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Journal of the American Society For... Dec 2016Metabolites are building blocks of cellular function. These species are involved in enzyme-catalyzed chemical reactions and are essential for cellular function. Upstream... (Review)
Review
Metabolites are building blocks of cellular function. These species are involved in enzyme-catalyzed chemical reactions and are essential for cellular function. Upstream biological disruptions result in a series of metabolomic changes and, as such, the metabolome holds a wealth of information that is thought to be most predictive of phenotype. Uncovering this knowledge is a work in progress. The field of metabolomics is still maturing; the community has leveraged proteomics experience when applicable and developed a range of sample preparation and instrument methodology along with myriad data processing and analysis approaches. Research focuses have now shifted toward a fundamental understanding of the biology responsible for metabolomic changes. There are several types of metabolomics experiments including both targeted and untargeted analyses. While untargeted, hypothesis generating workflows exhibit many valuable attributes, challenges inherent to the approach remain. This Critical Insight comments on these challenges, focusing on the identification process of LC-MS-based untargeted metabolomics studies-specifically in mammalian systems. Biological interpretation of metabolomics data hinges on the ability to accurately identify metabolites. The range of confidence associated with identifications that is often overlooked is reviewed, and opportunities for advancing the metabolomics field are described. Graphical Abstract ᅟ.
Topics: Animals; Chromatography, Liquid; Metabolome; Metabolomics; Tandem Mass Spectrometry
PubMed: 27624161
DOI: 10.1007/s13361-016-1469-y -
Cell May 2018Great strides have been made over the past decade toward comprehensive study of metabolism. Mass spectrometry (MS) has played a central role by enabling measurement of... (Review)
Review
Great strides have been made over the past decade toward comprehensive study of metabolism. Mass spectrometry (MS) has played a central role by enabling measurement of many metabolites simultaneously. Tracking metabolite labeling from stable isotope tracers can in addition reveal pathway activities. Here, we describe the basics of metabolite measurement by MS, including sample preparation, metabolomic analysis, and data interpretation. In addition, drawing on examples of successful experiments, we highlight the ways in which metabolomics and isotope tracing can illuminate biology.
Topics: Chromatography, High Pressure Liquid; Glycolysis; Humans; Isotope Labeling; Mass Spectrometry; Metabolome; Metabolomics; Mitochondria; Principal Component Analysis
PubMed: 29727671
DOI: 10.1016/j.cell.2018.03.055 -
Nature Reviews. Molecular Cell Biology Jul 2016Metabolomics, which is the profiling of metabolites in biofluids, cells and tissues, is routinely applied as a tool for biomarker discovery. Owing to innovative...
Metabolomics, which is the profiling of metabolites in biofluids, cells and tissues, is routinely applied as a tool for biomarker discovery. Owing to innovative developments in informatics and analytical technologies, and the integration of orthogonal biological approaches, it is now possible to expand metabolomic analyses to understand the systems-level effects of metabolites. Moreover, because of the inherent sensitivity of metabolomics, subtle alterations in biological pathways can be detected to provide insight into the mechanisms that underlie various physiological conditions and aberrant processes, including diseases.
Topics: Animals; Biomarkers; Humans; Metabolic Networks and Pathways; Metabolome; Metabolomics; Systems Biology
PubMed: 26979502
DOI: 10.1038/nrm.2016.25 -
Nature Reviews. Microbiology Mar 2022Microbiotas are a malleable part of ecosystems, including the human ecosystem. Microorganisms affect not only the chemistry of their specific niche, such as the human... (Review)
Review
Microbiotas are a malleable part of ecosystems, including the human ecosystem. Microorganisms affect not only the chemistry of their specific niche, such as the human gut, but also the chemistry of distant environments, such as other parts of the body. Mass spectrometry-based metabolomics is one of the key technologies to detect and identify the small molecules produced by the human microbiota, and to understand the functional role of these microbial metabolites. This Review provides a foundational introduction to common forms of untargeted mass spectrometry and the types of data that can be obtained in the context of microbiome analysis. Data analysis remains an obstacle; therefore, the emphasis is placed on data analysis approaches and integrative analysis, including the integration of microbiome sequencing data.
