The Metabolome

Agenda

Abstracts

Untargeted Plasma Metabolite Profiling for Discovery of Molecular Derangements that Result from Gene Mutations and Drug Treatments

Steven Gross, Weill Cornell Medical College

Untargeted metabolite profiling has enormous potential for the diagnosis of conditions that arise from defects in metabolism. Studies will be presented that describe the efficacy of plasma metabolite profiling for discovery of metabolic defects using a mouse model system and analysis of plasma from human babies with rare inborn errors of metabolism. In mice, we evaluated the capability of LC/MS-based metabolite profiling platform to broadly survey the plasma metabolome and discover a defect in purine metabolism that results when xanthine oxidoreductase (XOR) is inactivated, either by gene ablation or pharmacological inhibition with allopurinol. This approach allowed us to confidently survey >3,700 distinct plasma molecules using <5 µl of blood and confidently recognize those which change>2-fold (up or down) when XOR activity is attenuated. Molecular identification of the major differentially-expressed features was established from determinations of accurate mass, isotope ratios, chromatographic retention times and/or fragmentation patterns, relative to standards. Remarkably, knockdown of XOR activity (both genetically and pharmacologically) was associated with the discovery of all predicted major changes in purine metabolism, as well as numerous unanticipated changes. The unanticipated changes highlight unappreciated metabolic links involving XOR. In studies of plasma from several human babies with rare inborn errors of metabolism, untargeted metabolite profiling was similarly able to confidently identify metabolite perturbations and infer responsible gene mutations. These findings affirm the power of untargeted metabolite profiling as an unprecedented tool for diagnosis of pathophysiological conditions that arise from gene defects and drug actions.

Therapeutic Metabolomics Identifies Novel Treatments for Multiple Sclerosis and Chronic Pain

Gary Siuzdak, The Scripps Research Institute

Quantitative global analysis of endogenous metabolites from cells, tissues, fluids or whole organisms - metabolomics, is becoming an integral part of functional genomics efforts as well as a tool for understanding fundamental biochemistry. Where the genome and proteome is largely enabled by the predictable fragmentation pattern of peptides, metabolomics is complicated by the tremendous chemical diversity of metabolites. The experimental aim in our studies is to obtain a comprehensive quantitative with an unbiased quantitative view of the metabolome. We have explored multiple novel mass spectrometry platforms for metabolomics including both solution-based approaches and surface-based mass spectrometry, such as nanostructure-initiator mass spectrometry (NIMS) for tissue imaging. These platforms will also be presented in the context of its application to discovering new disease therapies for chronic pain and multiple sclerosis.

Metabolite Profiling for Personalized Medicine

Rima Kaddurah-Daouk, Duke University Medical Center

The "Metabolomics Network for Drug Response Phenotype" is a national network funded by NIH with a mission to integrate metabolomics in clinical pharmacology and pharmacogenomics research to achieve a deeper understanding of mechanisms implicated in drug-response variation towards a more personalized approach to therapy. We are testing the hypothesis that application of metabolomics analyses and the inclusion of metabolomics data would significantly enhance pharmacogenomic research by providing broad-based, biochemically precise phenotypes capable of supplementing and extending the clinical phenotypes currently used as pharmacogenomic “endpoints”. In addition, metabolomic “signatures” present in patients who do and do not respond to drug therapy, i.e., signatures that reflect the drug response phenotype, could lead to mechanistic hypotheses that would provide insight into the underlying basis for individual variation in drug response. We will exemplify approaches we are taking and early findings from the study of statins and SSRIs classes of therapies.

Viral Hijacking of Host Cell Metabolism

Joshua Rabinowitz, Princeton University

Viruses rely on the metabolic network of their cellular hosts to provide energy and building blocks for viral replication. We used liquid chromatography-mass spectrometry to quantitate metabolite concentration and flux changes induced by viral infections. The flux measurement approach relies on monitoring metabolome labeling kinetics after feeding cells (13)C-labeled forms of glucose and glutamine. For influenza A and herpes simplex virus (HSV), the most profound metabolic alterations occur in pathways that are the targets of current antiviral therapies: neuraminidase for influenza A and thymidine biosynthesis for HSV. In contrast, for human cytomegalovirus (HCMV), flux increases are broad based and include a particularly notable increase in flux through the tricarboxylic acid cycle and its efflux to the fatty acid biosynthesis pathway. Pharmacological inhibition of fatty acid biosynthesis suppresses the replication of HCMV. Intriguingly, it also blocks influenza A replication. These results show that systems-level metabolic flux profiling can identify metabolic targets for antiviral therapy.

Mining the Microbial Metabolome: Metabolomics-based Approaches to Infectious Diseases

Kyu Rhee, Weill Cornell Medical College and New York Presbyterian Hospital

Mtb is the causative agent of tuberculosis (TB), the leading bacterial cause of deaths worldwide. Among bacterial pathogens, Mtb is unique in that it resides in humans as its only known natural host and reservoir. Mtb has thus evolved to survive within a niche committed to its eradication. Prominent among Mtb’s adaptations to its singular niche are those pertaining to central carbon metabolism. Carbon metabolism has thus emerged as a major determinant of Mtb’s pathogenicity. Biochemical knowledge of Mtb carbon metabolism nonetheless remains scant. Here, we present the first metabolomic descriptions of Mtb’s central carbon metabolism and demonstrate the potential for metabolomics-based approaches to expand knowledge of its pathogenicity.

Metabolite Profiling for Discovery of Cancer Biomarkers

Chris Beecher, University of Michigan Medical School

The discovery of biochemical markers for diseases as complex as cancer has been hinted at since 1924 when Warburg discussed the metabolic abnormalities of cancer metabolism, and yet no significant small molecule biomarkers of cancer are currently used as diagnostic biomarkers. In a recent metabolomic investigation of Prostate cancer we have identified the compound sarcosine as both a key mechanistic component in, and significant biomarker for, the progression of cancer to a metastatic state. This Metabolomic study and its biochemical outcomes will be discussed.

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