Cargando…
Rerouting the Pathway for the Biosynthesis of the Side Ring System of Nosiheptide: The Roles of NosI, NosJ, and NosK
[Image: see text] Nosiheptide (NOS) is a highly modified thiopeptide antibiotic that displays formidable in vitro activity against a variety of Gram-positive bacteria. In addition to a central hydroxypyridine ring, NOS contains several other modifications, including multiple thiazole rings, dehydro-...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2017
|
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940322/ https://www.ncbi.nlm.nih.gov/pubmed/28343381 http://dx.doi.org/10.1021/jacs.7b01497 |
_version_ | 1783321093187043328 |
---|---|
author | Badding, Edward D. Grove, Tyler L. Gadsby, Lauren K. LaMattina, Joseph W. Boal, Amie K. Booker, Squire J. |
author_facet | Badding, Edward D. Grove, Tyler L. Gadsby, Lauren K. LaMattina, Joseph W. Boal, Amie K. Booker, Squire J. |
author_sort | Badding, Edward D. |
collection | PubMed |
description | [Image: see text] Nosiheptide (NOS) is a highly modified thiopeptide antibiotic that displays formidable in vitro activity against a variety of Gram-positive bacteria. In addition to a central hydroxypyridine ring, NOS contains several other modifications, including multiple thiazole rings, dehydro-amino acids, and a 3,4-dimethylindolic acid (DMIA) moiety. The DMIA moiety is required for NOS efficacy and is synthesized from l-tryptophan in a series of reactions that have not been fully elucidated. Herein, we describe the role of NosJ, the product of an unannotated gene in the biosynthetic operon for NOS, as an acyl carrier protein that delivers 3-methylindolic acid (MIA) to NosK. We also reassign the role of NosI as the enzyme responsible for catalyzing the ATP-dependent activation of MIA and MIA’s attachment to the phosphopantetheine moiety of NosJ. Lastly, NosK catalyzes the transfer of the MIA group from NosJ-MIA to a conserved serine residue (Ser102) on NosK. The X-ray crystal structure of NosK, solved to 2.3 Å resolution, reveals that the protein is an α/β-fold hydrolase. Ser102 interacts with Glu210 and His234 to form a catalytic triad located at the bottom of an open cleft that is large enough to accommodate the thiopeptide framework. |
format | Online Article Text |
id | pubmed-5940322 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-59403222018-05-09 Rerouting the Pathway for the Biosynthesis of the Side Ring System of Nosiheptide: The Roles of NosI, NosJ, and NosK Badding, Edward D. Grove, Tyler L. Gadsby, Lauren K. LaMattina, Joseph W. Boal, Amie K. Booker, Squire J. J Am Chem Soc [Image: see text] Nosiheptide (NOS) is a highly modified thiopeptide antibiotic that displays formidable in vitro activity against a variety of Gram-positive bacteria. In addition to a central hydroxypyridine ring, NOS contains several other modifications, including multiple thiazole rings, dehydro-amino acids, and a 3,4-dimethylindolic acid (DMIA) moiety. The DMIA moiety is required for NOS efficacy and is synthesized from l-tryptophan in a series of reactions that have not been fully elucidated. Herein, we describe the role of NosJ, the product of an unannotated gene in the biosynthetic operon for NOS, as an acyl carrier protein that delivers 3-methylindolic acid (MIA) to NosK. We also reassign the role of NosI as the enzyme responsible for catalyzing the ATP-dependent activation of MIA and MIA’s attachment to the phosphopantetheine moiety of NosJ. Lastly, NosK catalyzes the transfer of the MIA group from NosJ-MIA to a conserved serine residue (Ser102) on NosK. The X-ray crystal structure of NosK, solved to 2.3 Å resolution, reveals that the protein is an α/β-fold hydrolase. Ser102 interacts with Glu210 and His234 to form a catalytic triad located at the bottom of an open cleft that is large enough to accommodate the thiopeptide framework. American Chemical Society 2017-03-27 2017-04-26 /pmc/articles/PMC5940322/ /pubmed/28343381 http://dx.doi.org/10.1021/jacs.7b01497 Text en Copyright © 2017 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Badding, Edward D. Grove, Tyler L. Gadsby, Lauren K. LaMattina, Joseph W. Boal, Amie K. Booker, Squire J. Rerouting the Pathway for the Biosynthesis of the Side Ring System of Nosiheptide: The Roles of NosI, NosJ, and NosK |
title | Rerouting
the Pathway for the Biosynthesis of the
Side Ring System of Nosiheptide: The Roles of NosI, NosJ, and NosK |
title_full | Rerouting
the Pathway for the Biosynthesis of the
Side Ring System of Nosiheptide: The Roles of NosI, NosJ, and NosK |
title_fullStr | Rerouting
the Pathway for the Biosynthesis of the
Side Ring System of Nosiheptide: The Roles of NosI, NosJ, and NosK |
title_full_unstemmed | Rerouting
the Pathway for the Biosynthesis of the
Side Ring System of Nosiheptide: The Roles of NosI, NosJ, and NosK |
title_short | Rerouting
the Pathway for the Biosynthesis of the
Side Ring System of Nosiheptide: The Roles of NosI, NosJ, and NosK |
title_sort | rerouting
the pathway for the biosynthesis of the
side ring system of nosiheptide: the roles of nosi, nosj, and nosk |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940322/ https://www.ncbi.nlm.nih.gov/pubmed/28343381 http://dx.doi.org/10.1021/jacs.7b01497 |
work_keys_str_mv | AT baddingedwardd reroutingthepathwayforthebiosynthesisofthesideringsystemofnosiheptidetherolesofnosinosjandnosk AT grovetylerl reroutingthepathwayforthebiosynthesisofthesideringsystemofnosiheptidetherolesofnosinosjandnosk AT gadsbylaurenk reroutingthepathwayforthebiosynthesisofthesideringsystemofnosiheptidetherolesofnosinosjandnosk AT lamattinajosephw reroutingthepathwayforthebiosynthesisofthesideringsystemofnosiheptidetherolesofnosinosjandnosk AT boalamiek reroutingthepathwayforthebiosynthesisofthesideringsystemofnosiheptidetherolesofnosinosjandnosk AT bookersquirej reroutingthepathwayforthebiosynthesisofthesideringsystemofnosiheptidetherolesofnosinosjandnosk |