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Optimalityin Carbon

Metabolism

Ron MiloDepartment of Plant SciencesWeizmann Institute of Science

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Elad NoorArren Bar-Even

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Uri Alon

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What limits maximal growth rates?

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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?

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Are there simplifying principles to the structure of the central carbohydrate metabolism network?

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

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Are there simplifying principles to the structure of the central carbohydrate metabolism network?

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We develop a method to find shortest path from A to B

N

S

W E

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But what are the “steps” allowed in biochemistry?

?

?

? ?

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All possible reaction types are explored

aldehyde dehydrogenase (CoA):pyruvate ↔ acetyl-CoA + CO

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isomerase (keto to enol):pyruvate ↔ enolpyruvate

kinase (carboxyl):pyruvate ↔ pyruvate-P

Hatzimanikatis et al. (Bioinformatics 2005)

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EC numbers define 30 possible enzymatic reaction families

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EC numbers define 30 possible enzymatic reaction families

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)

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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)

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Are all pairs of metabolites connected by shortest possible paths? (as allowed by biochemistry rules)

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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

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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

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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

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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

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Central carbon metabolism network breaks down to minimality modules

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Biomass precursors are key metabolites

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• 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”

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Can carbon fixation metabolism be “enhanced”?

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Can we find “better” ways to achieve carbon fixation?

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There are several alternative carbon fixation pathways

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We systematically explore all possible synthetic carbon fixation pathways

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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)

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The number you need, with reference in just a minute

BioNumbers – Useful biological numbers database

Wiki-like, users edit and comment

Over 3500 properties & 5000 users/month

www.BioNumbers.org

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