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

赵 静

解放军后勤工程学院数学教研室

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!