The mycolic acid reductase Rv2509 has distinct structural motifs and is essential for growth in slow-growing mycobacteria.
Mycobacterium
dehydrogenase
mycolic acid
reductase
tuberculosis
Journal
Molecular microbiology
ISSN: 1365-2958
Titre abrégé: Mol Microbiol
Pays: England
ID NLM: 8712028
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
08
10
2018
revised:
11
11
2019
pubmed:
1
12
2019
medline:
11
11
2020
entrez:
1
12
2019
Statut:
ppublish
Résumé
The final step in mycolic acid biosynthesis in Mycobacterium tuberculosis is catalysed by mycolyl reductase encoded by the Rv2509 gene. Sequence analysis and homology modelling indicate that Rv2509 belongs to the short-chain fatty acid dehydrogenase/reductase (SDR) family, but with some distinct features that warrant its classification as belonging to a novel family of short-chain dehydrogenases. In particular, the predicted structure revealed a unique α-helical C-terminal region which we demonstrated to be essential for Rv2509 function, though this region did not seem to play any role in protein stabilisation or oligomerisation. We also show that unlike the M. smegmatis homologue which was not essential for growth, Rv2509 was an essential gene in slow-growing mycobacteria. A knockdown strain of the BCG2529 gene, the Rv2509 homologue in Mycobacterium bovis BCG, was unable to grow following the conditional depletion of BCG2529. This conditional depletion also led to a reduction of mature mycolic acid production and accumulation of intermediates derived from 3-oxo-mycolate precursors. Our studies demonstrate novel features of the mycolyl reductase Rv2509 and outline its role in mycobacterial growth, highlighting its potential as a new target for therapies.
Identifiants
pubmed: 31785114
doi: 10.1111/mmi.14437
pmc: PMC7065075
doi:
Substances chimiques
Bacterial Proteins
0
Mycolic Acids
0
Oxidoreductases
EC 1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
521-533Subventions
Organisme : Medical Research Council
ID : G0600105
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K00042X/1
Pays : United Kingdom
Informations de copyright
© 2019 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.
Références
Curr Protoc Microbiol. 2007 Jun;Chapter 10:Unit 10A.3
pubmed: 18770604
Biochemistry. 1995 May 9;34(18):6003-13
pubmed: 7742302
J Mol Biol. 1999 Sep 17;292(2):195-202
pubmed: 10493868
Mol Microbiol. 2015 Oct;98(1):7-16
pubmed: 26135034
Nature. 1991 Jun 6;351(6326):456-60
pubmed: 1904554
Biochemistry. 1997 Jan 7;36(1):34-40
pubmed: 8993315
Nucleic Acids Res. 2013 Jul;41(Web Server issue):W349-57
pubmed: 23748958
mBio. 2014 Jun 03;5(3):e01245-14
pubmed: 24895308
Nucleic Acids Res. 2009 Apr;37(6):1778-88
pubmed: 19174563
BMC Bioinformatics. 2009 Oct 27;10:356
pubmed: 19860910
PLoS Pathog. 2011 Sep;7(9):e1002251
pubmed: 21980284
Mol Microbiol. 2020 Feb;113(2):521-533
pubmed: 31785114
Mol Microbiol. 1990 Nov;4(11):1911-9
pubmed: 2082148
Proteins. 2009;77 Suppl 9:89-99
pubmed: 19701941
J Biochem. 2011 Jun;149(6):701-12
pubmed: 21349860
Microbiology (Reading). 2002 Oct;148(Pt 10):3007-3017
pubmed: 12368434
Nucleic Acids Res. 2016 Jul 8;44(W1):W344-50
pubmed: 27166375
Microbiology (Reading). 2005 Jul;151(Pt 7):2421-2427
pubmed: 16000732
Nucleic Acids Res. 2002 Jul 15;30(14):3059-66
pubmed: 12136088
Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W197-201
pubmed: 18463136
Microbiologyopen. 2014 Aug;3(4):484-96
pubmed: 24942069
Chem Biol. 2014 Jan 16;21(1):67-85
pubmed: 24374164
Nucleic Acids Res. 2015 Jan;43(Database issue):D222-6
pubmed: 25414356
J Biol Chem. 2007 Apr 13;282(15):11000-8
pubmed: 17308303
Appl Environ Microbiol. 2014 Jan;80(2):497-505
pubmed: 24212572
J Biol Chem. 2004 Oct 22;279(43):44847-57
pubmed: 15308633
Nat Methods. 2015 Jan;12(1):7-8
pubmed: 25549265
Proteins. 2004 Aug 1;56(2):250-60
pubmed: 15211509
Nucleic Acids Res. 2019 Jul 2;47(W1):W402-W407
pubmed: 31251384
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
Nucleic Acids Res. 2015 Jul 1;43(W1):W389-94
pubmed: 25883141
Chem Biol. 2008 Sep 22;15(9):930-9
pubmed: 18804030
Sci Rep. 2014 Sep 25;4:6471
pubmed: 25253464
Chem Biol. 2014 Dec 18;21(12):1660-9
pubmed: 25467124
Nucleic Acids Res. 2003 Jul 1;31(13):3320-3
pubmed: 12824317
Chem Biol Interact. 2003 Feb 1;143-144:271-8
pubmed: 12604213
PLoS Pathog. 2016 Dec 9;12(12):e1006043
pubmed: 27936238
Structure. 2013 Oct 8;21(10):1735-42
pubmed: 24035711
J Biol Chem. 2002 Jul 12;277(28):25677-84
pubmed: 11976334
Biochem J. 2013 Feb 15;450(1):127-39
pubmed: 23163771
Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):314-9
pubmed: 14695899
Biochim Biophys Acta. 2003 Jan 31;1645(1):89-94
pubmed: 12535615
Chem Biol. 2012 Apr 20;19(4):498-506
pubmed: 22520756
Mol Microbiol. 2016 Jul;101(2):194-209
pubmed: 26919556