Human liver rate-limiting enzymes influence metabolic flux via branch points and inhibitors

1. Human liver rate-limiting enzymes influence metabolic flux via branch points and inhibitors Min Zhao Center for Bioinformatics Peking University

2. Outline • Construction of rate-limiting enzyme database • Global analysis of rate-limiting enzyme in human liver

3. Outline • Construction of rate-limiting enzyme database • Global analysis of rate-limiting enzyme in human liver

4. Regulation of metabolic network • Living cells are self-regulating chemical engines, tuned to operate on the principle of maximum economy. —A. L. Lehninger • A pathway’s activity is often controlled by its end products through feedback inhibition of regulatory enzymes located at the start of the sequence and at branch points.

5. Rate-limiting enzymes in TCA • Krebs(1957) • Pacemaker • Bücher& Russmannn • (1963) • Rate-limiting

6. The properties of rate-limiting enzymes • Relatively low velocities • High flux-control coefficient • To improve the total output of the whole pathway, just need to improve [rate-limiting enzymes] • Extensively regulated • Defined by function • Cyclooxygenases, organisms

7. Construction of RLEdb

8. Data contents • 387 rate-limiting enzymes from15688 abstracts • Number of rate-limiting enzymes in database: 147 (human), 105 (rat), 96 (mouse), 16 (yeast) and 15 (E. coli) • Number of transcription factors: 330 • Pairs of transcription factors and rate-limiting enzymes: 478

10. Publication Http://rle.cbi.pku.edu.cn

11. Discover regulatory relations between rate-limiting enzymes and transcription factors

12. Outline • Construction of rate-limiting enzyme database • Global analysis of rate-limiting enzyme in human liver

13. Branch points • >=3 • >=1 consume • >=1 produce X is branch point(Heijnena,2004)

14. Datasets and Networks • 687 metabolic enzymes of human liver • all 1033 products of these 687 enzymes • 96 liver rate-limiting enzymes manually collected from 2682 PubMed abstracts • 132 branch points curated from KEGG pathway maps • 202 enzyme inhibitors collected from the BRENDA database • compound conversion network from rpair • inhibitory network

15. The 39 common compounds • the 28 compounds which take part in more than 100 reactions • 7 energy metabolism related nucleoside monophosphates, Nucleoside diphosphates and Nucleoside triphosphates • 4 too general compounds including RNA, DNA, Protein and Peptide

16. How many branch points are surrounded by rate-limiting enzymes

17. Topological relations between rate-limiting enzymes and branch points

18. Rate-limiting enzymes and branch points

19. Compound conversion network

20. The role of branch points

21. Rate-limiting enzymes produced nearly half enzymes inhibitors • According our in vivo inhibitor annotation, rate-limiting enzymes in human liver could produce nearly half enzymes inhibitors (99 versus 204)

22. Inhibitory network

23. Cross-pathway inhibitory relations

24. Regulability and Regulatory capacity • Regulability: the activity of the regulatory enzyme with which a regulator interacts directly can be altered by the regulator. • Regulatory capacity: The ability of the regulatory enzyme to transmit the changes to the rest of the system. - Flux control coeffieicent - Aldose reductase could initiate cell signaling and apoptosis of vascular endothelial cells via TNF-alpha (Ramana et al. , 2004)

25. Summary • Construction of RLEdb • Rate-limiting enzymes surround 76.5% branch point compounds in total. • Branch points show high degree, betweenness centrality and closeness centrality in compound conversion network. • Rate-limiting enzymes produced nearly half enzymes inhibitors.

26. Acknowledge • Prof Liping Wei • Prof Louis Tao • Prof Hong Qu • Prof Ge Gao • All CBI classmates

27. Thank you for your attention

28. Rate-limiting enzyme • a relative measure of how much a perturbation affects a system variable Avariants, i pathway, vi (Kacser & Burns 1973, Heinrich & Rapoport 1974, Burns et al. 1985)