Lecture #8

1. Lecture #8 Stoichiometric Structure

2. Outline • Cofactors and carriers • Bi-linear nature of reactions • Pathways versus cofactors • Basics of high energy bond exchange • Prototypic pathway models

3. Cofactors and Carriers

4. Basic Cofactor/Carrier Molecules in Metabolism

5. Some examples

6. Vitamins

7. The Bi-linear Nature of Biochemical Reactions: transfer/exchange of properties Motif: Donor (X) Carrier (C) Property (A) Acceptor (Y) transferred/exchanged moiety Highly connected carriers: Many donors ATP ADP t ≅ 1min Many, many acceptors

8. PATHWAY VS. KEY COFACTOR VIEW

9. Redox Trafficking in the Core Metabolic Pathways: pathway view classical viewpoint

10. Redox Trafficking in the Core Metabolic Pathways:cofactor view A tangle of cycles through pools systems viewpoint

11. HIGH ENERGY PHOSPHATE GROUP EXCHANGE

12. The Basics of High-Energy Phosphate Bond Trafficking

13. 1. Basic Equations vuse ATP ADP vform - + vdistr (+I/O) AMP ADP Input/ Output~0.0 = 0

14. Dynamic Response to a Load Perturbation 50% increase in kuse ATP ADP AMP ADP dynamic phase portrait of fluxes

15. Graphical Representation of Charge and Capacity fast slow here, capacity is constant at 4.2 mM since there are no I/O on the carrier molecule (Reich, J.G. and Sel’kov, E.E., Energy Metabolism of the Cell Academic Press, New York, 1981).

16. 2. Buffer on Energy Storage buffer molecule is creatine in mammalian tissues

17. Dynamic Response btot =10 Kbuff =1 kbuff =1000 total capacity with buffer same change as before

18. 3. Open System: AMP made and degraded 10 ATP ADP form AMP ADP drain 0.03 mM/min dAMP dt =vamp,form-vamp,drain+vdistr ≠ 0

19. Dynamic Response to a Load Perturbation (kuse,ATP50%) (flux phase portraits)

20. Dynamic Response: capacity and charge Capacity (ATP+ADP+AMP) fast response slow response Occupancy 2ATP+ADP p(t)=Px(t)

21. Charge and Capacity: Both Dynamic fast slow

22. PROTOTYPIC METABOLIC PATHWAYS WITH COFACTORS

23. Open System: charging and discharging metabolites enabling a load to be placed on a system • Energy bonds for charging < recovery • The basic structure of pathways: it takes P ($) to make P ($)

24. Dynamic Responses to a Load Perturbation Fast Slow

25. Dynamic Response (con’t) (flux phase portrait)

26. Differences from the un-coupled module • The pathway input flux is fixed • Thus the ADP->ATP will be fixed • System will return to the original steady state • The ATP rate of use is increased 50% as before

27. Summary • The bi-linear properties of biochemical reactions lead to complex patterns of exchange of key chemical moieties and properties. • Many such simultaneous exchange processes lead to a `tangle of cycles' in biochemical reaction networks. • Skeleton (or scaffold) dynamic models of biochemical processes can be carried out using dynamic mass balances based on elementary reaction representations and mass action kinetics. • Many dynamic properties are a result of the stoichiometric texture and do not result from intricate regulatory mechanisms or complex kinetic expressions. • Complex kinetic models are built in a bottom-up fashion, adding more and more details in a step-wise fashion making sure that every new feature is consistently integrated. • Once dynamic network models are formulated, the perturbations to which we simulate their responses are in fluxes, typically the exchange and demand fluxes. • A recurring theme is the formation of pools and the state of those pools in terms of how their total concentration is distributed among its constituent members. • The time scales are typically separated.