Thienopyrimidinone derivatives that inhibit bacterial tRNA (guanine37-N1)-methyltransferase (TrmD) by restructuring the active site with a tyrosine-flipping mechanism
Among the >120 modified ribonucleosides in the prokaryotic epitranscriptome, many tRNA modifications are critical to bacterial survival, which makes their synthetic enzymes ideal targets for antibiotic development. Here we performed a structure-based design of inhibitors of tRNA-(N1G37) methyltra...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2021
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/148942 |
| _version_ | 1826115640934531072 |
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| author | Zhong, Wenhe Pasunooti, Kalyan Kumar Balamkundu, Seetharamsing Wong, Yee Hwa Nah, Qianhui Gadi, Vinod Gnanakalai, Shanmugavel Chionh, Yok Hian McBee, Megan E. Gopal, Pooja Lim, Siau Hoi Olivier, Nelson Buurman, Ed T. Dick, Thomas Liu, Chuan Fa Lescar, Julien Dedon, Peter C. |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Zhong, Wenhe Pasunooti, Kalyan Kumar Balamkundu, Seetharamsing Wong, Yee Hwa Nah, Qianhui Gadi, Vinod Gnanakalai, Shanmugavel Chionh, Yok Hian McBee, Megan E. Gopal, Pooja Lim, Siau Hoi Olivier, Nelson Buurman, Ed T. Dick, Thomas Liu, Chuan Fa Lescar, Julien Dedon, Peter C. |
| author_sort | Zhong, Wenhe |
| collection | NTU |
| description | Among the >120 modified ribonucleosides in the prokaryotic epitranscriptome, many tRNA modifications are critical to bacterial survival, which makes their synthetic enzymes ideal targets for antibiotic development. Here we performed a structure-based design of inhibitors of tRNA-(N1G37) methyltransferase, TrmD, which is an essential enzyme in many bacterial pathogens. On the basis of crystal structures of TrmDs from Pseudomonas aeruginosa and Mycobacterium tuberculosis, we synthesized a series of thienopyrimidinone derivatives with nanomolar potency against TrmD in vitro and discovered a novel active site conformational change triggered by inhibitor binding. This tyrosine-flipping mechanism is uniquely found in P. aeruginosa TrmD and renders the enzyme inaccessible to the cofactor S-adenosyl-l-methionine (SAM) and probably to the substrate tRNA. Biophysical and biochemical structure-activity relationship studies provided insights into the mechanisms underlying the potency of thienopyrimidinones as TrmD inhibitors, with several derivatives found to be active against Gram-positive and mycobacterial pathogens. These results lay a foundation for further development of TrmD inhibitors as antimicrobial agents. |
| first_indexed | 2024-10-01T03:58:45Z |
| format | Journal Article |
| id | ntu-10356/148942 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:58:45Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1489422023-02-28T16:57:11Z Thienopyrimidinone derivatives that inhibit bacterial tRNA (guanine37-N1)-methyltransferase (TrmD) by restructuring the active site with a tyrosine-flipping mechanism Zhong, Wenhe Pasunooti, Kalyan Kumar Balamkundu, Seetharamsing Wong, Yee Hwa Nah, Qianhui Gadi, Vinod Gnanakalai, Shanmugavel Chionh, Yok Hian McBee, Megan E. Gopal, Pooja Lim, Siau Hoi Olivier, Nelson Buurman, Ed T. Dick, Thomas Liu, Chuan Fa Lescar, Julien Dedon, Peter C. School of Biological Sciences Singapore-MIT Alliance for Research and Technology Institute of Structural Biology Science::Biological sciences Inhibitors Peptides and Proteins Among the >120 modified ribonucleosides in the prokaryotic epitranscriptome, many tRNA modifications are critical to bacterial survival, which makes their synthetic enzymes ideal targets for antibiotic development. Here we performed a structure-based design of inhibitors of tRNA-(N1G37) methyltransferase, TrmD, which is an essential enzyme in many bacterial pathogens. On the basis of crystal structures of TrmDs from Pseudomonas aeruginosa and Mycobacterium tuberculosis, we synthesized