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Mycobacterium tuberculosis VadK required for regulation of the methylcitrate cycle and virulence

ABSTRACT:

The evolution of new enzymatic functions is constrained and guided by the architecture of an organism’s metabolic and regulatory networks and environmental constraints. Here, we identify a kinase that has evolved from pyruvate phosphate dikinase. Through biochemical and systems-level analyses, we show that this enzyme, encoded by Rv1127c in Mycobacterium tuberculosis (Mtb), has diverged from its ancestral role in central carbon metabolism to function as a histidine kinase in pathogenic mycobacteria and related species. We designate this enzyme Virulence Associated DiKinase (VadK), reflecting its ability to autophosphorylate and role in virulence. VadK is essential for the utilization of carbon sources critical for survival within the host and to cause tuberculosis in murine models. Furthermore, VadK interacts with enzymes of the methylcitrate cycle, and 13C-tracer experiments demonstrates that it fine-tunes flux through this pathway, with elevated flux proving growth limiting. Together, these findings identify VadK as a regulatory kinase that integrates metabolic control with virulence in Mtb, revealing a new facet of metabolic regulation in bacterial pathogenesis and a potential target for therapeutic intervention.

INSTRUMENT(S): Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS13906 | MetaboLights | 2026-04-21

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13906_LC-MS_negative_hilic_metabolite_profiling-1.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13906_LC-MS_negative_hilic_metabolite_profiling-1_v2_maf.tsv	Tabular
	s_MTBLS13906.txt	Txt

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