the metabolism problem: ingredients of an emerging theory eörs szathmáry & chrisantha fernando...
TRANSCRIPT
![Page 1: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/1.jpg)
The metabolism problem: ingredients of an emerging theory
Eörs Szathmáry & Chrisantha Fernando
Collegium Budapest Eötvös University Budapest
![Page 2: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/2.jpg)
Thanks to Günter!
![Page 3: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/3.jpg)
Pathways of supersystem evolution
boundary
template
metabolism M B
B T
M T M B T
INFRABIOLOGICAL SYSTEMS
![Page 4: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/4.jpg)
General background to the talk
![Page 5: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/5.jpg)
The problems of phylogenetic reconstruction (top-down)
• LUCA was too advanced • Reconstructions (e.g. Delaye et al. OLEB in press)
cannot reach deep enough• The fact that metabolic enzymes are not well
conserved does not mean that they were not there!• Scaffolds (pre-RNA, primitive metabolic
reactions) may have disappeared without leaving a trace behind!!!
• A more synthetic approach is needed• General evolutionary mechanisms must be sought
![Page 6: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/6.jpg)
Benner’s hypothetical ribo-organism (1999)
Membrane? Cofactors?
![Page 7: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/7.jpg)
This raises a lot of questions
• How could such a metabolic network build up? • Did the environment change or not during the
process? • What was the nature of the non-enzymatic
reactions producing (some of) these metabolites? • Is an autotrophic, non-enzymatic metabolism
feasible? • What are the constraints on metabolic evolution in
the context of supersystem evolution?
![Page 8: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/8.jpg)
Some elementary considerations
O L
Environment 1 Environment 2
Organic synthesis
Life
•Autotrophy impossible
•Enzymatic pathways are likely to be radically new inventions
L
O
•Autotrophy possible
•Enzymatic pathways may resemble non-enzymatic ones
![Page 9: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/9.jpg)
Further complication of supersystem organization
• The example of the Template/Boundary system: progressive distinction from the environment
Metabolites pass freely Metabolites are hindered
evolution
![Page 10: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/10.jpg)
Progressive sequestration
• Initially only templates are kept in• They can evolve catalytic properties• Carriers and channels can also evolve• Membrane permeability can become progressively
restrictive• Finally, only a very limited sample of molecules
can come in• Inner and outer environments differentiate• Membrane and metabolism coevolve gradually
![Page 11: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/11.jpg)
Evolution of metabolism: primitive heterotrophy with pathway innovation
A
B
C
D
Necessarily heterotrophic protocell
ABC
D
A
B
C
ABC
D
Evolved enzymatic reaction
Assume D is the most complex
![Page 12: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/12.jpg)
The final stage of innovation
AB
CD
This could be a heterotroph or autotroph (depending on the nature of A)
![Page 13: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/13.jpg)
Evolution of metabolism: primitive autotrophy with pathway retention
A
B
C
D
A
B
C
D
a
b
c
d
a
b
c
DRetroevolution is also likely because of membrane coevolution
![Page 14: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/14.jpg)
Reversible versus irreversible: the control of leakage
A C
Unfavourable:
Vulnerable to depletion in A
A C
B D
Favourable:
Resistant to depletion in A
![Page 15: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/15.jpg)
Two contrasting modes of enzymatic pathway evolution
Horowitz (1945) : retroevolution• Ancient non-enzymatic pathway:• A B C D• Progressive depletion of D, then C, then B, then A• Selection pressure for enzyme appearance in this order• Homologous enzymes will have different mechanisms
Jensen (1976) enzyme recruitment (patchwork)• One possible mechanism: ambiguity and progressive
evolution of specificity• Homologous enzymes will have related mechanisms• Enzyme recruitment from anywhere (opportunism)
![Page 16: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/16.jpg)
What evidence is there for the two mechanisms?
• New data using the whole armamentarium of bioinformatics
• It is about the evolution of PROTEIN enzymatic pathways
• Could be strongly suggestive for RIBOZYME-aided metabolism (the RNA world)
![Page 17: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/17.jpg)
The example of biotin metabolism
Light and Kraulis (2004) BMC Bioinformatics
Homology: strict cutoff in PSI-BLAST
![Page 18: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/18.jpg)
Enzymes as edges: the whole E.coli network is analyzed
![Page 19: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/19.jpg)
Minimal path length
![Page 20: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/20.jpg)
The most promiscuous 20 compounds
Frequency: the number of edges where is shows up
![Page 21: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/21.jpg)
Homology versus minimal path length
With the 20 Without the 20
![Page 22: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/22.jpg)
Different types of homologous enzyme pairs
Mechanistically similar
Mechanistically different
![Page 23: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/23.jpg)
A statistical analysis
Functionally similar Functionally dissimilar
![Page 24: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/24.jpg)
Conclusion
• There is some evidence for retroevolution
• BUT the dominant mode seems to fit the patchwork mechanism
• Same mechanisms might worrk for an RNA world!
![Page 25: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/25.jpg)
Patchwork and retroevolution can be made compatible
• A broader notion of retroevolution proposes just the (the frequent) retrograde appearance of consecutive enzymes, not that they are homologous within a pathway
• Pathways retroevolving in parallel can recruit enzymes in a pacthwork manner
![Page 26: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/26.jpg)
Evolution of catalytic proteins or on the origin of enzyme species by means of
natural selection • Kacser & Beeby (1984) J. Mol. Evol.• A precursor cell containing very few
multifunctional enzymes with low catalytic activities is shown to lead inevitably to descendants with a large number of differentiated monofunctional enzymes with high turnover numbers.
• Mutation and natural selection for faster growth are shown to be the only conditions necessary for such a change to have occurred.
• The division of labour for enzymes!
![Page 27: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/27.jpg)
Evolution of connectivity: Pfeiffer et al. (2005) PloS Biology
• Enzymes are initially specific for the group transferred but not for the substrates
• Metabolism is based on group transfer reactions between metabolites
• Without group transfer (D) only unimolecular reactions
![Page 28: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/28.jpg)
An emerging group transfer network
the frequency, P(k), of metabolites participating in k reactionsis given by k-c, where c is a constant coefficient
Hubs (127126 for group 1) emerge as consequence of selection for growth rate
![Page 29: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/29.jpg)
An emerging network without group transfer
![Page 30: The metabolism problem: ingredients of an emerging theory Eörs Szathmáry & Chrisantha Fernando Collegium BudapestEötvös University Budapest](https://reader035.vdocuments.net/reader035/viewer/2022062517/56649f265503460f94c3ce86/html5/thumbnails/30.jpg)
All these ingredients (and more) must be put together
• Supersystem evolution
• Alternative environments
• Progressive sequestration
• Duplication and divergence of enzymes
• Selection for cell fitness
• Network complexification