a series of thienopyrimidinone derivatives with nanomolar potency against TrmD in vitro and discovered a novel active site conformational change triggered by inhibitor binding. This tyrosine-flipping mechanism is uniquely found in P. aeruginosa TrmD and renders the enzyme inaccessible to the cofactor S-adenosyl-l-methionine (SAM) and probably to the substrate tRNA. Biophysical and biochemical structure-activity relationship studies provided insights into the mechanisms underlying the potency of thienopyrimidinones as TrmD inhibitors, with several derivatives found to be active against Gram-positive and mycobacterial pathogens. These results lay a foundation for further development of TrmD inhibitors as antimicrobial agents. Ministry of Education (MOE) National Research Foundation (NRF) Published version This research was supported by the National Research Foundation of Singapore through the Singapore-MIT-Alliance for Research and Technology (SMART) Infectious Disease and Antimicrobial Resistance Interdisciplinary Research Groups; SMART Innovation Centre grant ING137070-BIO to P.C.D., L.C.F., and J.L.; and AcRF grants Tier1 RG154/14 and MOE2015- T2-2-075 to J.L. 2021-05-10T07:56:08Z 2021-05-10T07:56:08Z 2019 Journal Article Zhong, W., Pasunooti, K. K., Balamkundu, S., Wong, Y. H., Nah, Q., Gadi, V., Gnanakalai, S., Chionh, Y. H., McBee, M. E., Gopal, P., Lim, S. H., Olivier, N., Buurman, E. T., Dick, T., Liu, C. F., Lescar, J. & Dedon, P. C. (2019). Thienopyrimidinone derivatives that inhibit bacterial tRNA (guanine37-N1)-methyltransferase (TrmD) by restructuring the active site with a tyrosine-flipping mechanism. Journal of Medicinal Chemistry, 62(17), 7788-7805. https://dx.doi.org/10.1021/acs.jmedchem.9b00582 0022-2623 https://hdl.handle.net/10356/148942 10.1021/acs.jmedchem.9b00582 31442049 2-s2.0-85072103389 17 62 7788 7805 en ING137070-BIO RG154/14 MOE2015- T2-2-075 Journal of Medicinal Chemistry © 2019 American Chemical Society. This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License, which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes. application/pdf |
| spellingShingle | Science::Biological sciences Inhibitors Peptides and Proteins Zhong, Wenhe Pasunooti, Kalyan Kumar Balamkundu, Seetharamsing Wong, Yee Hwa Nah, Qianhui Gadi, Vinod Gnanakalai, Shanmugavel Chionh, Yok Hian McBee, Megan E. Gopal, Pooja Lim, Siau Hoi Olivier, Nelson Buurman, Ed T. Dick, Thomas Liu, Chuan Fa Lescar, Julien Dedon, Peter C. Thienopyrimidinone derivatives that inhibit bacterial tRNA (guanine37-N1)-methyltransferase (TrmD) by restructuring the active site with a tyrosine-flipping mechanism |
| title | Thienopyrimidinone derivatives that inhibit bacterial tRNA (guanine37-N1)-methyltransferase (TrmD) by restructuring the active site with a tyrosine-flipping mechanism |
| title_full | Thienopyrimidinone derivatives that inhibit bacterial tRNA (guanine37-N1)-methyltransferase (TrmD) by restructuring the active site with a tyrosine-flipping mechanism |
| title_fullStr | Thienopyrimidinone derivatives that inhibit bacterial tRNA (guanine37-N1)-methyltransferase (TrmD) by restructuring the active site with a tyrosine-flipping mechanism |
| title_full_unstemmed | Thienopyrimidinone derivatives that inhibit bacterial tRNA (guanine37-N1)-methyltransferase (TrmD) by restructuring the active site with a tyrosine-flipping mechanism |
| title_short | Thienopyrimidinone derivatives that inhibit bacterial tRNA (guanine37-N1)-methyltransferase (TrmD) by restructuring the active site with a tyrosine-flipping mechanism |
| title_sort | thienopyrimidinone derivatives that inhibit bacterial trna guanine37 n1 methyltransferase trmd by restructuring the active site with a tyrosine flipping mechanism |
| topic | Science::Biological sciences Inhibitors Peptides and Proteins |
| url | https://hdl.handle.net/10356/148942 |
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