Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Screen for Small-Molecule Modulators of Circadian Rhythms Reveals Phenazine as a Redox-State Modifying Clockwork Tuner.

ABSTRACT: A high-throughput cell-based screen identified redox-active small molecules that produce a period lengthening of the circadian rhythm. The strongest period lengthening phenotype was induced by a phenazine carboxamide (VU661). Comparison to two isomeric benzquinoline carboxamides (VU673 and VU164) shows the activity is associated with the redox modulating phenazine functionality. Furthermore, ex vivo cell analysis using optical redox ratio measurements shows the period lengthening phenotype to be associated with a shift to the NAD/FAD oxidation state of nicotinamide and flavine coenzymes.

SUBMITTER: Kelly KP

PROVIDER: S-EPMC9398883 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Screen for Small-Molecule Modulators of Circadian Rhythms Reveals Phenazine as a Redox-State Modifying Clockwork Tuner.

Kelly Kevin P KP Borsetti Hugo H Wenzler Marta E ME Ustione Alessandro A Kim Kwangho K Christov Plamen P PP Ramirez Bianca B Bauer Joshua A JA Piston David W DW Johnson Carl Hirschie CH Sulikowski Gary A GA

ACS chemical biology 20220609 7

A high-throughput cell-based screen identified redox-active small molecules that produce a period lengthening of the circadian rhythm. The strongest period lengthening phenotype was induced by a phenazine carboxamide (VU661). Comparison to two isomeric benzquinoline carboxamides (VU673 and VU164) shows the activity is associated with the redox modulating phenazine functionality. Furthermore, ex vivo cell analysis using optical redox ratio measurements shows the period lengthening phenotype to be ...[more]

PMID: 35679588

Similar Datasets

Analysis of the redox oscillations in the circadian clockwork.

Project description:The evolution of tight coupling between the circadian system and redox homeostasis of the cell has been proposed to coincide roughly with the appearance of the first aerobic organisms, around 3 billion years ago. The rhythmic production of oxygen and its effect on core metabolism are thought to have exerted selective pressure for the temporal segregation of numerous metabolic pathways. Until recently, the only evidence for such coupling came from studies showing circadian cycles in the abundance of various redox metabolites, with many arguing that these oscillations are simply an output from the transcription-translation feedback loop. The recent discovery that the peroxiredoxin (PRX) proteins exhibit circadian cycles in their oxidation status, even in the absence of transcription, demonstrated the existence of autonomous oscillations in the redox status of the cell. The PRXs are a family of cellular thiol peroxidases, whose abundance and high reaction rate make them the major cellular sink for cellular peroxides. Interestingly, as part of the normal catalytic cycle, PRXs become inactivated by their own substrate via overoxidation of the catalytic residue, with the inactivated form of the enzyme displaying circadian accumulation. Here, we describe the biochemical properties of the PRX system, with particular emphasis on the features important for the experimental analysis of these enzymes. We will also present a detailed protocol for measuring PRX overoxidation across circadian time in adherent cell cultures, red blood cells, and fruit flies (Drosophila melanogaster), providing practical suggestions for ensuring consistency and reproducibility of the results.

| S-EPMC4770518 | biostudies-literature

Identification of pathways that regulate circadian rhythms using a larval zebrafish small molecule screen.

Project description:The circadian clock ensures that behavioral and physiological processes occur at appropriate times during the 24-hour day/night cycle, and is regulated at both the cellular and organismal levels. To identify pathways acting on intact animals, we performed a small molecule screen using a luminescent reporter of molecular circadian rhythms in zebrafish larvae. We identified both known and novel pathways that affect circadian period, amplitude and phase. Several drugs identified in the screen did not affect circadian rhythms in cultured cells derived from luminescent reporter embryos or in established zebrafish and mammalian cell lines, suggesting they act via mechanisms absent in cell culture. Strikingly, using drugs that promote or inhibit inflammation, as well as a mutant that lacks microglia, we found that inflammatory state affects circadian amplitude. These results demonstrate a benefit of performing drug screens using intact animals and provide novel targets for treating circadian rhythm disorders.

| S-EPMC6712016 | biostudies-literature

Rhythmic glucose metabolism regulates the redox circadian clockwork in human red blood cells.

Project description:Circadian clocks coordinate mammalian behavior and physiology enabling organisms to anticipate 24-hour cycles. Transcription-translation feedback loops are thought to drive these clocks in most of mammalian cells. However, red blood cells (RBCs), which do not contain a nucleus, and cannot perform transcription or translation, nonetheless exhibit circadian redox rhythms. Here we show human RBCs display circadian regulation of glucose metabolism, which is required to sustain daily redox oscillations. We found daily rhythms of metabolite levels and flux through glycolysis and the pentose phosphate pathway (PPP). We show that inhibition of critical enzymes in either pathway abolished 24-hour rhythms in metabolic flux and redox oscillations, and determined that metabolic oscillations are necessary for redox rhythmicity. Furthermore, metabolic flux rhythms also occur in nucleated cells, and persist when the core transcriptional circadian clockwork is absent in Bmal1 knockouts. Thus, we propose that rhythmic glucose metabolism is an integral process in circadian rhythms.

| S-EPMC7810875 | biostudies-literature

A cyanobacterial circadian clockwork.

