2014
DOI: 10.1021/ja413127v
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Abstract: We have obtained the structure of the bacterial diterpene synthase, tuberculosinol/iso-tuberculosinol synthase (Rv3378c) from Mycobacterium tuberculosis, a target for anti-infective therapies that block virulence factor formation. This phosphatase adopts the same fold as found in the Z- or cis-prenyltransferases. We also obtained structures containing the tuberculosinyl diphosphate substrate together with one bisphosphonate inhibitor-bound structure. These structures together with the results of site-directed … Show more

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Cited by 36 publications
(62 citation statements)
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“…Some but not all of the Rv3378c mutations, including those present in M. africanum , have been proven to inactivate lipid biosynthesis (Chan et al, 2014; Layre et al, 2014). Second, BCG vaccine strains are of particular interest because they cause false positive immunological tests.…”
Section: Resultsmentioning
confidence: 99%
“…Some but not all of the Rv3378c mutations, including those present in M. africanum , have been proven to inactivate lipid biosynthesis (Chan et al, 2014; Layre et al, 2014). Second, BCG vaccine strains are of particular interest because they cause false positive immunological tests.…”
Section: Resultsmentioning
confidence: 99%
“…Finding that two structurally similar bisphosphonates (Scheme 9) are able to inhibit different Mycobacterium tuberculosis enzymes, decaprenyl diphosphate synthase and tuberculosinol synthase, suggest that bisphosphonates could act as multi-targeting agents [184]. This possibility was confirmed by the ability of one of the inhibitors of undecaprenyl pyrophosphate synthase, shown in Scheme (9), to additionally intercalate with DNA [185].…”
Section: Antibacterial Bisphosphonatesmentioning
confidence: 94%
“…smegmatis, S. cerevisiae, S. aureus, and M. tuberculosis growth inhibition assays; the porcine liver mitochondria Δψ assay; ΔpH and Δψ assays with IMV; MD simulation of Rv3378c; Rv3378c inhibition; DSC; and EPR were performed as described previously (13,70,77,91,92), with full details given in SI Methods.…”
Section: Methodsmentioning
confidence: 99%