Metabolomics in Drug Target Discovery

ArticleinCold Spring Harbor Symposia on Quantitative Biology 76:235-46 · November 2011with23 Reads
DOI: 10.1101/sqb.2011.76.010694 · Source: PubMed
Abstract
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.
    • "In recent years there has been renewed interest in metabolism resulting from discoveries of its connections to gene regulation [1], epigenetics [2], immunity [3], and pathogenesis of diseases such as cancer456 . Independently, technological advances in metabolomics promise great improvement of our capabilities in metabolism studies and drug development78910. However, despite the surge of interest and technological advances, quantitative systemslevel characterization of the central trait of metabolism, metabolic flux, has been scarce and challenging. "
    [Show abstract] [Hide abstract] ABSTRACT: Fluxes are the central trait of metabolism and Kinetic Flux Profiling (KFP) is an effective method of measuring them. To generalize its applicability, we present an extension of the method that estimates the relative changes of fluxes using only relative quantitation of 13C-labeled metabolites. Such features are directly tailored to the more common experiment that performs only relative quantitation and compares fluxes between two conditions. We call our extension rKFP. Moreover, we examine the effects of common missing data and common modeling assumptions on (r)KFP, and provide practical suggestions. We also investigate the selection of measuring times for (r)KFP and provide a simple recipe. We then apply rKFP to 13C-labeled glucose time series data collected from cells under normal and glucose-deprived conditions, estimating the relative flux changes of glycolysis and its branching pathways. We identify an adaptive response in which de novo serine biosynthesis is compromised to maintain the glycolytic flux backbone. Together, these results greatly expand the capabilities of KFP and are suitable for broad biological applications.
    Full-text · Article · Nov 2014
    • "Interestingly, both PYC and ACC require biotin as cofactor, with this vitamin donating a carboxyl anion to the very specific organic acid substrate [45, 57]. 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 [58] illustrated using isotope tracer metabolites and a metabolomics research approach. Additional metabolomics-related approaches by de Carvalho et al. [19] 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.
    Full-text · Article · Mar 2014
    • "It is now our challenge to identify common targets to complement the current treatment of viral infections and to generate compounds directed toward these targets. Moreover, the targeting of metabolites or cellular enzymes needed for virus infection rather than inhibiting virus-encoded functions prevents the emergence of drug-resistant viruses and thus the need to use multidrug combinations [53]. Another important point of consideration is that ongoing monitoring of mitochondrial functions, especially in patients on antimetabolic drugs such as HAART, can help to minimize deleterious side effects. "
    [Show abstract] [Hide abstract] ABSTRACT: Mitochondria fulfil several key functions within cellular metabolic and antiviral signalling pathways, including their central role in ATP generation. Viruses, as intracellular parasites, require from their cellular host the building blocks for generation of their viral progeny and the energy that drives viral replication and assembly. While some viruses have adopted ways to manipulate the infected cell such that cellular metabolism supports optimal virus production, other viruses simply exhaust cellular resources. The association of viruses with mitochondria is influenced by several important factors such as speed of the viral replication cycle and viral dependence on cellular enzymes and metabolites. This review will highlight the complex interconnectivity of viral life cycles with the three main mitochondrial metabolic pathways, namely β-oxidation, the tricarboxylic (TCA) cycle, and oxidative phosphorylation. This interconnectivity has the potential to reveal interesting points for antiviral therapy with either prometabolites or antimetabolites and highlights the importance of the viral association with mitochondrial metabolism.
    Full-text · Article · Dec 2013
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