Cargando…

Modulating Enzyme Function via Dynamic Allostery within Biliverdin Reductase B

The biliverdin reductase B (BLVRB) class of enzymes catalyze the NADPH-dependent reduction of multiple flavin substrates and are emerging as critical players in cellular redox regulation. However, the role of dynamics and allostery have not been addressed, prompting studies here that have revealed a...

Descripción completa

Detalles Bibliográficos
Autores principales: Redzic, Jasmina S., Duff, Michael R., Blue, Ashley, Pitts, Todd M., Agarwal, Pratul, Eisenmesser, Elan Zohar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173106/
https://www.ncbi.nlm.nih.gov/pubmed/34095235
http://dx.doi.org/10.3389/fmolb.2021.691208
_version_ 1783702655278776320
author Redzic, Jasmina S.
Duff, Michael R.
Blue, Ashley
Pitts, Todd M.
Agarwal, Pratul
Eisenmesser, Elan Zohar
author_facet Redzic, Jasmina S.
Duff, Michael R.
Blue, Ashley
Pitts, Todd M.
Agarwal, Pratul
Eisenmesser, Elan Zohar
author_sort Redzic, Jasmina S.
collection PubMed
description The biliverdin reductase B (BLVRB) class of enzymes catalyze the NADPH-dependent reduction of multiple flavin substrates and are emerging as critical players in cellular redox regulation. However, the role of dynamics and allostery have not been addressed, prompting studies here that have revealed a position 15 Å away from the active site within human BLVRB (T164) that is inherently dynamic and can be mutated to control global micro-millisecond motions and function. By comparing the inherent dynamics through nuclear magnetic resonance (NMR) relaxation approaches of evolutionarily distinct BLVRB homologues and by applying our previously developed Relaxation And Single Site Multiple Mutations (RASSMM) approach that monitors both the functional and dynamic effects of multiple mutations to the single T164 site, we have discovered that the most dramatic mutagenic effects coincide with evolutionary changes and these modulate coenzyme binding. Thus, evolutionarily changing sites distal to the active site serve as dynamic “dials” to globally modulate motions and function. Despite the distal dynamic and functional coupling modulated by this site, micro-millisecond motions span an order of magnitude in their apparent kinetic rates of motions. Thus, global dynamics within BLVRB are a collection of partially coupled motions tied to catalytic function.
format Online
Article
Text
id pubmed-8173106
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-81731062021-06-04 Modulating Enzyme Function via Dynamic Allostery within Biliverdin Reductase B Redzic, Jasmina S. Duff, Michael R. Blue, Ashley Pitts, Todd M. Agarwal, Pratul Eisenmesser, Elan Zohar Front Mol Biosci Molecular Biosciences The biliverdin reductase B (BLVRB) class of enzymes catalyze the NADPH-dependent reduction of multiple flavin substrates and are emerging as critical players in cellular redox regulation. However, the role of dynamics and allostery have not been addressed, prompting studies here that have revealed a position 15 Å away from the active site within human BLVRB (T164) that is inherently dynamic and can be mutated to control global micro-millisecond motions and function. By comparing the inherent dynamics through nuclear magnetic resonance (NMR) relaxation approaches of evolutionarily distinct BLVRB homologues and by applying our previously developed Relaxation And Single Site Multiple Mutations (RASSMM) approach that monitors both the functional and dynamic effects of multiple mutations to the single T164 site, we have discovered that the most dramatic mutagenic effects coincide with evolutionary changes and these modulate coenzyme binding. Thus, evolutionarily changing sites distal to the active site serve as dynamic “dials” to globally modulate motions and function. Despite the distal dynamic and functional coupling modulated by this site, micro-millisecond motions span an order of magnitude in their apparent kinetic rates of motions. Thus, global dynamics within BLVRB are a collection of partially coupled motions tied to catalytic function. Frontiers Media S.A. 2021-05-20 /pmc/articles/PMC8173106/ /pubmed/34095235 http://dx.doi.org/10.3389/fmolb.2021.691208 Text en Copyright © 2021 Redzic, Duff, Blue, Pitts, Agarwal and Eisenmesser. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Redzic, Jasmina S.
Duff, Michael R.
Blue, Ashley
Pitts, Todd M.
Agarwal, Pratul
Eisenmesser, Elan Zohar
Modulating Enzyme Function via Dynamic Allostery within Biliverdin Reductase B
title Modulating Enzyme Function via Dynamic Allostery within Biliverdin Reductase B
title_full Modulating Enzyme Function via Dynamic Allostery within Biliverdin Reductase B
title_fullStr Modulating Enzyme Function via Dynamic Allostery within Biliverdin Reductase B
title_full_unstemmed Modulating Enzyme Function via Dynamic Allostery within Biliverdin Reductase B
title_short Modulating Enzyme Function via Dynamic Allostery within Biliverdin Reductase B
title_sort modulating enzyme function via dynamic allostery within biliverdin reductase b
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173106/
https://www.ncbi.nlm.nih.gov/pubmed/34095235
http://dx.doi.org/10.3389/fmolb.2021.691208
work_keys_str_mv AT redzicjasminas modulatingenzymefunctionviadynamicallosterywithinbiliverdinreductaseb
AT duffmichaelr modulatingenzymefunctionviadynamicallosterywithinbiliverdinreductaseb
AT blueashley modulatingenzymefunctionviadynamicallosterywithinbiliverdinreductaseb
AT pittstoddm modulatingenzymefunctionviadynamicallosterywithinbiliverdinreductaseb
AT agarwalpratul modulatingenzymefunctionviadynamicallosterywithinbiliverdinreductaseb
AT eisenmesserelanzohar modulatingenzymefunctionviadynamicallosterywithinbiliverdinreductaseb