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A mathematical model of microbial folate biosynthesis and utilisation: implications for antifolate development.
J Enrique Salcedo-Sora1, Mark T Mc Auley
1School of Health Science, Liverpool Hope University, Hope Park, Liverpool, L16 9JD, UK. salcede@hope.a.uk.
Molecular Biosystems
|January 23, 2016
Summary
This study presents a mathematical model of microbial folate metabolism to identify new drug targets. The model reveals key folate intermediates and effective enzyme inhibition strategies for developing novel antifolates against infectious diseases.
Area of Science:
- Biochemistry
- Systems Biology
- Computational Biology
Background:
- Folate metabolism is a complex network with implications for chemotherapy.
- Developing antifolates for infectious diseases remains a challenge.
- Mathematical modeling offers a tool to explore complex biochemical systems.
Purpose of the Study:
- To develop a mathematical model of microbial folate metabolism.
- To explore the dynamics of this complex biochemical network.
- To identify novel antimetabolite targets for antifolate drug development.
Main Methods:
- Assembly of a generic deterministic mathematical model.
- Analysis of folate intermediate overrepresentation and product inhibition.
- In silico screening for combinatorial enzyme inhibitions.
- Coding the model in Systems Biology Markup Language (SBML).
Main Results:
- Identified a small set of overrepresented folate intermediates.
- Quantified inhibitory profiles by key folate product levels.
- Discovered specific combinatorial enzyme targets to complement existing antifolates.
- Substantiated a substrate cycle in folinic acid biosynthesis.
Conclusions:
- The mathematical model provides insights into microbial folate metabolism dynamics.
- The model aids in identifying effective targets for new antifolate drugs.
- The developed model is publicly accessible for community use.
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