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Nonhydrolysable Ana...
Nonhydrolysable Analogues of (p)ppGpp and (p)ppApp Alarmone Nucleotides as Novel Molecular Tools
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- Mojr, Viktor (author)
- Academy of Sciences of the Czech Republic
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- Roghanian, Mohammad (author)
- Umeå University,Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Molekylär Infektionsmedicin, Sverige (MIMS),Umeå Centre for Microbial Research (UCMR),Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark
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- Tamman, Hedvig (author)
- Université Libre de Bruxelles (ULB)
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Pham, Duy Dinh Do (author)
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Petrova, Magdalena (author)
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Pohl, Radek (author)
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- Takada, Hiraku (author)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Molekylär Infektionsmedicin, Sverige (MIMS),Umeå Centre for Microbial Research (UCMR),Faculty of Life Sciences, Kyoto Sangyo University, Kyoto, Japan
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- Van Nerom, Katleen (author)
- Université Libre de Bruxelles (ULB)
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Ainelo, Hanna (author)
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Caballero-Montes, Julien (author)
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- Jimmy, Steffi (author)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Molekylär Infektionsmedicin, Sverige (MIMS),Umeå Centre for Microbial Research (UCMR),Deutsches Elektronen-Synchrotron DESY, Centre for Structural Systems Biology (CSSB), Hamburg, Germany,German Electron Synchrotron (DESY)
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- Garcia-Pino, Abel (author)
- Université Libre de Bruxelles (ULB)
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- Hauryliuk, Vasili, 1980- (author)
- Umeå University,Lund University,Lunds universitet,Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Molekylär Infektionsmedicin, Sverige (MIMS),Umeå Centre for Microbial Research (UCMR),University of Tartu, Institute of Technology, Tartu, Estonia; Department of Experimental Medical Science, Lund University, Lund, Sweden,Molekylär enzymologi,Forskargrupper vid Lunds universitet,Molecular Enzymology,Lund University Research Groups
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- Rejman, Dominik (author)
- Academy of Sciences of the Czech Republic
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(creator_code:org_t)
- 2021-09-03
- 2021
- English.
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In: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 16:9, s. 1680-1691
- Related links:
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https://dipot.ulb.ac...
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https://pubs.acs.org...
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http://dx.doi.org/10...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://lup.lub.lu.s...
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Abstract
Subject headings
Close
- While alarmone nudeotides guanosine-3',5'-bisdiphosphate (ppGpp) and guanosine-5'-triphosphate-3'-diphosphate (pppGpp) are archetypical bacterial second messengers, their adenosine analogues ppApp (adenosine-3',5'-bisdiphosphate) and pppApp (adenosine-5'-triphosphate-3'-diphosphate) are toxic effectors that abrogate bacterial growth. The alarmones are both synthesized and degraded by the members of the ReIA-SpoT Homologue (RSH) enzyme family. Because of the chemical and enzymatic liability of (p)ppGpp and (p)ppApp, these alarmones are prone to degradation during structural biology experiments. To overcome this limitation, we have established an efficient and straightforward procedure for synthesizing nonhydrolysable (p)ppNu(N)pp analogues starting from 3'-azido-3'-deoxyribonucleotides as key intermediates. To demonstrate the utility of (p)ppG(N)pp as a molecular tool, we show that (i) as an HD substrate mimic, ppG(N)pp competes with ppGpp to inhibit the enzymatic activity of human MESHI Small Alarmone Hyrolase, SAH; and (ii) mimicking the allosteric effects of (p)ppGpp, (p)ppG(N)pp acts as a positive regulator of the synthetase activity of long ribosome-associated RSHs Rel and ReIA. Finally, by solving the structure of the N-terminal domain region (NTD) of T. thermophilus Rel complexed with pppG(N)pp, we show that as an HD substrate mimic, the analogue serves as a bona fide orthosteric regulator that promotes the same intra-NTD structural rearrangements as the native substrate.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Keyword
- molekylärbiologi
- Molecular Biology
- Biochemistry
- biokemi
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Mojr, Viktor
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Roghanian, Moham ...
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Tamman, Hedvig
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Pham, Duy Dinh D ...
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Petrova, Magdale ...
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Pohl, Radek
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show more...
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Takada, Hiraku
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Van Nerom, Katle ...
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Ainelo, Hanna
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Caballero-Montes ...
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Jimmy, Steffi
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Garcia-Pino, Abe ...
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Hauryliuk, Vasil ...
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Rejman, Dominik
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
- Articles in the publication
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ACS Chemical Bio ...
- By the university
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Umeå University
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Lund University