Abstract:
:Mycobacterium tuberculosis (Mtb) is the causative agent of the human disease Tuberculosis, and remains a worldwide health threat responsible for ∼1.7 million deaths annually. During infection, Mtb prevents acidification of the engulfing phagosome, thus blocking endocytic progression and eventually leading to stable residence. The diterpenoid metabolite isotuberculosinol (isoTb) exhibits biological activity indicative of a role in this early arrest of phagosome maturation. Presumably, isoTb production should be induced by phagosomal entry. However, the relevant enzymatic genes are not transcriptionally upregulated during engulfment. Previous examination of the initial biosynthetic enzyme (Rv3377c/MtHPS) involved in isoTb biosynthesis revealed striking inhibition by its Mg(2+) cofactor, leading to the hypothesis that the depletion of Mg(2+) observed upon phagosomal engulfment may act to trigger isoTb biosynthesis. While Mtb is typically grown in relatively high levels of Mg(2+) (0.43 mM), shifting Mtb to media with phagosomal levels (0.1 mM) led to a significant (∼10-fold) increase in accumulation of the MtHPS product, halimadienyl diphosphate, as well as easily detectable amounts of the derived bioactive isoTb. These results demonstrate isoTb production by Mtb specifically under conditions that mimic phagosomal cation concentrations, and further support a role for isoTb in the Mtb infection process.
journal_name
Mol Microbioljournal_title
Molecular microbiologyauthors
Mann FM,VanderVen BC,Peters RJdoi
10.1111/j.1365-2958.2011.07545.xsubject
Has Abstractpub_date
2011-03-01 00:00:00pages
1594-601issue
6eissn
0950-382Xissn
1365-2958journal_volume
79pub_type
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