Whydo

metabolicnetworks

lookliketheydo?

PetterHolme

What is similar?

What is similar?

Fundamental constraints om

physics,chemistry & biology.

What is similar?

What is different?

Fundamental constraints om

physics,chemistry & biology.

What is similar?

What is different?

Fundamental constraints om

physics,chemistry & biology.

Mechanisms of evolution & adaptation.

What do metabolic networks look like?

What do metabolic networks look like?

What do metabolic networks look like?

What is a metabolic network?

What do metabolic networks look like?

What is a metabolic network?

O + O₃ → 3O₂2O₂ + CH₄ → CO₂ + 2H₂O

OH⁻

What do metabolic networks look like?

What is a metabolic network?

What do metabolic networks look like?

What is a metabolic network?

What do metabolic networks look like?

What is a metabolic network?

Graph types

What do metabolic networks look like?

What is a metabolic network?

Representations / projectionsGraph types

What do metabolic networks look like?

What is a metabolic network?

Currency metabolitesRepresentations / projectionsGraph types

Complex

Graph types

Simple

Complex

Graph types

Simplelittle info, many methods

Complex

Graph types

Simplelittle info, many methods

lots of info, few methods

Representations2O₂ + CH₄ → CO₂ + 2H₂O

CH₄

O₂

H₂O

CO₂

Representations2O₂ + CH₄ → CO₂ + 2H₂O

CH₄

O₂

H₂O

CO₂

Representations2O₂ + CH₄ → CO₂ + 2H₂O

CH₄

O₂

H₂O

CO₂SUBSTRATE–PRODUCT GRAPH

Representations2O₂ + CH₄ → CO₂ + 2H₂O

CH₄

O₂

H₂O

CO₂SUBSTRATE–SUBSTRATE GRAPH

Representations2O₂ + CH₄ → CO₂ + 2H₂O

CH₄

O₂

H₂O

CO₂SUBSTANCE GRAPH

Hypothesis: Network clusters ~ functional modules Holme, Huss, Jeong, 2003. Subnetwork hierarchies of biochemical pathways, Bioinformatics 19:532–538.

Hypothesis: Network clusters ~ functional modules Holme, Huss, Jeong, 2003. Subnetwork hierarchies of biochemical pathways, Bioinformatics 19:532–538.

Hypothesis: Network clusters ~ functional modules Holme, Huss, Jeong, 2003. Subnetwork hierarchies of biochemical pathways, Bioinformatics 19:532–538.

match

ing sc

ore

0.25

0

0.75

0.5

substrate–product

substrate–substrate substance

Huma

n (KE

GG)

S. ce

revisi

ae (K

EGG)

S. ce

revisi

ae (B

iGG)

C. ele

gans

M. m

uscu

lus

R. no

rvegic

us

D. me

lanog

aster

M. ge

nitali

um

E. co

li

Huma

n (BiG

G)

Matching network clusters & annotated functions

match

ing sc

ore

0.25

0

0.75

0.5

substrate–product

substrate–substrate substance

Huma

n (KE

GG)

S. ce

revisi

ae (K

EGG)

S. ce

revisi

ae (B

iGG)

C. ele

gans

M. m

uscu

lus

R. no

rvegic

us

D. me

lanog

aster

M. ge

nitali

um

E. co

li

Huma

n (BiG

G)

Holme, Huss, 2010. Substance networks are optimal simple-graph representations of metabolism, Chinese Sci. Bull. 55:3161-3168.

Currency metabolites

Currency metabolites

Currency metabolites

Currency metabolites

Currency metabolites

Exists throughout the cell(i.e. many modules)

Can react with a great variety of other substances

Currency metabolites

Exists throughout the cell(i.e. many modules)

Can react with a great variety of other substances

Jing, Holme, 2010. Lecture Notes in Operations Research 13:13–21.

Currency metabolites

Exists throughout the cell(i.e. many modules)

Can react with a great variety of other substances

lowers the modularity

Currency metabolites

Exists throughout the cell(i.e. many modules)

Can react with a great variety of other substances

lowers the modularity

high degree

Currency metabolites

Currency metabolites

Currency metabolites

Exists throughout the cell (i.e. many modules)

Can react with a great variety of other substances

lowers the modularity

high degree

Currency metabolites1. calculate modularity2. remove the vertex with highest

degree3. go to 1e deleted vertex set with highestmodularity are the currency metbolites

Currency metabolites

0.15

0.14

!

