# Exploring Biomass Precursor Synthesis as a Determinant in Microbial Adaptation to Unadapted Carbon Sources with AdaptUC

## TL;DR

This paper introduces AdaptUC, a computational tool that helps microbes adapt to new carbon sources by predicting optimal gene knockouts.

## Contribution

AdaptUC introduces a novel framework linking precursor synthesis to microbial adaptation and predicts gene knockouts to accelerate evolution.

## Key findings

- Smaller precursor dependency fractions correlate with stronger evolutionary driving forces.
- AdaptUC successfully identifies gene knockout strategies validated in Escherichia coli and Corynebacterium glutamicum.
- The framework reduces experimental screening by prioritizing strains with high adaptation potential.

## Abstract

Industrial microorganisms often struggle to utilize renewable substrates such as methanol, formate, and xylose. Here, we introduce AdaptUC, a computational framework that demonstrates how the fraction of biomass precursors synthesized from unadapted carbon sources governs both the evolutionary driving force and the minimal substrate requirement. AdaptUC predicts gene knockout strategies for constructing the starting strain for adaptive laboratory evolution by selectively blocking metabolic pathways, thereby rendering specific precursor pools dependent on the unadapted substrate. We show that smaller dependency fractions correspond to higher driving forces for evolution of the starting strain. Case studies in Escherichia coli and Corynebacterium glutamicum, validated against experimental records and literature, confirm AdaptUC’s ability to identify knockout combinations that fine-tune precursor dependency and accelerate adaptation. By leveraging genome-scale metabolic models, AdaptUC navigates vast candidate pools without combinatorial explosion, reducing experimental screening and prioritizing strains with stronger evolutionary drives.