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From genomes to Pathway tools and from Pathway Tools to Metabolic Models. Jeremy Zucker Broad Institute of MIT and Harvard. Outline. Enzyme prediction with EFICAz TBCyc curation FungiCyc curation Network debugging tools. From genome sequences to Metabolic flux models. Enzyme predictor.

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from genomes to pathway tools and from pathway tools to metabolic models

From genomes to Pathway tools and from Pathway Tools to Metabolic Models

Jeremy Zucker

Broad Institute of MIT and Harvard

outline
Outline
  • Enzyme prediction with EFICAz
  • TBCyccuration
  • FungiCyccuration
  • Network debugging tools
from genome sequences to metabolic flux models
From genome sequences to Metabolic flux models

Enzyme predictor

Pathway predictor

Model

Omics data

Predictions

enzyme prediction
Enzyme Prediction
  • EFICAz:
    • Predicts Enzyme Commision Numbers
    • Functionally Discriminating Residues
      • Homofunctional MSA
      • Heterofunctional MSA
    • Support Vector Machine
    • Sequence Identity Threshold
    • Integrates 9 independent methods to achieve maximal accuracy
  • KEGG-BLAST
enzyme prediction1
Enzyme Prediction
  • EficazTool incorporated into Calhoun web interface
  • Runs on LSF cluster for all Transcripts in an AnalysisRun
  • Automatically assigns EC number OntologyTerm and ToolEvidence to Transcript
tbcyc curation1
TBCyccuration
  • TBDB TBCyc integration
  • Palsson Flux models => curated pathways
  • McFadden flux model => curated pathways
  • Literature => curated pathways
  • Expression data => Omics viewer
  • Chip-Seq => curated gene regulatory network
  • Coming soon:
    • annotation jamboree for TB
    • Connect to Decode Open source drug discovery for TB
neurospora curation
Neurosporacuration
  • Resources:
    • Model organism
    • Active Community Annotation Project
    • Recent genome assembly and annotation
    • Systems Biology grant
      • Chip-seq
      • KO library
      • Biofuels
biofuels from neurospora
Biofuels from Neurospora?
  • Growing interest for obtaining biofuels from fungi
  • Neurosporacrassahas more cellulytic enzymes than Trichodermareesei
  • N. crassacan degrade cellulose and hemicellulose to ethanol [Rao83]
  • Simultaneous saccharification and fermentation means that N. crassais a possible candidate for consolidated bioprocessing

Xylose

Ethanol

effects of oxygen limitation on xylose fermentation in neurospora crassa
Effects of Oxygen limitation on Xylose fermentation in Neurosporacrassa

Intermediate O2

Xylose

Ethanol conversion (%)

Glycolysis

Pyruvate

Respiration

Fermentation

Low O2

High O2

TCA

Ethanol

Oxygen level (mmol/L*g)

Zhang, Z., Qu, Y., Zhang, X., Lin, J., March 2008. Effects of oxygen limitation on xylose fermentation, intracellular metabolites, and key enzymes of Neurosporacrassaas3.1602. Applied biochemistry and biotechnology 145 (1-3), 39-51.

