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Reconstruction of diaminopimelic acid biosynthesis allows characterisation of Mycobacterium tuberculosis N-succinyl-L,L-diaminopimelic acid desuccinylase
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Usha, Veeraraghavan, Lloyd, Adrian J., Roper, David I., Dowson, Christopher G., Kozlov, Guennadi, Gehring, Kalle, Chauhan, Smita, Imam, Hasan T., Blindauer, Claudia A. and Besra, Gurdyal S. (2016) Reconstruction of diaminopimelic acid biosynthesis allows characterisation of Mycobacterium tuberculosis N-succinyl-L,L-diaminopimelic acid desuccinylase. Scientific Reports, 6 . 23191. doi:10.1038/srep23191 ISSN 2045-2322.
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Official URL: http://dx.doi.org/10.1038/srep23191
Abstract
With the increased incidence of tuberculosis (TB) caused by Mycobacterium tuberculosis there is an urgent need for new and better anti-tubercular drugs. N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is a key enzyme in the succinylase pathway for the biosynthesis of meso-diaminopimelic acid (meso-DAP) and L-lysine. DapE is a zinc containing metallohydrolase which hydrolyses N-succinyl L,L diaminopimelic acid (L,L-NSDAP) to L,L-diaminopimelic acid (L,L-DAP) and succinate. M. tuberculosis DapE (MtDapE) was cloned, over-expressed and purified as an N-terminal hexahistidine ((His)6) tagged fusion containing one zinc ion per DapE monomer. We redesigned the DAP synthetic pathway to generate L,L-NSDAP and other L,L-NSDAP derivatives and have characterised MtDapE with these substrates. In contrast to its other Gram negative homologues, the MtDapE was insensitive to inhibition by L-captopril which we show is consistent with novel mycobacterial alterations in the binding site of this drug.
| Item Type: | Journal Article | ||||||||
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| Subjects: | Q Science > QR Microbiology R Medicine > RA Public aspects of medicine R Medicine > RC Internal medicine R Medicine > RM Therapeutics. Pharmacology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||
| Library of Congress Subject Headings (LCSH): | Tuberculosis, Mycobacterium tuberculosis, Multidrug-resistant tuberculosis, Antitubercular agents | ||||||||
| Journal or Publication Title: | Scientific Reports | ||||||||
| Publisher: | Nature Publishing Group | ||||||||
| ISSN: | 2045-2322 | ||||||||
| Official Date: | 15 March 2016 | ||||||||
| Dates: |
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| Volume: | 6 | ||||||||
| Article Number: | 23191 | ||||||||
| DOI: | 10.1038/srep23191 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||
| Date of first compliant deposit: | 29 March 2016 | ||||||||
| Date of first compliant Open Access: | 29 March 2016 | ||||||||
| Funder: | Wellcome Trust (London, England), Medical Research Council (Great Britain) (MRC), Birmingham Science City | ||||||||
| Adapted As: |
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