# Unveiling the Catalytic Mechanism of Abl1 Kinase: A Single-Magnesium Ion Pathway for Phosphoryl Transfer

## TL;DR

This paper reveals that Abl1 kinase uses a single magnesium ion to catalyze phosphoryl transfer, differing from other kinases that use two ions.

## Contribution

The study identifies a unique single-magnesium ion pathway in Abl1 kinase for efficient phosphoryl transfer.

## Key findings

- Abl1 uses a dissociative mechanism with one magnesium ion in Site I for phosphoryl transfer.
- The single-magnesium pathway matches experimentally observed catalytic rates.
- This mechanism differs from other kinases that typically use two magnesium ions.

## Abstract

Abl1, a nonreceptor tyrosine kinase closely related to
Src kinase,
regulates critical cellular processes like proliferation, differentiation,
cytoskeletal dynamics, and response to environmental cues through
phosphorylation-driven activation. Dysregulation places it centrally
in the oncogenic pathway leading to blood cancers. making it an ideal
drug target for small molecule inhibitors. We sought to understand
the underlying mechanism of the phosphoryl-transfer step from the
ATP molecule to the substrate tyrosine, as carried out by the Abl1
enzyme. By calculating free energy profiles for the reaction using
the empirical valence bond representation of the reacting fragments
paired with molecular dynamics and free energy perturbation calculations,
a combination of several plausible reaction pathways, ATP conformations,
and the number of magnesium ion cofactors have been investigated.
For the best-catalyzed pathway, which proceeds through a dissociative
mechanism with a single magnesium ion situated in Site I, a close
agreement was reached with the experimentally determined catalytic
rates. We conclude that the catalytic mechanism in Abl1 requires one
magnesium ion for efficient catalysis, unlike other kinases, where
two ions are utilized. A better overall understanding of the phosphoryl-transfer
reactions in Abl1 can be used for type-I inhibitor development and
generally contributes to a comprehensive overview of the mechanism
for ATP-driven reactions.