Mathematical models show the behavior of cellular enzymes, Everything that a cell does from dividing to migrating to other parts of the body is controlled by enzymes that chemically change other proteins in the cell.

Princeton University researchers have developed new mathematical techniques to describe the behavior of many cellular enzymes.

The approach, published in Current Biology on February 13, will help researchers determine how genetic mutations change the behavior of these enzymes to cause various human diseases, including cancer. Mathematical models show the behavior of cellular enzymes.

An enzyme called kinase can add phosphate molecules in various places to other proteins (including other kinases) and change their activity in the cell.

The study of this “multisitic phosphorylation reaction” is complicated because the phosphate groups can be added quickly and in different sequences, which can affect the storage of modified proteins in cells.

This makes it difficult to understand what’s wrong when the kinase mutates.

A Princeton research team led by Martin Weir, an assistant in molecular biology, and Stanislav Schwartzman, professor of chemical and biological process engineering at Princeton and researchers at the Flatiron Institute, have developed mathematical models, such as a kinase called MEK, into two added molecules . called ERK. Mathematical models show the behavior of cellular enzymes.

This double phosphorylation activates ERK so that it can manage various cellular processes, including cell growth and division. Mutations in MEK and ERK can cause various diseases, including cancer.

“There are many mutations in MEK that affect the total number of double ERKs,” the researchers said, but the effect of these mutations on the mechanism of ERK activation is unknown.

The researchers’ model shows how quickly each phosphate group is added and how often both phosphates are added by the same enzyme.

Most often, one MEK enzyme binds to ERK and adds a phosphate molecule before separation, allowing a second MEK enzyme to bind and add a second phosphate.

The researchers then used their model to analyze the mutated version of MEK found in human cancer. This MEK mutant is twice as fast as to add the first phosphate to the ERK and is far more likely to remain attached and add the second phosphate group itself. Mathematical models show the behavior of cellular enzymes.

Together, it increases ERK activation and accelerates the growth of cancer cells.

The researchers then analyzed two other MEK mutations that caused various developmental abnormalities, including congenital heart abnormalities and growth abnormalities.

This mutation does not affect the ability of MEK to add phosphate molecules to ERK. Instead, they strengthen the activation of MEK by another kinase called Raf, which adds two phosphate molecules to MEK.

The precise discovery of how mutations change the function of enzymes can help researchers develop new therapeutic strategies that normalize their function. Researchers say: Our approach is not limited to kinases and applies to a variety of biochemical mechanisms in which enzymes modify several sites on their substrates.