Metabolomics and Drug Discovery

© All rights reserved

P. Paulsharma Chakravarthy,

School of Genomics, Loyola College

www.milser.co.in

bioinfopaul@gmail.com

Metabolomics…..

• Metabolomics is the study of metabolite profiles in biological samples, particularly urine, saliva and blood plasma; the total number of metabolites in the human is unknown: estimates range from 3000 to 30000

• The study of global metabolite profile in cells, tissues and organisms. The metabolite profiles are typically generated with high throughput NMR spectroscopy and mass spectroscopy

• These profiles are represented by analytical spectra, the metabolite profiles of different cellular condition are compared using statistical techniques like pattern recognition

Metabolomics vs. other “omic” sciences

• Metabolite profile profiles provides knowledge and information rather than mere data

• The genes and proteins predicts cell functioning but metabolites reflect actual cellular condition at the time of sampling

• The sampling for the analysis is simpler compared to the genomics and proteomics

• Can be used as Biomarkers for diagnostics and therapeutic monitoring

• Metabolic profiling, the elucidation of the small molecule components of a cell, tissue or organism, has emerged as a useful technique in such diverse fields as drug discovery, clinical diagnostics and plant biochemistry

• Metabolome is a pattern of molecules that reflects the cell’s status. It is the totality of metabolic processes including anabolism and catabolism, as well as all the related cellular processes such as absorption, distribution, and detoxification of natural and xenobiotic materials, energy utilization, signal transduction, and regulation.

• It results from the expression of the genome and proteome in response to the cellular environment. While the Genome is representative of what might be, and the Proteome is what is expressed, it is the Metabolome that represents the current status of the cell or tissue.

Metabolomics – Field Scenario

•The Metabolome gives a direct picture of the cells activity and its environment. It presents a powerful portrait, reflecting health, disease, aging and the effects of drugs and the environment.

•One method for extracting information is to separate and quantify the compounds of the Metabolome

Future Perspectives

• Detection of unusual metabolitic profile will aid in early cancer detection• Need for more public databases for Metabolomics research• Linking the metabolite datasets to genomics and proteomics

Metabolism Basics…..

Definition - Metabolic pathways

Is a series of consecutive enzymatic reactions that produce specific productsTheir reactants, intermediates and products are referred to as metabolites.

Basic concepts of Metabolic pathways

• Metabolic pathways are irreversible• Every pathway has a first committed step• All metabolic pathways are regulated• Metabolic pathways in Eukaryotic cells occur in specific cellular locations

Study of Metabolome

- In terms of sequence of reactions by which a specific nutrients is converted to end products, and the energetics of these reaction.

- In terms of the mechanisms by which each intermediate is converted to its successor. Such an analysis requires the isolation and characterization of the specific enzymes that catalyze the reactions

- In terms of the control mechanisms that regulate the flow of metabolites through the pathway.

Metabolic Inhibitors, growth studies and Biochemical Genetics Isotopes in Biochemistry Isolated Organs, cells and sub cellular organelles.

Experimental Approaches

Experimental approaches

Metabolic Pathway Databases

Representation of Pathways…

Gene Information - KEGG

Genome Map Representation - KEGG

Pathway AssistTranspathGenmappPathmetricsMetacorePmapPathway EditorSlirppPathway Analysis

Metabolic pathway Mapping Tools

Practical Approaches

•Unique Biomolecules

•Biosynthetic Pathway Targets

A Practical Example - Mycobacterium tuberculosis H37Rv

•Pathogenesis Process

•Cell Wall Confers The Virulence

•Biosynthetic Pathway of Cell wall Components as Potential Drug Targets

• If only one enzyme-encoding gene out of a pathway of several steps is found in an annotated genome, it is likely to be a mistaken assignment.

• Conversely, if all but one or two enzymes in a pathway have corresponding genes in the annotated genome, the missing steps are likely to be present amongst the unidentified genes and are worth hunting down.

• Studying the metabolism of disease-causing organisms can also be an excellent means of identifying new drug targets.

• Many pathogenic bacteria and parasitic eukaryotes are the subjects of ongoing genome sequencing projects.

•If metabolic pathways can be identified which are essential in the pathogen but absent in the host, new drugs targeting the enzymes in these pathways are likely to be very effective.

Applications of In Silico Mapping

Isoprenoids

Screening for Drug Target Pathways

DOXP and Mevalonate Pathway

Screening for Drug Target Pathways

Organisms DXS DXR YgbP Ygb B Ych B

Rhodopseudomonas palustris + + + + +

Caulobacter crescentus + + + + +

Neisseria meningitidis + + + + +

Bordetella pertussis + + + + +

Bordetella bronchisceptica + + + + +

Vibrio cholerae + + + + +

Escherichia coli + + + + +

Haemophilus influenzae + + + + +

Pseudomonas aeruginosa + + + + +

Pseudomonas putida + + + + +

Pseudomonas fluorescens -- + -- -- --

Salmonella typhi + + + + +

Salmonella typhimurium + + + + +

Pasteurella multocida + + + + +

Yersinia pestis + + + + +

Erwinia carotovora + + + + +

Campylobacter jejuni + + + + +

Helicobacter pylori + + + + +

Thank you…

bioinfopaul@gmail.com