0.13

0.12Orthophosphate

Pyrophosphate

CO2

CoA

AMP

NH3

UDP S–Adenosyl–L–m

ethionine

H!O

H+ O 2 NADPH

NADP

NADH

ATP NAD

ADP

L–Glutamate

H 2O 2

deleted vertex number1 5 10 15

+ +

Currency metabolitesWagner, Fell Schuster & al. Ma & Zeng

ATP ATP ATPADP ADP ADP

NADP+ NADP+ NADP+NADPH NADPHNAD+ NAD+NADH

Pi PiH2O H2OH+PPiCMP CO2

O2NH3

Currency metabolitesWagner, Fell Schuster & al. Ma & Zeng

ATP ATP ATPADP ADP ADP

NADP+ NADP+ NADP+NADPH NADPHNAD+ NAD+NADH

Pi PiH2O H2OH+PPiCMP CO2

O2NH3

Huss, Holme, 2007. Currency and commodity metabolites, IET Systems Biology 1:280–285.

So what do metabolic networks look like?

So what do metabolic networks look like?

Broad degree distributions0.1

10 –2

10 –3

10 –4

10 –5

10 –6

10 3100101

p(k)

degree, k

So what do metabolic networks look like?

Broad degree distributionsCore-periphery structure +a weak but significant modular structure

So what do metabolic networks look like?

Broad degree distributionsCore-periphery structure +a weak but significant modular structure

So what do metabolic networks look like?

Broad degree distributionsCore-periphery structure +a weak but significant modular structure

So what do metabolic networks look like?

Broad degree distributionsCore-periphery structure +a weak but significant modular structure Network modules ~ subcellular localization

Į

N

Į

S

H O2

pyruvate, CO2

H O2CO2

ATP, ADP

pyrophosphateNADPH, NADH

substratereaction nodelinkin!flowout!flow

!D!ribose 1!phosphate

CoA

orthophosphateadenine

deoxyadenosine

inosineadenosine

hypoxanthine

guanine

guanosine

deoxyguanosine

D!glucosamine 1!phosphate

1!phosphate!acetyl!D!glucosamine

acetyl!CoA

dihydrolipoamide

!D!ribose 1!pyrophosphate

!acetyldihydrolipoamide

pyrophosphate

2!deoxy!D!ribose 1!phosphate

iiiiii

Compared to what?

Compared to what?e problem of null-models

Compared to what?e problem of null-models

Rewired networks violate mass balance

Compared to what?e problem of null-models

Rewired networks violate mass balance

Other reaction systems

Compared to what?

Compared to what?

Holme, Huss, Lee, 2011. Atmospheric reaction systems as null-models to identify structural traces of evolution in metabolism, PLoS ONE 6:e19759.

0.1

0.2

0.3

0.4

0.5

0.6

10 3100 103100 1040

2

3

4

5

6

1

7

number of vertices, N number of edges, M

relati

ve m

odula

rity, !

numb

er of

curre

ncy v

ertice

s, c

0

planetsorganisms

Finally: Why?Is the weak modularity

related to robustness?

Finally: Why?

3.3

3.4

3.5

3.6

3.7

3.8

0.70 0.75 0.80 0.85modularity

robus

tness

1.27

1.29

1.31

1.33

1.35

1.37

0.70 0.75 0.80 0.85rob

ustn

essmodularity

genetic perturbations chemical perturbations

x!Mikael HussJing ZhaoSang Hoon Lee

x!Mikael HussJing ZhaoSang Hoon Lee

Compared to what?

Holme, 2009. Model validation of simple-graphrepresentations of metabolism. J Roy Soc Interface 40:1027–1034.

Compared to what?

Holme, 2009. Model validation of simple-graphrepresentations of metabolism. J Roy Soc Interface 40:1027–1034.

Compared to what?

Holme, 2009. Model validation of simple-graphrepresentations of metabolism. J Roy Soc Interface 40:1027–1034.