Topics: Animals; Humans; Mass Spectrometry; Metabolome; Metabolomics; Microbiota
PubMed: 34552265
DOI: 10.1038/s41579-021-00621-9 -
Nature Reviews. Molecular Cell Biology Jun 2019The metabolome, the collection of small-molecule chemical entities involved in metabolism, has traditionally been studied with the aim of identifying biomarkers in the... (Review)
Review
The metabolome, the collection of small-molecule chemical entities involved in metabolism, has traditionally been studied with the aim of identifying biomarkers in the diagnosis and prediction of disease. However, the value of metabolome analysis (metabolomics) has been redefined from a simple biomarker identification tool to a technology for the discovery of active drivers of biological processes. It is now clear that the metabolome affects cellular physiology through modulation of other 'omics' levels, including the genome, epigenome, transcriptome and proteome. In this Review, we focus on recent progress in using metabolomics to understand how the metabolome influences other omics and, by extension, to reveal the active role of metabolites in physiology and disease. This concept of utilizing metabolomics to perform activity screens to identify biologically active metabolites - which we term activity metabolomics - is already having a broad impact on biology.
Topics: Animals; Biomarkers; Humans; Metabolome; Metabolomics
PubMed: 30814649
DOI: 10.1038/s41580-019-0108-4 -
Current Protocols in Molecular Biology Apr 2012The metabolome is the terminal downstream product of the genome and consists of the total complement of all the low-molecular-weight molecules (metabolites) in a cell,...
The metabolome is the terminal downstream product of the genome and consists of the total complement of all the low-molecular-weight molecules (metabolites) in a cell, tissue, or organism. Metabolomics aims to measure a wide breadth of small molecules in the context of physiological stimuli or disease states. Metabolomics methodologies fall into two distinct groups: untargeted metabolomics, an intended comprehensive analysis of all the measurable analytes in a sample including chemical unknowns, and targeted metabolomics, the measurement of defined groups of chemically characterized and biochemically annotated metabolites. The methodologies considered in this unit focus on the processes of conducting targeted metabolomics experiments, and the advantages of this general approach are highlighted herein. This unit outlines procedures for extracting nitrogenous metabolites (including amino acids), lipids, and intermediary metabolites (including TCA cycle oxoacids) from blood plasma. Specifically, protocols are described for analyzing these metabolites using targeted metabolomics experiments based on liquid chromatography-mass spectrometry.
Topics: Animals; Chromatography, Liquid; Humans; Mass Spectrometry; Metabolome; Metabolomics; Plasma
PubMed: 22470063
DOI: 10.1002/0471142727.mb3002s98 -
Signal Transduction and Targeted Therapy Mar 2023Metabolic abnormalities lead to the dysfunction of metabolic pathways and metabolite accumulation or deficiency which is well-recognized hallmarks of diseases.... (Review)
Review
Metabolic abnormalities lead to the dysfunction of metabolic pathways and metabolite accumulation or deficiency which is well-recognized hallmarks of diseases. Metabolite signatures that have close proximity to subject's phenotypic informative dimension, are useful for predicting diagnosis and prognosis of diseases as well as monitoring treatments. The lack of early biomarkers could lead to poor diagnosis and serious outcomes. Therefore, noninvasive diagnosis and monitoring methods with high specificity and selectivity are desperately needed. Small molecule metabolites-based metabolomics has become a specialized tool for metabolic biomarker and pathway analysis, for revealing possible mechanisms of human various diseases and deciphering therapeutic potentials. It could help identify functional biomarkers related to phenotypic variation and delineate biochemical pathways changes as early indicators of pathological dysfunction and damage prior to disease development. Recently, scientists have established a large number of metabolic profiles to reveal the underlying mechanisms and metabolic networks for therapeutic target exploration in biomedicine. This review summarized the metabolic analysis on the potential value of small-molecule candidate metabolites as biomarkers with clinical events, which may lead to better diagnosis, prognosis, drug screening and treatment. We also discuss challenges that need to be addressed to fuel the next wave of breakthroughs.
Topics: Humans; Biomarkers; Metabolomics; Metabolome; Metabolic Networks and Pathways
PubMed: 36941259
DOI: 10.1038/s41392-023-01399-3 -
Nucleic Acids Research Jan 2022The Human Metabolome Database or HMDB (https://hmdb.ca) has been providing comprehensive reference information about human metabolites and their associated biological,...
The Human Metabolome Database or HMDB (https://hmdb.ca) has been providing comprehensive reference information about human metabolites and their associated biological, physiological and chemical properties since 2007. Over the past 15 years, the HMDB has grown and evolved significantly to meet the needs of the metabolomics community and respond to continuing changes in internet and computing technology. This year's update, HMDB 5.0, brings a number of important improvements and upgrades to the database. These should make the HMDB more useful and more appealing to a larger cross-section of users. In particular, these improvements include: (i) a significant increase in the number of metabolite entries (from 114 100 to 217 920 compounds); (ii) enhancements to the quality and depth of metabolite descriptions; (iii) the addition of new structure, spectral and pathway visualization tools; (iv) the inclusion of many new and much more accurately predicted spectral data sets, including predicted NMR spectra, more accurately predicted MS spectra, predicted retention indices and predicted collision cross section data and (v) enhancements to the HMDB's search functions to facilitate better compound identification. Many other minor improvements and updates to the content, the interface, and general performance of the HMDB website have also been made. Overall, we believe these upgrades and updates should greatly enhance the HMDB's ease of use and its potential applications not only in human metabolomics but also in exposomics, lipidomics, nutritional science, biochemistry and clinical chemistry.
