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5
growth
Why is Rubisco slow and non specific?
What governs maximal growth rates?
Design principles in photosynthesis – wavelengths used
and saturation
Synthetic carbon fixation pathways
for higher efficiency
What governs the efficiency of photosynthesis and carbon fixation?
04/19/23
Converts between 5 and 6 carbon sugars
e.g Ribose-5P is used for making nucleotides
e.g Fructose-6P is used for building the cell wall
Was analyzed as an optimization problem (Meléndez-Hevia & Isodoro 1994)
We use this as a starting point
An illustrative example: the Pentose Phosphate cycle
04/19/23
The Pentose Phosphate Pathway defined as a game
Goal:
Turn 6 Pentoses into 5 Hexoses
Rules:
Transfer 2-3 carbons between two molecules
Never leave a molecule with 1-2 carbons
Optimization function:
Minimize the number of steps (simplicity)
?
E. Meléndez-Hevia et al. (Journal of theoretical Biology 1994)
TK
TA
5 5 5 5 5 5
6 6 6 6 6
04/19/23
Solution to Pentose Phosphate game in 7 steps
Corresponds to natural pathway
Doesn't explain why the rules exist
Supports the idea of simplicity
10
Are there simplifying principles to the structure of the central carbohydrate metabolism network?
13
All possible reaction types are explored
aldehyde dehydrogenase (CoA):pyruvate ↔ acetyl-CoA + CO
2
isomerase (keto to enol):pyruvate ↔ enolpyruvate
kinase (carboxyl):pyruvate ↔ pyruvate-P
Hatzimanikatis et al. (Bioinformatics 2005)
04/19/23
EC rules were encoded into commands
C C O C O O
C 0 1 0 0 0 0
C 1 0 2 1 0 0
O 0 2 0 0 0 0
C 0 1 0 0 2 1
O 0 0 0 2 0 0
O 0 0 0 1 0 0
C C O C O O
C 0 2 0 0 0 0
C 2 0 1 1 0 0
O 0 1 0 0 0 0
C 0 1 0 0 2 1
O 0 0 0 2 0 0
O 0 0 0 1 0 0Hatzimanikatis et al. (Bioinformatics 2005)
17
Optimization function finds minimal number of steps between any two metabolites
The shortest path can be found efficiently using a customized BFS (breadth first search)
18
Are all pairs of metabolites connected by shortest possible paths? (as allowed by biochemistry rules)
19
Are all pairs of metabolites connected by shortest possible paths? (as allowed by biochemistry rules)
• Some pairs are connected by possible shortest paths • Other pairs can be connected in less steps via shortcuts
20
Are all pairs of metabolites connected by shortest possible paths? (as allowed by biochemistry rules)
• Some pairs are connected by possible shortest paths • Other pairs can be connected in less steps via shortcuts
• Cluster together pairs that connect via shortest paths• Define these as minimality modules
21
minimality modules are defined to contain shortest paths
Only metabolites connected by shortest possible paths are contained in an minimality module
Existing reactions
(in organism)
Possible EC reactions
(biochemistry)
Minimality modules
A
B
C
D
E
F
A
B
C
D
E
F
A
B
C
D
E
F
22
GAP 3PG (EC 1.2) is biochemically feasible (exists in plants), but is not part of E. coli central metabolism
Therefore glycolysis is not as short as possible and breaks down into minimality modules
GAP
BPG
3PG
DHAP
2PG
EC 1.2
Example: possible shortcut in glycolysis break it into modules
GAP
BPG
3PG
DHAP
2PG
GLU
PYR
04/19/23
• Design principle:
minimal number of enzymatic steps connecting every pair of consecutive precursors
central carbon metabolism is a minimal walk between the 13 biomass precursors
“Make things as simple as possible but not simpler”
30
Future directions – metabolic networks optimization and synthesis
• Try to implement alternative carbon fixation in-vitro or in-vivo
• “Test case”: can we convert E.coli to being an autotroph?
• Couple synthetic carbon fixation to energy sources fuel production from sunlight/wind
or at least learn something about the logic of evolution,
and how: “evolution is smarter than you are” (Orgel’s law)
31
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