why do metabolic networks look like they do?
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What is similar?
What is different?
Fundamental constraints om
physics,chemistry & biology.
Mechanisms of evolution & adaptation.
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?
Representations / projectionsGraph types
What do metabolic networks look like?
What is a metabolic network?
Currency metabolitesRepresentations / projectionsGraph types
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
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
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?
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?e problem of null-models
Rewired networks violate mass balance
Other reaction systems
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?
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
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.
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