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Updated: Jun 18, 2025
07:32
Preparation of Mycobacterium Tuberculosis Culture Filtrate to Understand TB Pathogenesis
Published on: March 28, 2025
344
Evolutionarily divergent Mycobacterium tuberculosis CTP synthase filaments are under selective pressure
Eric M Lynch1, Yao Lu2, Jin Ho Park2
1Department of Biochemistry, University of Washington, Seattle, WA 98195.
Biorxiv : the Preprint Server for Biology
|August 2, 2024
Summary
Mycobacterium tuberculosis CTP synthase (CTPS) forms unique filaments that stabilize its active form and resist inhibition. This filament formation is crucial for bacterial viability and may offer a new chemotherapy target.
Area of Science:
- Biochemistry
- Structural Biology
- Microbiology
Background:
- CTP synthase (CTPS) is essential for pyrimidine biosynthesis in Mycobacterium tuberculosis.
- CTP, the enzyme's product, is vital for DNA, RNA, lipid, and cell wall synthesis.
- CTPS typically forms higher-order filaments in other organisms.
Purpose of the Study:
- To investigate if Mycobacterium tuberculosis CTPS (mtCTPS) forms higher-order structures.
- To understand the role of mtCTPS filamentation in enzyme activity and cellular function.
- To explore the potential of mtCTPS as a drug target.
Main Methods:
- Structural analysis
- Biochemical assays
- Cellular imaging techniques
Main Results:
- mtCTPS forms filaments with a unique architecture.
- Filament polymerization stabilizes the active enzyme conformation and prevents product inhibition.
- mtCTPS filaments localize near the chromosome segregation complex, and polymerization-defective mutants impair this complex formation.
- Mutations affecting filament formation are positively selected in clinical M. tuberculosis isolates.
Conclusions:
- mtCTPS filamentation is an unusual mechanism for spatially organized CTP production in M. tuberculosis.
- This filamentation is critical for bacterial viability and chromosome segregation.
- mtCTPS filamentation represents a potential vulnerability for chemotherapy development.
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