Topics: Databases, Genetic; Humans; Lipidomics; Mass Spectrometry; Metabolome; Metabolomics; User-Computer Interface
PubMed: 34986597
DOI: 10.1093/nar/gkab1062 -
Journal of Cachexia, Sarcopenia and... Feb 2018Cachexia is a multifactorial metabolic syndrome with high morbidity and mortality in patients with advanced cancer. The diagnosis of cancer cachexia depends on objective...
BACKGROUND
Cachexia is a multifactorial metabolic syndrome with high morbidity and mortality in patients with advanced cancer. The diagnosis of cancer cachexia depends on objective measures of clinical symptoms and a history of weight loss, which lag behind disease progression and have limited utility for the early diagnosis of cancer cachexia. In this study, we performed a nuclear magnetic resonance-based metabolomics analysis to reveal the metabolic profile of cancer cachexia and establish a diagnostic model.
METHODS
Eighty-four cancer cachexia patients, 33 pre-cachectic patients, 105 weight-stable cancer patients, and 74 healthy controls were included in the training and validation sets. Comparative analysis was used to elucidate the distinct metabolites of cancer cachexia, while metabolic pathway analysis was employed to elucidate reprogramming pathways. Random forest, logistic regression, and receiver operating characteristic analyses were used to select and validate the biomarker metabolites and establish a diagnostic model.
RESULTS
Forty-six cancer cachexia patients, 22 pre-cachectic patients, 68 weight-stable cancer patients, and 48 healthy controls were included in the training set, and 38 cancer cachexia patients, 11 pre-cachectic patients, 37 weight-stable cancer patients, and 26 healthy controls were included in the validation set. All four groups were age-matched and sex-matched in the training set. Metabolomics analysis showed a clear separation of the four groups. Overall, 45 metabolites and 18 metabolic pathways were associated with cancer cachexia. Using random forest analysis, 15 of these metabolites were identified as highly discriminating between disease states. Logistic regression and receiver operating characteristic analyses were used to create a distinct diagnostic model with an area under the curve of 0.991 based on three metabolites. The diagnostic equation was Logit(P) = -400.53 - 481.88 × log(Carnosine) -239.02 × log(Leucine) + 383.92 × log(Phenyl acetate), and the result showed 94.64% accuracy in the validation set.
CONCLUSIONS
This metabolomics study revealed a distinct metabolic profile of cancer cachexia and established and validated a diagnostic model. This research provided a feasible diagnostic tool for identifying at-risk populations through the detection of serum metabolites.
Topics: Aged; Cachexia; Female; Humans; Male; Metabolome; Metabolomics; Middle Aged; Neoplasms; Prognosis
PubMed: 29152916
DOI: 10.1002/jcsm.12246 -
Cell Jun 2020Metabolism during pregnancy is a dynamic and precisely programmed process, the failure of which can bring devastating consequences to the mother and fetus. To define a...
Metabolism during pregnancy is a dynamic and precisely programmed process, the failure of which can bring devastating consequences to the mother and fetus. To define a high-resolution temporal profile of metabolites during healthy pregnancy, we analyzed the untargeted metabolome of 784 weekly blood samples from 30 pregnant women. Broad changes and a highly choreographed profile were revealed: 4,995 metabolic features (of 9,651 total), 460 annotated compounds (of 687 total), and 34 human metabolic pathways (of 48 total) were significantly changed during pregnancy. Using linear models, we built a metabolic clock with five metabolites that time gestational age in high accordance with ultrasound (R = 0.92). Furthermore, two to three metabolites can identify when labor occurs (time to delivery within two, four, and eight weeks, AUROC ≥ 0.85). Our study represents a weekly characterization of the human pregnancy metabolome, providing a high-resolution landscape for understanding pregnancy with potential clinical utilities.
Topics: Adult; Biomarkers; Female; Fetus; Gestational Age; Humans; Metabolic Networks and Pathways; Metabolome; Metabolomics; Pregnancy; Pregnant Women
PubMed: 32589958
DOI: 10.1016/j.cell.2020.05.002