2. Metabolic inheritance Eörs Szathmáry Collegium Budapest AND Eötvös University

3. The formose ‘reaction’ formaldehyd e glycolaldehyde autocatalysi s Butlerow, 1861

4. Von Kiedrowski’s replicator

5. Replication in the formose reaction Replication is non-informational Autocatalysis – YES Heredity – NO Good for metabolism Not good for genetics

6. Gánti’s chemoton model (1974) ALL THREE SUBSYSTEMS ARE AUTOCATALYTIC template copying metabolism membrane growth

7. Is this just logical or also historical order? How much evolution did take place (presumably on surfaces) before protocells appeared?

8. The latest edition: OUP 2003 After several editions in Hungarian Two previous books (the Principles and Contra Crick) plus one essay Essays appreciating the biological and philosophical importance

9. Pathways of supersystem evolution boundary template metabolism M BM B B TB T M TM T M B TM B T INFRABIOLOGICAL SYSTEMS

10. Contemporary autocatalytic biochemical cycles The Calvin cycle (sugar-phosphate making more sugar-phosphate) Reverse citric acid cycle

11. Primitive ancestry of the reverse citric acid cycle Was proposed by Günter Wächtershäuser (1990) Coupled to CO 2 fixation and pyrite formation around deep-sea hydrothermal vents

12. The archaic version He even imagined alternative („mutant”) cycles No experimental evidence so far

13. Units of evolution (JMS) hereditary traits affecting survival and/or reproduction 1.multiplication 2.heredity 3.variation

14. Classification of replicators Limited heredity Unlimited heredity Holisticformose ModularVon Kiedrowski genes Limited(# of individuals)  (# of types) Unlimited(# of individuals) << (# of types)

15. King (1980): evolution of the coenzymes He looked at the metabolic maps then Coenzymes looked auto- and cross-catalytic BUT the situation is slightly more complicated The idea nicely links to the assumed primitive ancestry of coenzymes (related to the idea of the RNA world)

16. An autocatalytic cycle in the given environment

17. Although A is autocatalytic, it is not strictly needed Dependent on the environment!

18. Autocatalysis of the pair (A, B) is more complicated, but easy to see

19. If this is big, you may not realize the autocatalysts

20. The basic question Could one kick-start metabolism just with external molecules and macromolecules (genes an enzymes)? Influx  buildup of metabolism?

21. What to do? Work with B. Papp and Á. Kun Use Heinrich’s scope analyis to identify absolutely essential INTERNAL molecules Look for those molecules that yield the largest increase in metabolic scope Stop when there is a functional metabolism Check the results with flux balance analysis (FBA) for the producible compounds in steady state

22. Autocatalytic synthesis of CoA in Synechocysts sp. Note: the same cofactor can be autocatalytic in different ways in different organisms

23. Metabolic networks

24. Environmental dependence E. coli network under a condition where only glucose and inorganic compounds were included in the food set. In addition to ATP, NAD, CoA and quinones were also identified as autocatalytic seeds under this condition

25. Conlusions Essentially, Gánti and King were right There IS an autocatalytic seed At least one coenzyme is always in the seed BUT the set is environment-dependent Puts constraints on artifical (re)construction of (proto)cells BIOINFORMATICS HELPS ANSWER OLD, FUNDAMENTAL QUESTIONS