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Transcript
The Evolution of Metabolism
Chrisantha Fernando
School of Computer Science
Birmingham University
17th November 2005. Systems Biology Group Meeting
Pre-Enzymatic Metabolic
Evolution
Part 1.
Pathways of supersystem evolution
metabolism
MB
boundary
MT
template
BT
MBT
Pre-enzymatic and post-enzymatic stages can be distinguished.
Background
All living systems today have
metabolism.
 An organism without metabolism would be one
that did not synthesize any of its constituents, but
obtained them all preformed from the environment
or from its parent(s).
 Heterotrophic theories of the origin of life
(Oparin, Haldane, Lancet, Eigen, Kauffman,
Farmer, Fox, Szostak) assume such ‘organisms’
were possible.
The Problem of
o
1 Heterotrophy.
 Initial bolus of complex organics from space.
 Chemical energy used to form organism depletes
this bolus.
 Low gross primary production of complex
organics (because no autotrophs).
 Therefore any 1o heterotroph exists in an
ecological transient, and can be saved only by the
evolution of an autotroph.
 In the long term, [metabolic entities] are rate
limiting to non-metabolic entities.
All known cellular life has an
autocatalytic metabolism.
 Remove all metabolites, leaving water and
informational macromolecules in place + ATP. The
network cannot be re-created from the food
materials alone.
 All cells possess a distributive autocatalytic
network, that cannot be seeded from outside,
because some of its seed components cannot be
taken up (or synthesized) from the medium.
The Chemoton
(T. Ganti 1971)
Benefits of autocatalytic
metabolism.
 During hard times, key metabolites cannot escape,
whereas the non-autocatalytic entity could loose
its metabolites by reactions running in reverse.
 Contemporary metabolic networks are
endogenously autocatalytic.
 The unit of chemical evolution is the autocatalytic
cycle, (existing within a recycling system).
How likely is it for autocatalytic
cycles to arise and persist?
 Imagine an experiment, C,H,N,O,P,S,
heterogeneous environments and flux keeps
system away from equilibrium.
 Under what circumstances will the system settle
down into a boring point attractor (tar) and when
will it produce life?
 G.A.M. King. Selection of rate coefficients and
concentrations of reagents are needed to make
anything but the smallest cycle to persist. [The
problem of side-reactions/specificity].
Pre-enzymatic symbiosis of
autocatalytic particles.
 If symbiosis can reduce the rate of decay of
the symbiont (i.e. increase specificity), then
even if the growth rate of the symbiont is
lower than its components, the coupled
cycle has a selective advantage.
 But a successful symbiosis is not easy,
(“The Good Symbiont”, ECAL 2005).
Modeling Chemical Evolution.
 A model of a heterogenious, interestingly
structured, platonic, chemical space which can be
explored.
 Ensure conservation of mass and energy.
 Allow niche selection in chemical space.
 Allow physical niche selection (i.e. selection of
abiotic catalysts, and selection of diffusion
limiting lipid membranes).
 The system must be capable of discovery of
scaffolding/channeling systems that reduce sidereactions.
Possible approaches so far…
 Gil Benko.
 My DPhil Chapter 2.
 The problem is to develop a valid model of
chemistry in which chemical evolution can be
explored.
 Then to expose this model to appropriate
environments.
 Efforts underway in Germany to Ix. Formose
cycle metabolism evolution.
Post-Enzymatic Metabolic
Evolution
Part 2.
General Assumptions
 Assume an underlying (non/minimal-enzymatic)
metabolism in a protocell capable of synthesizing
ribozymes.
 Since there is no relationship between the catalytic
power of a given RNA and the protein for which it
encodes, there is no clear path from the RNA to
the protein world. Therefore protein cladistics
reach a historical limit.
 Evolution of metabolism is by genetic assimilation
of underlying chemical pathways.
 Several evolutionary motifs have been proposed.
i) Horowitz’s Retro-extension
Evolved
enzymatic
reaction
A
A
B
C
B
C
D
D
A
Necessarily heterotrophic
protocell
Assume D is the most
complex
A
B
C
C
B
D
The final stage of innovation
B
A
C
D
Horowitz’s assumptions and their
consequences.
