scholarly journals A widely distributed metalloenzyme class enables gut microbial metabolism of host- and diet-derived catechols

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Vayu Maini Rekdal ◽  
Paola Nol Bernadino ◽  
Michael U Luescher ◽  
Sina Kiamehr ◽  
Chip Le ◽  
...  
Keyword(s):  
Small Molecules ◽  
Electron Acceptor ◽  
Molecular Basis ◽  
Distinct Group ◽  
Microbial Metabolism ◽  
Human Gut ◽  
Primary And Secondary Metabolism ◽  
Gut Microorganisms ◽  
Chemical Strategies ◽  
Mediate Metabolism

Catechol dehydroxylation is a central chemical transformation in the gut microbial metabolism of plant- and host-derived small molecules. However, the molecular basis for this transformation and its distribution among gut microorganisms are poorly understood. Here, we characterize a molybdenum-dependent enzyme from the human gut bacterium Eggerthella lenta that dehydroxylates catecholamine neurotransmitters. Our findings suggest that this activity enables E. lenta to use dopamine as an electron acceptor. We also identify candidate dehydroxylases that metabolize additional host- and plant-derived catechols. These dehydroxylases belong to a distinct group of largely uncharacterized molybdenum-dependent enzymes that likely mediate primary and secondary metabolism in multiple environments. Finally, we observe catechol dehydroxylation in the gut microbiotas of diverse mammals, confirming the presence of this chemistry in habitats beyond the human gut. These results suggest that the chemical strategies that mediate metabolism and interactions in the human gut are relevant to a broad range of species and habitats.

scholarly journals A widely distributed metalloenzyme class enables gut microbial metabolism of host- and diet-derived catechols

2019 ◽  
Author(s):  
Vayu Maini Rekdal ◽  
Paola Nol Bernardino ◽  
Michael U. Luescher ◽  
Sina Kiamehr ◽  
Peter J. Turnbaugh ◽  
...  
Keyword(s):  
Small Molecules ◽  
Molecular Basis ◽  
Distinct Group ◽  
Microbial Metabolism ◽  
Anaerobic Conditions ◽  
Human Gut ◽  
Primary And Secondary Metabolism ◽  
Gut Microorganisms ◽  
Chemical Strategies ◽  
Mediate Metabolism

AbstractCatechol dehydroxylation is a central chemical transformation in the gut microbial metabolism of plant- and host-derived small molecules. However, the molecular basis for this transformation and its distribution among gut microorganisms are poorly understood. Here, we characterize a molybdenum-dependent enzyme from the prevalent human gut bacteriumEggerthella lentathat specifically dehydroxylates catecholamine neurotransmitters available in the human gut. Our findings suggest that this activity enablesE. lentato use dopamine as an electron acceptor under anaerobic conditions. In addition to characterizing catecholamine dehydroxylation, we identify candidate molybdenum-dependent enzymes that dehydroxylate additional host-and plant-derived small molecules. These gut bacterial catechol dehydroxylases are specific in their substrate scope and transcriptional regulation and belong to a distinct group of largely uncharacterized molybdenum-dependent enzymes that likely mediate both primary and secondary metabolism in multiple environments. Finally, we observe catechol dehydroxylation in the gut microbiotas of diverse mammals, suggesting that this chemistry is present in habitats beyond the human gut. Altogether, our data reveal the molecular basis of catechol dehydroxylation among gut bacteria and suggest that the chemical strategies that mediate metabolism and interactions in the human gut are relevant to a broad range of species and habitats.

scholarly journals Bioactive small molecules produced by the human gut microbiome modulate Vibrio cholerae sessile and planktonic lifestyles

Gut Microbes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 1-19
Author(s):  
Heidi Pauer ◽  
Felipe Lopes Teixeira ◽  
Avery V. Robinson ◽  
Thiago E. Parente ◽  
Marília A. F. De Melo ◽  
...  
Keyword(s):  
Small Molecules ◽  
Vibrio Cholerae ◽  
Gut Microbiome ◽  
Human Gut ◽  
Human Gut Microbiome

Computational Prediction of a New ADMET Endpoint for Small Molecules: Anticommensal Effect on Human Gut Microbiota

2018 ◽  
Vol 59 (3) ◽  
pp. 1215-1220 ◽  
Author(s):  
Suqing Zheng ◽  
Wenping Chang ◽  
Wenxin Liu ◽  
Guang Liang ◽  
Yong Xu ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Small Molecules ◽  
Computational Prediction ◽  
Human Gut ◽  
Human Gut Microbiota

scholarly journals How does the mood stabilizer lithium bind ATP, the energy currency of the cell

