Are we ready for…
Genome-scale Metabolic
Modeling in
plants
Yoav Teboulle
October 2012
Collakova, E. et al. (2012). Are we ready for genome-scale modeling in plants? Plant Science, 1–18.
Outline
 Motivation
 What’s been done…
 Why is it tough to model plants?
 What are we doing about it?
 The future…
Motivation: Why genome-scale
modeling?
Reductionist
Tinkering
studies of
approaches to
individual
metabolic
reactions and
engineering
pathways
Rational design
An integrated
approach to
view of
metabolic
metabolism
engineering
Motivation: Why plants?
Motivation: Why plants?
Manipulation
of plant
metabolism
Food
Pharm
Feed
Fuel
Hibberd, J. M., & Weber, A. P. M. (2012). Plant metabolism and physiology. Current opinion in plant biology, 15(3), 225–227.
So far: existing plant models
Arabidopsis
(Poolman, 2009)
Barley
C4 Plants: maize,
sugarcane, sorghum
(Grafahrend-Belau, 2009)
Oilseed rape
(Dal’Molin, 2010)
(Hay, 2011)
Zea mays
(Saha, 2011)
Tomato…Rice…Lemna…?
Is that it?! What’s so hard about
modeling plants?
 Plant cell metabolism is complex…
E.coli
Base pairs
Genes
Proteins included
in GSMM
4.6M
4000-5000
1366 (30%+)
30000
3500 (10%+)
Arabidopsis 135M
 Collectively, plants produce over
and secondary) metabolites
(primary
Is that it?! What’s so hard about
modeling plants?
 The complexity of plant cell metabolism means
that little is known…
 Experimental data is of limited coverage & bad quality
Zhu et al., Elements of a dynamic systems model of canopy photosynthesis, Current Opinion in Plant Biology, Volume 15, Issue
3, June 2012, Pages 237-244
 …which subsequently leads to poor annotation
 Experimentally determined molecular function
~15%
 Computationally determined molecular function
~40%
 ???
~45%
 …which leave us with relatively poor models
Hibberd, J. M., & Weber, A. P. M. (2012). Plant metabolism and physiology. Current opinion in plant biology, 15(3), 225–227.
Is that it?! What’s so hard about
modeling plants?
 Enzyme sub-cellular compartmentalization
presents another challenge in plant modeling
 Duplicated pathways of central carbon metabolism, such
as glycolysis
 Different organelles provide different conditions for
metabolism in terms of
• pH
• Salt concentrations
• Energy/redox status
 Transporters between organelles and cytosol need to be
identified
de Oliveira Dal’Molin, C. G., & Nielsen, L. K. (2012). Plant genome-scale metabolic reconstruction and modeling. Current Opinion in Biotechnology, 1–7.
Is that it?! What’s so hard about
modeling plants?
 Photosynthesis & photorespiration also contribute
to the complexity…
 Model assurance is unclear when dealing with tissues
whose photosynthesis is not clear-cut
 Different pathways active in light and dark
 …as do the diversity of plant cell and tissue
types…
 …which causes difficulty in the selection of
appropriate objective functions
de Oliveira Dal’Molin, C. G., & Nielsen, L. K. (2012). Plant genome-scale metabolic reconstruction and modeling. Current Opinion in Biotechnology, 1–7.
Excuses, you say…?
Numerous
stresses
Multiple
Objectives
Redirected
Flux
So what CAN the models do…?
 Existing models are predictive where central
metabolism is concerned, less so in secondary
metabolism
These models demonstrate the applicability of
metabolic modeling approaches to plant cells…
…but still have difficulty in providing meaningful
metabolic and mutant predictions
What are WE doing about it?
Arabidopsis
Zea Mays
What are WE doing about it?
 Two newer Arabidopsis models
AraGEM model
MOm
(de Oliveira Dal’Molin, Plant Physiology, ‘10)
(Mintz-Oron et al. PNAS, 2011)
Primary metabolism
Primary and secondary metabolism
1567 reactions
3509 reactions
1748 metabolites
2930 metabolites
cytoplasm, mitochondrion, plastid,
peroxisome, and vacuole
cytoplasm, plastid, mitochondrion,
endoplasmic reticulum, peroxisome,
vacuole and golgi-apparatus
Minimal medium
Rich + minimal media
What are WE doing about it?
 Model improvement
 Apply existing datasets
 Apply novel datasets: Asaph Aharoni’s Lab, Weizmann
• biomass measurements
• organelle-specific ‘omics
• gene essentiality data
• flux measurements
What are WE doing about it?
 Searching for ways to augment the production of:
 Tocopherol (vitamin E) – antioxidant function
 Thiamine (vitamin B1) – prevention of neural and other
disorders
What are WE doing about it?
 Mays model
 Verification and improvement of the existing model
Saha, R., Suthers, P. F., & Maranas, C. D. (2011). Zea mays iRS1563: a comprehensive genome-scale metabolic
reconstruction of maize metabolism. PloS one, 6(7), e21784.
 Progress to a tissue-specific model
• Use transcriptome and proteome data to extract a subset of
reactions
• Define tissue-specific biomass composition and metabolite
exchange
 Increased yield in target pathways based on bacterial
gene transformation
The FUTURE
 Focus on secondary metabolism
 Progress in ‘omics technologies
 Better use of what we know!
 Choose model systems we can experimentally validate
 Apply known constraints
 Define appropriate objective functions
 Integrate regulatory mechanisms
The FUTURE
Rational Plant
Metabolic Engineering
Biomass
Production
Resistance
Stress
Tolerance
So, are we ready for genome-scale modeling
in plants?
Definitely!
Questions...?
THANKS!