Are we ready for… Genome-scale Metabolic Modeling in plants
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Transcript of Are we ready for… Genome-scale Metabolic Modeling in plants
Are we ready for… Genome-scale Metabolic Modeling in plants
Yoav TeboulleOctober 2012Collakova, E. et al. (2012). Are we ready for genome-scale modeling in plants? Plant Science, 1–18.
OutlineMotivationWhat’s been done…Why is it tough to model plants?What are we doing about it?The future…
An integrated view of
metabolism
Reductionist studies of individual
reactions and pathways
Rational design approach to metabolic
engineering
Tinkering approaches to
metabolic engineering
Motivation: Why genome-scale modeling?
Motivation: Why plants?
Manipulation of plant
metabolismFood
Feed Fuel
Pharm
Motivation: Why plants?
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 modelsArabidopsis (Poolman, 2009)
Barley(Grafahrend-Belau, 2009)
C4 Plants: maize, sugarcane, sorghum (Dal’Molin, 2010) Oilseed rape
(Hay, 2011)
Zea mays (Saha, 2011)
Tomato…Rice…Lemna?…
Is that it?! What’s so hard about modeling plants?Plant cell metabolism is complex…
Collectively, plants produce over 200,000 (primary and secondary) metabolites
Proteins included in GSMM
Genes Base pairs
1366 (30%+) 4000-5000 4.6M E.coli
3500 (10%+) 30000 135M Arabidopsis
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
…which subsequently leads to poor annotationExperimentally 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.
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
Is that it?! What’s so hard about modeling plants?Enzyme sub-cellular compartmentalization
presents another challenge in plant modelingDuplicated pathways of central carbon metabolism, such
as glycolysisDifferent 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(de Oliveira Dal’Molin, Plant Physiology, ‘10)
MOm(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 modelSaha, 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 FUTUREFocus on secondary metabolism
Progress in ‘omics technologies
Better use of what we know!Choose model systems we can experimentally validateApply known constraintsDefine appropriate objective functions
Integrate regulatory mechanisms
The FUTURE
Biomass Production
Resistance
Stress Tolerance
Rational Plant Metabolic Engineering
So, are we ready for genome-scale modeling
in plants?
Definitely!
Questions...?
THANKS!