2019 ◽  
Author(s):  
A. Haimovich ◽  
A. Goldbourt
Keyword(s):  
Small Molecules ◽  
Solid State Nmr ◽  
Molecular Basis ◽  
Mood Stabilizer ◽  
Sodium Ions ◽  
Lithium Ions ◽  
Cellular Targets ◽  
Biochemical Pathways ◽  
Narrow Therapeutic Range ◽  
Fourth Coordination

AbstractLithium, in the form of a salt, is a mood stabilizer and a leading drug for the treatment of bipolar disorder. It has a very narrow therapeutic range and a variety of side effects. Lithium can replace magnesium and other cations in enzymes and small molecules, among them ATP, thereby affecting and inhibiting many biochemical pathways. The form of binding of lithium ions to ATP is not known.Here we extract the binding environment of lithium in solid ATP using a multi-nuclear multi-dimensional solid-state NMR approach.We determine that the coordination sphere of lithium includes, at a distance of 3.0(±0.4) Å, three phosphates; the two phosphates closest to the ribose ring from one ATP molecule, and the middle phosphate from another ATP molecule. A water molecule most probably completes the fourth coordination. Despite the use of excess lithium in the preparations, sodium ions still remain bound to the sample, at distances of 4.3-5.5 Å from Li, and coordinate the first phosphate and two terminal phosphates.In conclusion, solid-state NMR enables to unravel the exact coordination of lithium in ATP showing binding to three phosphates from two molecules, none of which are the terminal gamma phosphate. The methods we use are applicable to study lithium bound to a variety of ATP-bound enzymes, or to other cellular targets of lithium, consequently suggesting a molecular basis for its mode of action.

scholarly journals Antivirulence Activity of the Human Gut Metabolome

mBio ◽  
2014 ◽  
Vol 5 (4) ◽  
Author(s):  
L. Caetano M. Antunes ◽  
Julie A. K. McDonald ◽  
Kathleen Schroeter ◽  
Christian Carlucci ◽  
Rosana B. R. Ferreira ◽  
...  
Keyword(s):  
Small Molecules ◽  
Chemical Cues ◽  
Therapeutic Potential ◽  
Host Cells ◽  
Human Gut ◽  
Complex Ecosystem ◽  
Microbe Interactions ◽  
Health And Disease ◽  
Host Microbe Interactions

ABSTRACTThe mammalian gut contains a complex assembly of commensal microbes termed microbiota. Although much has been learned about the role of these microbes in health, the mechanisms underlying these functions are ill defined. We have recently shown that the mammalian gut contains thousands of small molecules, most of which are currently unidentified. Therefore, we hypothesized that these molecules function as chemical cues used by hosts and microbes during their interactions in health and disease. Thus, a search was initiated to identify molecules produced by the microbiota that are sensed by pathogens. We found that a secreted molecule produced by clostridia acts as a strong repressor ofSalmonellavirulence, obliterating expression of theSalmonellapathogenicity island 1 as well as host cell invasion. It has been known for decades that the microbiota protects its hosts from invading pathogens, and these data suggest that chemical sensing may be involved in this phenomenon. Further investigations should reveal the exact biological role of this molecule as well as its therapeutic potential.IMPORTANCEMicrobes can communicate through the production and sensing of small molecules. Within the complex ecosystem formed by commensal microbes living in and on the human body, it is likely that these molecular messages are used extensively during the interactions between different microbial species as well as with host cells. Deciphering such a molecular dialect will be fundamental to our understanding of host-microbe interactions in health and disease and may prove useful for the design of new therapeutic strategies that target these mechanisms of communication.

scholarly journals Repression of Salmonella Host Cell Invasion by Aromatic Small Molecules from the Human Fecal Metabolome

2017 ◽  
Vol 83 (19) ◽  
Author(s):  
Rafael J. M. Peixoto ◽  
Eduardo S. Alves ◽  
Melody Wang ◽  
Rosana B. R. Ferreira ◽  
Alessandra Granato ◽  
...  
Keyword(s):  
Biological Activity ◽  
Small Molecules ◽  
Host Cell ◽  
Small Molecule ◽  
Cell Invasion ◽  
Salmonella Enterica ◽  
Chemical Diversity ◽  
Host Cell Invasion ◽  
Human Gut ◽  
Content Type