Project description:Cyanobacteria have become a major model system for analyzing circadian rhythms. The temporal program in this organism enhances fitness in rhythmic environments and is truly global--essentially all genes are regulated by the circadian system. The topology of the chromosome also oscillates and possibly regulates the rhythm of gene expression. The underlying circadian mechanism appears to consist of both a post-translational oscillator (PTO) and a transcriptional/translational feedback loop (TTFL). The PTO can be reconstituted in vitro with three purified proteins (KaiA, KaiB, and KaiC) and ATP. These three core oscillator proteins have been crystallized and structurally determined, the only full-length circadian proteins to be so characterized. The timing of cell division is gated by a circadian checkpoint, but the circadian pacemaker is not influenced by the status of the cell division cycle. This imperturbability may be due to the presence of the PTO that persists under conditions in which metabolism is repressed. Recent biochemical, biophysical, and structural discoveries have brought the cyanobacterial circadian system to the brink of explaining heretofore unexplainable biochemical characteristics of a circadian oscillator: the long time constant, precision, and temperature compensation.

| S-EPMC2585598 | biostudies-literature

Recent advances in modulators of circadian rhythms: an update and perspective.

Project description:Circadian rhythm is a universal life phenomenon that plays an important role in maintaining the multiple physiological functions and regulating the adaptability to internal and external environments of flora and fauna. Circadian alignment in humans has the greatest effect on human health, and circadian misalignment is closely associated with increased risk for metabolic syndrome, cardiovascular diseases, neurological diseases, immune diseases, cancer, sleep disorders, and ophthalmic diseases. The recent description of clock proteins and related post-modification targets was involved in several diseases, and numerous lines of evidence are emerging that small molecule modulators of circadian rhythms can be used to rectify circadian disorder. Herein, we attempt to update the disclosures about the modulators targeting core clock proteins and related post-modification targets, as well as the relationship between circadian rhythm disorders and human health as well as the therapeutic role and prospect of these small molecule modulators in circadian rhythm related disease.

| S-EPMC7717701 | biostudies-literature

"Cancersensor": Circadian Rhythms

Project description:Observational, non randomized study aimed at measuring the circadian rhythms in the urinary concentrations of physiological modified nucleosides in 30 patients with metastatic colorectal cancer and in 30 age and sex-matched healthy subjects.

| 2132582 | ecrin-mdr-crc

Coupling allows robust mammalian redox circadian rhythms despite heterogeneity and noise.

Project description:Circadian clocks are endogenous oscillators present in almost all cells that drive daily rhythms in physiology and behavior. There are two mechanisms that have been proposed to explain how circadian rhythms are generated in mammalian cells: through a transcription-translation feedback loop (TTFL) and based on oxidation/reduction reactions, both of which are intrinsically stochastic and heterogeneous at the single cell level. In order to explore the emerging properties of stochastic and heterogeneous redox oscillators, we simplify a recently developed kinetic model of redox oscillations to an amplitude-phase oscillator with 'twist' (period-amplitude correlation) and subject to Gaussian noise. We show that noise and heterogeneity alone lead to fast desynchronization, and that coupling between noisy oscillators can establish robust and synchronized rhythms with amplitude expansions and tuning of the period due to twist. Coupling a network of redox oscillators to a simple model of the TTFL also contributes to synchronization, large amplitudes and fine-tuning of the period for appropriate interaction strengths. These results provide insights into how the circadian clock compensates randomness from intracellular sources and highlight the importance of noise, heterogeneity and coupling in the context of circadian oscillators.

| S-EPMC10835301 | biostudies-literature

A small molecule modulates circadian rhythms through phosphorylation of the period protein.

Project description: Not available

| S-EPMC3755734 | biostudies-literature

The molecular clockwork of a protein-based circadian oscillator.

Project description:The circadian clock of the cyanobacterium Synechococcus elongatus PCC 7942 is governed by a core oscillator consisting of the proteins KaiA, KaiB, and KaiC. Remarkably, circadian oscillations in the phosphorylation state of KaiC can be reconstituted in a test tube by mixing the three Kai proteins and adenosine triphosphate. The in vitro oscillator provides a well-defined system in which experiments can be combined with mathematical analysis to understand the mechanism of a highly robust biological oscillator. In this Review, we summarize the biochemistry of the Kai proteins and examine models that have been proposed to explain how oscillations emerge from the properties of the oscillator's constituents.

| S-EPMC2810098 | biostudies-literature

Elucidating the ticking of an in vitro circadian clockwork.

Project description:A biochemical oscillator can be reconstituted in vitro with three purified proteins, that displays the salient properties of circadian (daily) rhythms, including self-sustained 24-h periodicity that is temperature compensated. We analyze the biochemical basis of this oscillator by quantifying the time-dependent interactions of the three proteins (KaiA, KaiB, and KaiC) by electron microscopy and native gel electrophoresis to elucidate the timing of the formation of complexes among the Kai proteins. The data are used to derive a dynamic model for the in vitro oscillator that accurately reproduces the rhythms of KaiABC complexes and of KaiC phosphorylation, and is consistent with biophysical observations of individual Kai protein interactions. We use fluorescence resonance energy transfer (FRET) to confirm that monomer exchange among KaiC hexamers occurs. The model demonstrates that the function of this monomer exchange may be to maintain synchrony among the KaiC hexamers in the reaction, thereby sustaining a high-amplitude oscillation. Finally, we apply the first perturbation analyses of an in vitro oscillator by using temperature pulses to reset the phase of the KaiABC oscillator, thereby testing the resetting characteristics of this unique circadian oscillator. This study analyzes a circadian clockwork to an unprecedented level of molecular detail.

| S-EPMC1831719 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data