Most diseases result in metabolic changes. In many cases, these changes play a causative role in disease progression. By identifying pathological metabolic changes, metabolomics can point to potential new sites for therapeutic intervention. Particularly promising enzymatic targets are those that carry increased flux in the disease state. Definitive assessment of flux requires the use of isotope tracers. Here we present techniques for finding new drug targets using metabolomics and isotope tracers. The utility of these methods is exemplified in the study of three different viral pathogens. For influenza A and herpes simplex virus, metabolomic analysis of infected versus mock-infected cells revealed dramatic concentration changes around the current antiviral target enzymes. Similar analysis of human-cytomegalovirus-infected cells, however, found the greatest changes in a region of metabolism unrelated to the current antiviral target. Instead, it pointed to the tricarboxylic acid (TCA) cycle and its efflux to feed fatty acid biosynthesis as a potential preferred target. Isotope tracer studies revealed that cytomegalovirus greatly increases flux through the key fatty acid metabolic enzyme acetyl-coenzyme A carboxylase. Inhibition of this enzyme blocks human cytomegalovirus replication. Examples where metabolomics has contributed to identification of anticancer drug targets are also discussed. Eventual proof of the value of metabolomics as a drug target discovery strategy will be successful clinical development of therapeutics hitting these new targets.
"Interestingly, both PYC and ACC require biotin as cofactor, with this vitamin donating a carboxyl anion to the very specific organic acid substrate  . There is limited information on PYC in the metabolomics literature, but ACC has been the subject of more metabolic research due to it potentially serving as an antibiotic drug target, which Rabinowitz and coworkers  illustrated using isotope tracer metabolites and a metabolomics research approach. Additional metabolomics-related approaches by de Carvalho et al.  pertaining to these genes associated with fatty acids revealed compartmentalized cocatabolism of carbon substrates in M. tuberculosis and a description of how various carbohydrates and fatty acids can be channeled simultaneously to their respective metabolic fates. "
[Show abstract][Hide abstract] ABSTRACT: Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a fatal infectious disease, resulting in 1.4 million deaths globally per annum. Over the past three decades, genomic studies have been conducted in an attempt to elucidate the functionality of the genome of the pathogen. However, many aspects of this complex genome remain largely unexplored, as approaches like genomics, proteomics, and transcriptomics have failed to characterize them successfully. In turn, metabolomics, which is relatively new to the "omics" revolution, has shown great potential for investigating biological systems or their modifications. Furthermore, when these data are interpreted in combination with previously acquired genomics, proteomics and transcriptomics data, using what is termed a systems biology approach, a more holistic understanding of these systems can be achieved. In this review we discuss how metabolomics has contributed so far to characterizing TB, with emphasis on the resulting improved elucidation of M. tuberculosis in terms of (1) metabolism, (2) growth and replication, (3) pathogenicity, and (4) drug resistance, from the perspective of systems biology.
[Show abstract][Hide abstract] ABSTRACT: Metabolites, the chemical entities that are transformed during metabolism, provide a functional readout of cellular biochemistry. With emerging technologies in mass spectrometry, thousands of metabolites can now be quantitatively measured from minimal amounts of biological material, which has thereby enabled systems-level analyses. By performing global metabolite profiling, also known as untargeted metabolomics, new discoveries linking cellular pathways to biological mechanism are being revealed and are shaping our understanding of cell biology, physiology and medicine.
[Show abstract][Hide abstract] ABSTRACT: Metabolomics is the global and unbiased survey of the complement of small molecules (say, <1kDa) in a biofluid, tissue, organ or organism and measures the end-products of the cellular metabolism of both endogenous and exogenous substrates. Many drug candidates fail during Phase II and III clinical trials at an enormous cost to the pharmaceutical industry in terms of both time lost and of financial resources. The constantly evolving model of drug development now dictates that biomarkers should be employed in preclinical development for the early detection of likely-to-fail candidates. Biomarkers may also be useful in the preselection of patients and through the subclassification of diseases in clinical drug development. Here we show with examples how metabolomics can assist in the preclinical development phases of discovery, pharmacology, toxicology, and ADME. Although not yet established as a clinical trial patient prescreening procedure, metabolomics shows considerable promise in this regard. We can be certain that metabolomics will join genomics and transcriptomics in lubricating the wheels of clinical drug development in the near future.
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