| Structural highlights
Function
[HTM_MYCTU] Involved in cellular response to chemical stress and may contribute to resistance toward antimicrobial natural compounds as well as drugs (Probable). Catalyzes the methylation and detoxification of the P.aeruginosa toxin 2-heptyl-1-hydroxy-4(1H)-quinolinone (HQNO) to 2-heptyl-1-methoxy-4(1H)-quinolinone (HMOQ) (PubMed:33064871). Can also methylate 3-bromo-2-heptyl-1-hydroxy-4(1H)-quinolinone, and shows much lower activity with 1-hydroxyquinolin-4(1H)-one, quercetin, 4-hydroxyquinolin-2(1H)-one (DHQ) and 4-hydroxyisoquinolin-1(2H)-one (PubMed:33064871). In addition, N-methylates and abolishes the mycobactericidal activity of 3-methyl-1-oxo-2-[3-oxo-3-(pyrrolidin-1-yl)propyl]-1,5-dihydrobenzo[4,5]imidazo[1,2-a]pyridine-4-carbonitrile (compound 14), an inhibitor of DprE1 (PubMed:27432954). Also methylates and reduces the inhibitory effect of TPSA (2-[5-(2-{[4-(2-thienyl)-2-pyrimidinyl]sulfanyl}acetyl)-2-thienyl]acetic acid), an inhibitor of GlmU acetyltransferase (PubMed:31380295).[1] [2] [3] [4]
Publication Abstract from PubMed
The S-adenosyl-L-methionine-dependent methyltransferase Rv0560c of Mycobacterium tuberculosis belongs to an orthologous group of heterocyclic toxin methyltransferases (Htm) which likely contribute to resistance of mycobacteria towards antimicrobial natural compounds as well as drugs. HtmM.t. catalyzes the methylation of the Pseudomonas aeruginosa toxin 2-heptyl-1-hydroxyquinolin-4(1H)-one (also known as 2-heptyl-4-hydroxyquinoline N-oxide), a potent inhibitor of respiratory electron transfer, its 1-hydroxyquinolin-4(1H)-one core (QNO), structurally related (iso)quinolones, and some mycobactericidal compounds. In this study, crystal structures of HtmM.t. in complex with S-adenosyl-L-homocysteine (SAH) and the methyl-accepting substrates QNO or 4-hydroxyisoquinoline-1(2H)-one, or the methylated product 1-methoxyquinolin-4(1H)-one, were determined at < 1.9 A resolution. The monomeric protein exhibits the typical Rossmann fold topology and conserved residues of class I methyltransferases. Its SAH binding pocket is connected via a short tunnel to a large solvent-accessible cavity, which accommodates the methyl-accepting substrate. Residues W44, F168, and F208 in connection with F212 form a hydrophobic clamp around the heteroaromatic ring of the methyl-accepting substrate and likely play a major role in substrate positioning. Structural and biochemical data suggest that H139 and T136 are key active site residues, with H139 acting as general base that activates the methyl-accepting hydroxy group. Our structural data may contribute to the design of Htm inhibitors or of antimycobacterial drugs unamenable for methylation.
Structural basis of O-methylation of (2-heptyl-)1-hydroxyquinolin-4(1H)-one and related compounds by the heterocyclic toxin methyltransferase Rv0560c of Mycobacterium tuberculosis.,Sartor P, Denkhaus L, Gerhardt S, Einsle O, Fetzner S J Struct Biol. 2021 Sep 20;213(4):107794. doi: 10.1016/j.jsb.2021.107794. PMID:34506908[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Warrier T, Kapilashrami K, Argyrou A, Ioerger TR, Little D, Murphy KC, Nandakumar M, Park S, Gold B, Mi J, Zhang T, Meiler E, Rees M, Somersan-Karakaya S, Porras-De Francisco E, Martinez-Hoyos M, Burns-Huang K, Roberts J, Ling Y, Rhee KY, Mendoza-Losana A, Luo M, Nathan CF. N-methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4523-30. doi:, 10.1073/pnas.1606590113. Epub 2016 Jul 18. PMID:27432954 doi:http://dx.doi.org/10.1073/pnas.1606590113
- ↑ Chen C, Han X, Yan Q, Wang C, Jia L, Taj A, Zhao L, Ma Y. The Inhibitory Effect of GlmU Acetyltransferase Inhibitor TPSA on Mycobacterium tuberculosis May Be Affected Due to Its Methylation by Methyltransferase Rv0560c. Front Cell Infect Microbiol. 2019 Jul 17;9:251. doi: 10.3389/fcimb.2019.00251., eCollection 2019. PMID:31380295 doi:http://dx.doi.org/10.3389/fcimb.2019.00251
- ↑ Sartor P, Bock J, Hennecke U, Thierbach S, Fetzner S. Modification of the Pseudomonas aeruginosa toxin 2-heptyl-1-hydroxyquinolin-4(1H)-one and other secondary metabolites by methyltransferases from mycobacteria. FEBS J. 2021 Apr;288(7):2360-2376. doi: 10.1111/febs.15595. Epub 2020 Nov 8. PMID:33064871 doi:http://dx.doi.org/10.1111/febs.15595
- ↑ Sartor P, Bock J, Hennecke U, Thierbach S, Fetzner S. Modification of the Pseudomonas aeruginosa toxin 2-heptyl-1-hydroxyquinolin-4(1H)-one and other secondary metabolites by methyltransferases from mycobacteria. FEBS J. 2021 Apr;288(7):2360-2376. doi: 10.1111/febs.15595. Epub 2020 Nov 8. PMID:33064871 doi:http://dx.doi.org/10.1111/febs.15595
- ↑ Sartor P, Denkhaus L, Gerhardt S, Einsle O, Fetzner S. Structural basis of O-methylation of (2-heptyl-)1-hydroxyquinolin-4(1H)-one and related compounds by the heterocyclic toxin methyltransferase Rv0560c of Mycobacterium tuberculosis. J Struct Biol. 2021 Sep 20;213(4):107794. doi: 10.1016/j.jsb.2021.107794. PMID:34506908 doi:http://dx.doi.org/10.1016/j.jsb.2021.107794
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