The nonmevalonate pathway of isoprenoid biosynthesis in mycobacterium tuberculosis is essential and transcriptionally regulated by dxs

Brown, Amanda C., Eberl, Matthias ORCID: https://orcid.org/0000-0002-9390-5348, Crick, Dean C., Jomaa, Hassan and Parish, Tanya 2010. The nonmevalonate pathway of isoprenoid biosynthesis in mycobacterium tuberculosis is essential and transcriptionally regulated by dxs. Journal of Bacteriology 192 (9) , pp. 2424-2433. 10.1128/JB.01402-09

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Abstract

Mycobacterium tuberculosis synthesizes isoprenoids via the nonmevalonate or DOXP pathway. Previous work demonstrated that three enzymes in the pathway (Dxr, IspD, and IspF) are all required for growth in vitro. We demonstrate the essentiality of the key genes dxs1 and gcpE, confirming that the pathway is of central importance and that the second homolog of the synthase (dxs2) cannot compensate for the loss of dxs1. We looked at the effect of overexpression of Dxr, Dxs1, Dxs2, and GcpE on viability and on growth in M. tuberculosis. Overexpression of dxs1 or dxs2 was inhibitory to growth, whereas overexpression of dxr or gcpE was not. Toxicity is likely to be, at least partially, due to depletion of pyruvate from the cells. Overexpression of dxs1 or gcpE resulted in increased flux through the pathway, as measured by accumulation of the metabolite 4-hydroxy-3-methyl-but-2-enyl pyrophosphate. We identified the functional translational start site and promoter region for dxr and demonstrated that it is expressed as part of a polycistronic mRNA with gcpE and two other genes. Increased expression of this operon was seen in cells overexpressing Dxs1, indicating that transcriptional control is effected by the first enzyme of the pathway via an unknown regulator.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > QR Microbiology > QR180 Immunology
Additional Information:	Pdf uploaded in accordance with publisher's policy at http://www.sherpa.ac.uk/romeo/issn/0021-9193/ (accessed 25/02/2014)
Publisher:	American Society for Microbiology
ISSN:	0021-9193
Date of First Compliant Deposit:	30 March 2016
Last Modified:	04 May 2023 12:28
URI:	https://orca.cardiff.ac.uk/id/eprint/27413

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