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Evolutionarily divergent Mycobacterium tuberculosis CTP synthase filaments are under selective pressure
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Journal Article
Evolutionarily divergent Mycobacterium tuberculosis CTP synthase filaments are under selective pressure
2025
Overview
The final and rate-limiting enzyme in pyrimidine biosynthesis, cytidine triphosphate synthase (CTPS), is essential for the viability of
Mycobacterium tuberculosis
and other mycobacteria. Its product, cytidine triphosphate (CTP), is critical for RNA, DNA, lipid and cell wall synthesis, and is involved in chromosome segregation. In various organisms across the tree of life, CTPS assembles into higher-order filaments, leading us to hypothesize that
M. tuberculosis
CTPS (mtCTPS) also forms higher-order structures. Here, we show that mtCTPS does assemble into filaments but with an unusual architecture not seen in other organisms. Through a combination of structural, biochemical, and cellular techniques, we show that polymerization stabilizes the active conformation of the enzyme and resists product inhibition, potentially allowing for the highly localized production of CTP within the cell. Indeed, CTPS filaments localize near the CTP-dependent complex needed for chromosome segregation, and cells expressing mutant enzymes unable to polymerize are altered in their ability to robustly form this complex. Intriguingly, mutants that inhibit filament formation are under positive selection in clinical isolates of
M. tuberculosis
, pointing to a critical role needed to withstand pressures imposed by the host and/or antibiotics. Taken together, our data reveal an unexpected mechanism for the spatially organized production of a critical nucleotide in
M. tuberculosis
, which may represent a vulnerability of the pathogen that can be exploited with chemotherapy.
Cytidine triphosphate synthase, a key enzyme in nucleotide synthesis, forms distinct filaments in
Mycobacterium tuberculosis
that resist cytidine triphosphate feedback inhibition, which are characterised through structural, biochemical, and cellular methods.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14/35
/ 14/63
/ Ammonia
/ Bacterial Proteins - chemistry
/ Bacterial Proteins - genetics
/ Bacterial Proteins - metabolism
/ Carbon-Nitrogen Ligases - chemistry
/ Carbon-Nitrogen Ligases - genetics
/ Carbon-Nitrogen Ligases - metabolism
/ CTP
/ Cytidine Triphosphate - metabolism
/ Humanities and Social Sciences
/ Insects
/ Lipids
/ Mutants
/ Mutation
/ Mycobacterium tuberculosis - enzymology
/ Mycobacterium tuberculosis - genetics
/ Science
