| Structural highlights
Function
PKNA_MYCTU Key component of a signal transduction pathway that regulates cell growth and cell division via phosphorylation of target proteins such as FtsZ, Wag31, GlmU, FhaB, PstP, EmbR and Rv1422. Shows a strong preference for Thr versus Ser as the phosphoacceptor.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Drug resistant tuberculosis (TB) infections are on the rise and antibiotics that inhibit Mycobacterium tuberculosis through a novel mechanism could be an important component of evolving TB therapy. Protein kinase A (PknA) and protein kinase B (PknB) are both essential serine-threonine kinases in M. tuberculosis. Given the extensive knowledge base in kinase inhibition, these enzymes present an interesting opportunity for antimycobacterial drug discovery. This study focused on targeting both PknA and PknB while improving the selectivity window over related mammalian kinases. Compounds achieved potent inhibition (Ki approximately 5 nM) of both PknA and PknB. A binding pocket unique to mycobacterial kinases was identified. Substitutions that filled this pocket resulted in a 100-fold differential against a broad selection of mammalian kinases. Reducing lipophilicity improved antimycobacterial activity with the most potent compounds achieving minimum inhibitory concentrations ranging from 3 to 5 muM (1-2 mug/mL) against the H37Ra isolate of M. tuberculosis.
Mtb PKNA/PKNB Dual Inhibition Provides Selectivity Advantages for Inhibitor Design To Minimize Host Kinase Interactions.,Wang T, Bemis G, Hanzelka B, Zuccola H, Wynn M, Moody CS, Green J, Locher C, Liu A, Gao H, Xu Y, Wang S, Wang J, Bennani YL, Thomson JA, Muh U ACS Med Chem Lett. 2017 Nov 28;8(12):1224-1229. doi:, 10.1021/acsmedchemlett.7b00239. eCollection 2017 Dec 14. PMID:29259738[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kang CM, Abbott DW, Park ST, Dascher CC, Cantley LC, Husson RN. The Mycobacterium tuberculosis serine/threonine kinases PknA and PknB: substrate identification and regulation of cell shape. Genes Dev. 2005 Jul 15;19(14):1692-704. Epub 2005 Jun 28. PMID:15985609 doi:https://dx.doi.org/10.1101/gad.1311105
- ↑ Sharma K, Gupta M, Krupa A, Srinivasan N, Singh Y. EmbR, a regulatory protein with ATPase activity, is a substrate of multiple serine/threonine kinases and phosphatase in Mycobacterium tuberculosis. FEBS J. 2006 Jun;273(12):2711-21. PMID:16817899 doi:https://dx.doi.org/10.1111/j.1742-4658.2006.05289.x
- ↑ Parikh A, Verma SK, Khan S, Prakash B, Nandicoori VK. PknB-mediated phosphorylation of a novel substrate, N-acetylglucosamine-1-phosphate uridyltransferase, modulates its acetyltransferase activity. J Mol Biol. 2009 Feb 20;386(2):451-64. Epub 2008 Dec 24. PMID:19121323 doi:10.1016/j.jmb.2008.12.031
- ↑ Sureka K, Hossain T, Mukherjee P, Chatterjee P, Datta P, Kundu M, Basu J. Novel role of phosphorylation-dependent interaction between FtsZ and FipA in mycobacterial cell division. PLoS One. 2010 Jan 6;5(1):e8590. doi: 10.1371/journal.pone.0008590. PMID:20066037 doi:https://dx.doi.org/10.1371/journal.pone.0008590
- ↑ Jani C, Eoh H, Lee JJ, Hamasha K, Sahana MB, Han JS, Nyayapathy S, Lee JY, Suh JW, Lee SH, Rehse SJ, Crick DC, Kang CM. Regulation of polar peptidoglycan biosynthesis by Wag31 phosphorylation in mycobacteria. BMC Microbiol. 2010 Dec 29;10:327. doi: 10.1186/1471-2180-10-327. PMID:21190553 doi:https://dx.doi.org/10.1186/1471-2180-10-327
- ↑ Sajid A, Arora G, Gupta M, Upadhyay S, Nandicoori VK, Singh Y. Phosphorylation of Mycobacterium tuberculosis Ser/Thr phosphatase by PknA and PknB. PLoS One. 2011 Mar 9;6(3):e17871. doi: 10.1371/journal.pone.0017871. PMID:21423706 doi:https://dx.doi.org/10.1371/journal.pone.0017871
- ↑ Wang T, Bemis G, Hanzelka B, Zuccola H, Wynn M, Moody CS, Green J, Locher C, Liu A, Gao H, Xu Y, Wang S, Wang J, Bennani YL, Thomson JA, Muh U. Mtb PKNA/PKNB Dual Inhibition Provides Selectivity Advantages for Inhibitor Design To Minimize Host Kinase Interactions. ACS Med Chem Lett. 2017 Nov 28;8(12):1224-1229. doi:, 10.1021/acsmedchemlett.7b00239. eCollection 2017 Dec 14. PMID:29259738 doi:https://dx.doi.org/10.1021/acsmedchemlett.7b00239
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