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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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slide1

Spatial & Temporal Modeling

of Human Metabolism

Emilia Lim

metabolomics
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
Metabolic Networks

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.

inborn errors of metabolism
Inborn Errors Of Metabolism

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 temporal visualization
Spatial & Temporal Visualization

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.

biol 499 project objectives
BIOL 499 - Project Objectives

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.

other efforts
Other Efforts

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

1 manual curation text mining
1. Manual Curation & Text Mining

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.

slide12

Presently…

  • 80 Unique Pathways Listed In The HMDB
  • ~99 Human Metabolic Pathways In Total
  • We’ve drawn over 100 Pathways based on:
    • KEGG
    • Reactome
    • HumanCyc
diseased pathways
Diseased Pathways

The diseased pathways include additional information from the Handbook of 1H-NMR spectroscopy in inborn errors of metabolism

summary of pathways drawn
Summary of Pathways Drawn

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.

Hyperchoslestrolemia

Phenylketonuria

Cytochrome P450 Drug Metabolism Of Acetaminophen

slide17

Impact of HMDB Metabolic Pathways

  • Describes and visualizes meaningful relationships between HMDB metabolites.
  • Gives the next edition of the HMDB a snazzy new look.
  • Pieces together other metabolic pathway databases and provides a bulk of information on one image.
hypercholestrolemia
Hypercholestrolemia

(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.

phenylketonuria
Phenylketonuria

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.

cytochrome p450 metabolism of acetaminophen
Cytochrome P450 Metabolism of Acetaminophen

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.

simcell
SimCell

a Java application that uses Dynamic Cellular Automata to model motions, interactions, transport and transformations at the meso-scale or at the cell level.

slide25

Will Be Replaced By Live Demo

Tyrosine Degredation As Simulated By SimCell

caveman
CaveMan

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.

limitations
Limitations

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

conclusion
Conclusion

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.

future work
Future Work

t=1 t=2

t=3 t=4

impact of project thus far
Impact of Project Thus Far

Encouraging E-mails

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)