Reconstruction and analysis of human liver-specific metabolic network based on CNHLPP data Jing Zhao...
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Transcript of Reconstruction and analysis of human liver-specific metabolic network based on CNHLPP data Jing Zhao...
Reconstruction and analysis Reconstruction and analysis of human liver-specific of human liver-specific
metabolic network based on metabolic network based on CNHLPP dataCNHLPP data
Reconstruction and analysis Reconstruction and analysis of human liver-specific of human liver-specific
metabolic network based on metabolic network based on CNHLPP dataCNHLPP data
Jing Zhao
Logistical Engineering University
The 6th Chinese Conference of Complex Networks , October 15-18, 2010. Suzhou, China
OutLine• Background• Reconstruction of metabolic networks• Basic topological features of metabolic networks for human liver and Homo sapiens genome• Functional organization of liver revealed by topological modules in liver-specific metabolic network• Enzyme abundance in topological modules of liver-specific metabolic network• Comparison of metabolic network of human liver with that of the Homo sapiens genome
• producing substances that break down fats
• converting glucose to glycogen
• producing urea
• making certain amino acids
• filtering harmful substances from the blood
• storing vitamins and minerals
• maintaining a proper level of glucose in the blood
Function of liver
Network representation of Metabolism: Substrate graph
HLPP: The Human Liver Proteome Project
The first initiative on human tissues/organs launched by the Human Proteome Organization (HUPO)
Data used in this study
• Data from CNHLPP
6788 distinct proteins (IPI codes) and protein quantitation data , confidence level 95% 6220 distinct genes 1421 genes encode 721 distinct enzymes
• BiGG database
3311 reactions 1555 enzyme-catalyzed reactions 1756 auto-catalytic reactions
Human metabolic network
Liver metabolic network
Reconstruction of liver metabolic network
1. original core reaction set : 1047 liver enzyme-catalyzed reactions initial candidate reaction set: all of the auto-catalytic reactions
2. Extract all metabolites appearing in core reaction set to get core metabolite set.
3. Scan the list of candidate reactions for core metabolites. If all substrates for one reaction can be found in core metabolite set, add this reaction into core reaction set and remove it from the candidate set.
4. If step 3 cannot add any more reactions into core reaction set, stop; else, go to step 2.
Added: 427 auto-catalytic reactions
CNHLPP data BiGG
380 enzymes, 1047 enzyme-catalyzed reactions
Basic graph metrics of metabolic networks
Metabolic networkNetwork for human
liverNetwork for H.sapiens gen
ome
Nodes 1093 1473
Arcs 2209 3361
Density 0.0019 0.0016
Degree distribution P(k)~k-2.73 P(k)~k-2.67
Average path length 8.5 9.8
Diameter 28 49
Biggest cluster Nodes 1026 1407
Arcs 2159 3314
Bowtie of biggest cluster
GSC 424 (41.3%) 987 (70.2%)
S 262 (25.5%) 117 (8.32%)
P 187 (18.2%) 272 (19.3%)
IS 153 (14.9%) 31 (2.2%)
Comparison of the liver metabolic network with its random counterparts
Nodes ArcsDensit
y
Average path
length
Diameter
Fraction of nodes in
the biggest cluster
Liver network 1093 2209 0.0019 8.5 28 0.9387
100 type I random sub-networks(same arcs as the liver network)
Mean 1317 2209 0.0013 10.1 29.7 0.8575
Z-score
-21.83 - 29.03 -3.27 -0.47 5.24
100 type II random sub-networks(same nodes as the liver network)
Mean 1093 1870 0.0016 9.6 30.2 0.8309
Z-score
- 5.25 5.25 -1.25 -0.39 5.09
100 type III random sub-networks(same enzyme-catalyzed reactions as the liver network)
Mean 1240 2287 0.0015 8.95 26.3 0.8806
Z-score
-23.2 -6.17 27.2 -1.8 0.67 5.04
Functional organization of liver revealed by topological modules in liver metabolic network
Core-periphery organization
Main derivative metabolism functions of the topological modules for human liver-specific metabolic network
Main Function category
Module Main Function
Glycan biosynthesis and metabolism
5 Biosynthesis of chondroitin / heparan sulfate and keratan sulfate
13 Biosynthesis of N-glycan
12 Degradation of heparan sulfate and N-glycan
14 Degradation of chondroitin sulfate
16 Degradation of keratan sulfate
Metabolism of cofactors and vitamins
1 Metabolism of folate and vitamin B6
3 R group synthesis
6 Heme biosynthesis
9 Heme degradation and vitamin A metabolism
11 Tetrahydrobiopterin; Vitamin B12 Metabolism
Xenobiotics biodegradation and metabolism
2 ROS detoxification
5 CYP metabolism
Enzyme abundance in topological modules of liver-specific metabolic network
P (Q >2.35)=10%; P (Q <0.5)=70%.
Comparison of metabolic network of human liver with that of the Homo sapiens genome
10 of the 16 modules ( Module 1,2,3,4,6,8,9,11,12,13) :
P-value < 0.05
1
0
1
0
1)(1k
i
k
i
n
N
in
KN
i
K
ifp
P-value
Quantitative difference between categories: overlap score
XY (x,y) X (x)Y (y)yY
xX
),max( YYXX
XYXY
Prototypical overlap score
Normalized overlap score
X ,Y : two categorizations
X(x) ,Y(y) : the fraction of metabolites in category x X, y Y, respectively
XY(x,y): the joint frequency of x and y, i.e. the fraction of vertices that are categorized both as x X and y Y.
Quantative difference between a feature of the real metabolic network and its randomized counterparts: Z- score
r
r
f
ffZ
f : the metric of the feature in the real network
rf
rf: the standard deviation of the corresponding metric in the randomized ensemble
: the mean of the corresponding metric in the randomized ensemble
v = 0.72; Z =68.5
AcknowledgementShanghai Center for Bioinformation and Technology:
Lin Tao, Duanfeng Zhang, Kailin Tang ,Ruixin Zhu , Hong Yu ,Yixue Li, Zhiwei Cao
Beijing Proteome Research Center:
Chao Geng, Ying Jiang,Fuchu He
Second Military Medical University:
Weidong Zhang
Petter Holme
Eytan Ruppin
Livnat Jerby
Ori Folger
National Natural Science Foundation of China (10971227, 30900832)
Ministry of Science and Technology China(2006AA02312, 2009zx10004-601, 2010CB833601
Shanghai Municipal Education Commission (2000236018).
Thanks!