Spatial & Temporal Modeling of Human Metabolism. Emilia Lim. Background…. Metabolomics. A newly emerging field of ‘omics’ research concerned with the high-throughput identification, quantification and characterization of small molecule metabolites in the metabolome. Metabolic Networks.
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of Human Metabolism
A newly emerging field of ‘omics’ research concerned with the high-throughput identification, quantification and characterization of small molecule metabolites in the metabolome.
Complete sets of metabolic and physical processes that determine the physiological and biochemical properties of a cell. Individual enzymes and their functions are sorted into a pathway. The result facilitates analysis of reactions within the perspective of the entire body, provides a platform to visualize and analyze metabolomic data, and creates a framework for metabolic simulation.
are a class of genetic diseases typically due to defects of single genes that code for enzymes. problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds.
Spatial and Temporal Visualization of diseased metabolic patterns allows monitoring of their spatial manifestation in the body over time. It is particularly useful for diseases that do not have a completely elucidated mechanism of action and affect multiple locations in the body.
To generate a complete database of normal and inborn error (diseased) human metabolic pathways
To contribute to HMDB.ca
Run simulations to derive spatial and temporal data for the pathways.
That will be used by the 4D CaveMan which is maintained at the University of Calgary.
E-cell Project and BioSpice Project: metabolic simulation based on solving differential equations.
Constraint based computational models for predicting human tissue-specific metabolic behavior.
The IUPS physiome project: database of metabolic information at various spatial and temporal scales
The metabolic pathway database, is created from a series pathway drawings in Microsoft PowerPoint.
Complete list of human metabolic pathways is from HumanCyc.
Basic framework (metabolites, enzymes, reactions, associated pathways) is from KEGG.
Cellular compartment information is from the Reactome database and a biochemistry textbooks.
The diseased pathways include additional information from the Handbook of 1H-NMR spectroscopy in inborn errors of metabolism
Currently, we have interactive pathway maps on the HMDB:
72 pathways in the Pathway Database
>60 pathways in the Diseased Pathway Database
Pathways for the three diseased states of our focus drawn.
Cytochrome P450 Drug Metabolism Of Acetaminophen
(literally: high blood cholesterol) is the presence of high levels of cholesterol in the blood.
Elevated cholesterol in the blood is due to abnormalities in the levels of lipoproteins, the particles that carry cholesterol in the bloodstream.
This may be related to diet, genetic factors (such as LDL receptor mutations in familial hypercholesterolemia) and the presence of other diseases such as diabetes and an underactive thyroid.
an autosomal recessive genetic disorder characterized by a deficiency in the enzyme hepatic phenylalanine hydroxylase (PAH).
PAH is necessary to metabolize the amino acid phenylalanine to the amino acid tyrosine. When PAH is deficient, phenylalanine accumulates and is converted into phenylpyruvate, which is detected in the urine.
Left untreated, this condition can cause problems with brain development, leading to progressive mental retardation and seizures.
is a widely used over-the-counter drug. It is commonly used for the relief of fever, headaches, and other minor aches and pains, and is a major ingredient in numerous cold and flu remedies.
It is usually ingested, and absorbed by the GI tract.
It is mainly metabolized in the liver and kidney, and passed out as urine.
It also accumulates in the brain and bloodstream.
a Java application that uses Dynamic Cellular Automata to model motions, interactions, transport and transformations at the meso-scale or at the cell level.
Tyrosine Degredation As Simulated By SimCell
an object-oriented computer model of a human body, projected in a virtual reality CAVE. The model is built upon data from basic anatomy textbooks. Fundamental body systems and organs were rendered into animated drawings by a graphic artist, and converted into Java 3DTM to bring them to life. One can use a joy stick to manipulate the 3D projection – shifting it from side to side, dissecting it, and marking organs and body fluids with different colours.
No automatic update of pathways
No searching of pathways
No automatic addition/identification of newly discovered inborn errors of metabolism
Simulations can only be done one scale at a time
This project has built a collection of human metabolic pathways under normal and diseased conditions had has begun to use them for metabolic simulations.
Our future work:
Obtaining accurate concentration and kinetic values for SimCell and ADME simulations.
Verifying simulated data with other simulations and data on other databases.
Extending pathway database to include metabolism of other drugs and toxins.
Publication: Wishart D.S., et.al.. 2009. HMDB: a knowledgebase for the human metabolome. Nucleic Acids Res. 37(Database issue):D603-10.
Best Poster Award: Canadian Student Conference in Biomedical Computing 2009 (UBC)