 D is indeed available at an early stage.
 C,B, and A are available in excess in the
environment.
 This is only likely where autotrophs produce them.
 Therefore, retroevolution may be important when
a heterotroph co-evolves closely with an
autotroph.
 Retroevolution is also likely due to membrane coevolution, i.e. where D can no longer enter, and so
must be synthesized.
Wachtershauser’s Operations.
Loss of pathways.
 ABCD : AB
 Using various combinations of the above
primitives, predictions can be made about
evolutionary trajectories leading to extant
metabolic systems.
 However the possible trajectories are
underdetermined, so additional assumptions
are required.
Assume Evolutionary
Opportunism
 Melendez-Hevia et al.
Is there an evolutionary trace of
the actual trajectory?
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)
Light and Kraulis (2004)
 Homologous enzyme pairs abound at the
minimum path length of one, (i.e. the product of
one is the substrate of the other).
 But does not corroborate retro-extension because,
 Only small homology between mpl 2 and 3 pairs.
 Most enzyme pairs with mpl 1 have similar EC
numbers, hence are functionally related.
 Retro-extension may still have been important in the
RNA world.
With 20 promis.
Function Similar
Without 20 promis.
Function Dissimilar.
But patchwork and retro-extension are
not mutually exclusive.
 A broader notion of retroevolution proposes
just the (frequent) retrograde appearance of
consecutive enzymes, not that they are
homologous within a pathway
 Pathways retroevolving in parallel can
recruit enzymes in a patchwork manner
Why Scale-Free?
- Preferential attachment (Light, Kraulis,
Elofsson 2005).
 Older enzymes are more highly connected
(duplic and diverged enzyme may preserve past
reagents).
 HGT enzymes are more highly connected (may
aid retention?
The origin of enzyme species by 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.
 Duplication and divergence and natural selection for faster
growth are shown to be the only conditions necessary for
such a change to have occurred.
 Assumes that increasing the copy number of one enzyme
gene decreases numbers of other enzymes.
From K&B
 The thermodynamic constraints within which cells operate
do not define the particular kinetic organization that we
observe.
 A clever student of biochemistry could invent a variety of
metabolic maps and associated enzymes which differ
substantially from those now.
 Pathways existed prior to the arrival of enzymes. Their
presence allows the kinetic realization of a particular
subset of all thermodynamically possible steps. Another set
of enzymes would produce another map.
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
What should we do?
 Make a model of the underlying platonic
metabolic pathways, coupled with a model of
enzyme evolution, and cell level fitness subject to
reasonable environmental conditions.
 How in principle could such systems co-evolve?
 E.g. Pfeiffer et al showed co-evolution of
increasing specific group transfer metabolite coenzymes with their specific enzymes, in a grouptransfer network, selected for growth rate.
Biasing Assumptions.






1. They assumed that initially ALL enzymes were present capable of catalysing all possible metabolic group
transfers. A more reasonable possibility is that no genetically encoded enzymes are present (only nonencoded catalysts), but that there is an inherent rate of underlying group transfer reactions. In the model
there is no underlying metabolic thermodynamics or kinetics.
2. Enzyme kinetics were capable of being arbitrarily uniformly mutated, with free energies of forward and
backward reactions being easy to alter arbitrarily by mutation. Is this reasonable? Could an enzyme really
be so flexible in its functional response to mutation?
3. They assume that enzyme concentrations cannot be influenced by end products, that enzymes cannot
be inhibited or activated by normal substrates. Not so bad for a first attempt.
4. They assume that enzymes specificity is for acceptor and donor groups, but that there is no evolution of
enzyme specificity for the catalysed group itself, rather this remains constant throughout. Is this
reasonable?
5. Increasing the copy number of one enzyme gene did not decrease the concentrations of other enzymes.
6. They assume that the environment over all evolutionary history consists of 0000000 and 1111111,
therefore not properly testing the scenarios would have allowed evolution by retro-extension.