, for herself. But she says that the feeling of going on stage and performing a piano piece is unbeatable. Performing on stage requires to give your all in order to deliver even the smallest detail to perfection. She has the same ambition for scientific presentations, too. But, over time, she has gotten better at not imposing quite such high demands on herself.

“It is not exactly the same thing, but the totality is important to me. I am very ambitious, and this probably colours my whole approach, both as a researcher and in my relationships with friends and colleagues. I want to be into – and understand – everything, and get to the bottom of most of it. This is perhaps not always my best side. But I am working on it, and I have gotten better at it over the years,” says Lynn Kamerlin.

 

Susanna Eriksson

 

2017-12-04

 

 

FACTS LYNN KAMERLIN

Age: 36 years

Title: Newly appointed professor at the Department of Cell and Molecular Biology, in the program for Structural and Molecular Biology

Education: PhD in Chemistry, University of Birmingham

Selected qualifications and experience: Three-year program grant in 2017 of USD 1.2 million within the Human Frontier Science Program, HFSP, together with international colleagues; ERC Starting Grant 2012-2017; Wallenberg Academy Fellow, 2013; former Chair of the Young Academy of Europe; Fellow of the Royal Society of Chemistry

Family: Husband Peter Kasson

How I ended up in Uppsala: I got one of the last research assistant positions from the Swedish Research Council in 2011. Uppsala University is a fantastic environment for my particular research area with many world leading researchers on site.

Makes me happy: Playing the piano and dancing the tango.

Would like to do more of: Photography, learning new languages

Favourite subjects in primary school: Artistic disciplines, broadly defined, e.g. music, art, dance

Dream about: Spending more time in Australia

 

More about Lynn Kamerlin and the research at the Kamerlin lab

 Video: Lynn Kamerlin’s installation lecture

 Column: Tracing the mechanisms of enzymes 

Article: New study to resurrect enzymes billions of years old