ABSTRACT The human microbiome is a collection of microorganisms that inhabit every surface of the body that is exposed to the environment, generally coexisting peacefully with their host. These microbes have important functions, such as producing vitamins, aiding in maturation of the immune system, and protecting against pathogens. We have previously shown that a small-molecule extract from the human fecal microbiome has a strong repressive effect on Salmonella enterica serovar Typhimurium host cell invasion by modulating the expression of genes involved in this process. Here, we describe the characterization of this biological activity. Using a series of purification methods, we obtained fractions with biological activity and characterized them by mass spectrometry. These experiments revealed an abundance of aromatic compounds in the bioactive fraction. Selected compounds were obtained from commercial sources and tested with respect to their ability to repress the expression of hilA, the gene encoding the master regulator of invasion genes in Salmonella. We found that the aromatic compound 3,4-dimethylbenzoic acid acts as a strong inhibitor of hilA expression and of invasion of cultured host cells by Salmonella. Future studies should reveal the molecular details of this phenomenon, such as the signaling cascades involved in sensing this bioactive molecule. IMPORTANCE Microbes constantly sense and adapt to their environment. Often, this is achieved through the production and sensing of small extracellular molecules. The human body is colonized by complex communities of microbes, and, given their biological and chemical diversity, these ecosystems represent a platform where the production and sensing of molecules occur. In previous work, we showed that small molecules produced by microbes from the human gut can significantly impair the virulence of the enteric pathogen Salmonella enterica. Here, we describe a specific compound from the human gut that produces this same effect. The results from this work not only shed light on an important biological phenomenon occurring in our bodies but also may represent an opportunity to develop drugs that can target these small-molecule interactions to protect us from enteric infections and other diseases.

scholarly journals A Molecular Basis for Reciprocal Regulation between Pheromones and Hormones in Response to Dietary Cues in C. elegans

2020 ◽  
Vol 21 (7) ◽  
pp. 2366
Author(s):  
Saeram Park ◽  
Jun Young Park ◽  
Young-Ki Paik
Keyword(s):  
Gene Expression ◽  
Small Molecules ◽  
Molecular Basis ◽  
Biosynthetic Gene ◽  
Reciprocal Regulation ◽  
C Elegans ◽  
Aging Period ◽  
Transcriptional Regulatory ◽  
Dietary Cues ◽  
Development And Aging

Under stressful conditions, the early larvae of C. elegans enter dauer diapause, a non-aging period, driven by the seemingly opposite influence of ascaroside pheromones (ASCRs) and steroid hormone dafachronic acids (DAs). However, the molecular basis of how these small molecules engage in competitive crosstalk in coordination with insulin/IGF-1 signaling (IIS) remains elusive. Here we report a novel transcriptional regulatory pathway that seems to operate between the ASCR and DA biosynthesis under ad libitum (AL) feeding conditions or bacterial deprivation (BD). Although expression of the ASCR and DA biosynthetic genes reciprocally inhibit each other, ironically and interestingly, such dietary cue-mediated modulation requires the presence of the competitors. Under BD, induction of ASCR biosynthetic gene expression required DA, while ASCR suppresses the expression of the DA biosynthetic gene daf-36. The negative regulation of DA by ASCR was IIS-dependent, whereas daf-36 regulation appeared to be independent of IIS. These observations suggest that the presence of ASCR determines the IIS-dependency of DA gene expression regardless of dietary conditions. Thus, our work defines a molecular basis for a novel reciprocal gene regulation of pheromones and hormones to cope with stressful conditions during development and aging.

Benzothiadiazole building units in solution-processable small molecules for organic photovoltaics

2016 ◽  
Vol 4 (41) ◽  
pp. 15771-15787 ◽  
Author(s):  
Jia Du ◽  
Michael C. Biewer ◽  
Mihaela C. Stefan
Keyword(s):  
Small Molecules ◽  
Electron Acceptor ◽  
Organic Photovoltaics ◽  
Photovoltaic Performance ◽  
Optoelectronic Properties ◽  
Recent Advances ◽  
Solution Processable ◽  
Molecular Semiconductors ◽  
The Relationship

This review attempts to summarize recent advances with respect to solution-processable molecular semiconductors having 2,1,3-benzothiadiazole or its fluorine substituted derivatives as electron-acceptor units published in the last few years. The relationship between the structure, optoelectronic properties, and photovoltaic performance of these molecular semiconductors is discussed.

Sign in / Sign up

Export Citation Format

Share Document