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 Donor (X) Carrier (C) Property (A) Acceptor (Y) Motif: transferred/exchanged moiety Many donors ATPADP Many, many acceptors Highly connected carriers: t 1min

8. Ultra-Structure of Metabolic Pathways Reich, J.G. and Selkov, E.E., Energy Metabolism of the Cell Academic Press, New York, 1981 Recon 1

9. PATHWAY VS. KEY COFACTOR VIEW

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

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

12. HIGH ENERGY PHOSPHATE GROUP EXCHANGE

13. The Basics of High-Energy Phosphate Bond Trafficking

14. 1. Basic Equations ATP ADP v form v use AMPADP v distr + - Input/ Output~0.0 = 0 (+I/O)

15. Dynamic Response to a Load Perturbation ATP ADP AMPADP 50% increase in k use dynamic phase portrait of fluxes

16. 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 Selkov, E.E., Energy Metabolism of the Cell Academic Press, New York, 1981).

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

18. Dynamic Response b tot =10 K buff =1 k buff =1000 total capacity with buffer same change as before

19. 3. Open System: AMP made and degraded ATP ADP AMPADP 10 0.03 mM/min dAMP dt =v amp,form -v amp,drain +v distr 0 form drain

20. Dynamic Response to a Load Perturbation (k use,ATP 50%) (flux phase portraits)

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

22. Charge and Capacity: Both Dynamic fast slow

23. PROTOTYPIC METABOLIC PATHWAYS WITH COFACTORS

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

25. Dynamic Responses to a Load Perturbation Fast Slow

26. Dynamic Response (cont) (flux phase portrait)

27. 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

28. 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.