slide12

Pentose phosphate

Xylose degradation

Xylose

Two paths from xylose to xylitol

Glycolysis

Model of Xylose

Fermentation

Aerobic respiration

Fermentation

Oxygen

Ethanol

TCA Cycle

ATP

slide13

Pentose phosphate

Xylose degradation

High

Oxygen

NADPH

Regeneration

Glycolysis

NADPH &

NAD+

Utilization

Aerobic respiration

Fermentation

Oxygen=5

NAD+

Regeneration

TCA Cycle

ATP=16.3

slide14

Pentose phosphate

Xylose degradation

Low

Oxygen

Glycolysis

Aerobic respiration

Fermentation

Oxygen=0

Ethanol

TCA Cycle

slide15

Pentose phosphate

Xylose degradation

Intermediate

Oxygen

Optimal

Ethanol

NADPH

Regeneration

Glycolysis

NADPH &

NAD

Utilization

Aerobic respiration

Fermentation

Oxygen=0.5

All O2 used to regenerate NAD used in first step

Ethanol

NAD

Regeneration

TCA Cycle

ATP=2.8

slide16

Pentose phosphate

Xylose degradation

Intermediate

Oxygen

Optimal

Ethanol

NADPH

Regeneration

Glycolysis

NADPH &

NAD

Utilization

Improve NADH

enzyme

Bottleneck

Pyruvate

decarboxylase

Aerobic respiration

Fermentation

Oxygen=0.5

All O2 used to regenerate NAD used in first step

Ethanol

NAD

Regeneration

TCA Cycle

ATP=2.8

xylose lipids
XyloseLipids
  • col-2 (Glucose-6-phosphate dehydrogenase) mutant produces lipids from xylose and glucose
    • 35x more TAGS than WT
    • 12% biomass is lipid
  • Mapping out the metabolic pathways to explain this phenomenon.
  • Lipids for NADPH regeneration?
algorithms for debugging metabolic networks
Algorithms for Debugging Metabolic Networks
  • Metabolic network is too complicated.
  • The metabolic network is infeasible.
  • E-flux results in dead model.
minimal organism
Minimal Organism
  • Given a feasible model under the given nutrient conditions, find the fewest number of nonzero fluxes that still results in a viable organism.

minimize card(v)

subject to:

Sv = 0,

l <= v <= u

minimal reaction adjustment
Minimal Reaction Adjustment
  • Given an infeasible model, find a reaction with the smallest number of reactants and products that results in a feasible model.

minimizecard( r )

subject to

Sv + r = 0

l <= v <= u

minimal limit adjustment
Minimal Limit Adjustment
  • Given a set of (feasible) baseline limits, and an (infeasible) set of expression-constrained flux limits, find the smallest number of adjustments to the flux limits that results in feasible model (without exceeding the baseline constraints).

minimize card(dl) + card(du)

subject to:

Sv = 0,

l – dl <= v <= u+du

l-dl >= l_0, u+ du <= u_0

dl >= 0, du >= 0.

minimum cardinality
Minimum Cardinality
  • Each of these problems is a special case of the minimum cardinality problem

Minimize card( x )

Subject to

Ax + By >= f

Cx + Dy >= g

  • Caveat: the minimum cardinality problem is NP-Hard!
sparse optimization to the rescue
Sparse Optimization to the rescue!
  • Recent results from Compressed Sensing have shown that minimizing the L1-norm is a decent heuristic
  • Iterative methods can improve the results
  • Instead of minimize card( x ),

Minimize norm(diag(w) x, 1) = sum(w_i|x_i| )

Update w_i = 1/(epsilon + |x_i|), i=1,…,k

implementations
Implementations
  • 3 software packages in matlab
    • Cvx (Sedumi and spdt3)
    • Glpkmex (GLPK)
    • Cplexmex (CPLEX)
  • min cardinality
    • MILP and L1 heuristic version
  • min limit adjustment
    • MILP and L1 heuristic version
  • Min limit adjustment => min cardinality
acknowledgements
Acknowledgements

Program Project

Heather Hood

SRI

Peter Karp

Markus Krumenacker

Suzanne Paley

Mario Latendresse

Tomer Altman…

Broad Institute

James Galagan

Bruce Birren

Brian Haas

Aaron Brandes

Matt Henn

Li Jun Ma

Christina Cuomo

Carsten Russ

Broad Genome Sequencing Platform

Finishing Team

Margaret Priest

HarindraArachchi

Lynne Aftuck

Mike Fitzgerald

Genome Assembly

Sarah Young

Sean Sykes

Annotation Team

Brian Haas

Mike Koehrsen

QianZeng

Tom Walk

outline1
Outline
  • e354f1709c
  • ICS Guest network