1. Processing Function Terms Amelia Ireland

2. Function Problems Function-process crossover  Function and process are not orthogonal  Functions appear in process and vice versa The ‘One Step Rule’  ‘Steps’ vary between terms ‘Clean’ and ‘dirty’ functions  Many functions don’t fit the def ‘elemental activities describing the actions of a gene product at the molecular level’ GO function is not what people mean when they talk about the ‘function of a protein’

3. The Proposal Move function terms representing steps in a process into the process ontology

4. Function Problems Function-process crossover  Function and process are not orthogonal  Functions appear in process and vice versa The ‘One Step Rule’  ‘Steps’ vary between terms ‘Clean’ and ‘dirty’ functions  Many functions don’t fit the def ‘elemental activities describing the actions of a gene product at the molecular level’ GO function is not what people mean when they talk about the ‘function of a protein’

5. The Process-Function Crossover Functions in process  Detection  The series of events in which a stimulus type stimulus is received by a cell and converted into a molecular signal.  i.e. binding during a signaling pathway  Metabolism  The chemical reactions involving xxx  binding is a chemical reaction  chemical reactions ‘involving’ xxx limits metabolism to reactions in which X is the product or those where X is the reactant, i.e. one step reactions  Many terms under ‘protein modification’

6. The Function-Process Crossover Processes in function  ent-kaurene oxidase activity, 1.14.13.78  Catalysis of three successive oxidations of the 4- methyl group of ent-kaurene resulting in kaurenoic acid. 1. ent-kaur-16-ene + NADPH + O 2 = ent-kaur-16-en- 19-ol + NADP + + H 2 O 2. ent-kaur-16-en-19-ol + NADPH + O 2 = ent-kaur- 16-en-19-al + NADP + + 2 H 2 O 3. ent-kaur-16-en-19-al + NADPH + O 2 = ent-kaur- 16-en-19-oate + NADP + + H 2 O

7. The Process-Function Crossover Identical processes and functions  histone H3-K4 methylation  The modification of histone H3 by addition of a methyl group to lysine at position 4 of the histone.  histone lysine N-methyltransferase activity (H3-K4 specific)  Catalysis of the addition of a methyl group onto lysine at position 4 of the histone H3 protein.

8. Function Problems Function-process crossover  Function and process are not orthogonal  Functions appear in process and vice versa The ‘One Step Rule’  ‘Steps’ vary between terms ‘Clean’ and ‘dirty’ functions  Many functions don’t fit the def ‘elemental activities describing the actions of a gene product at the molecular level’ GO function is not what people mean when they talk about the ‘function of a protein’

9. The ‘One Step’ Rule Currently use the ‘one step rule’ to decide between process and function  One step --> function  More than one step --> process But what level should the ‘steps’ be at?

10. The ‘One Step’ Rule One step… or many? fructose-bisphosphate aldolase activity http://www.bu.edu/aldolase/lab/aldolase/intro/mechanism.html

11. The ‘One Step’ Rule glycerol-3-phosphate transporter activity http://student.biology.arizona.edu/honors2004/group02/home02.html (1) an inorganic phosphate (Pi) from the periplasm binds to Co; (2) the Co pore increases in diameter; (3) a G3P binds to the Co and brings the enlarged Co pore to normal size; (4) the Co pore continues to decrease in diameter until it closes completely, which forces the G3P to the cytoplasmic end where it attaches to the Ci end; (5) the Ci pore enlarges to a certain point; (6) the Ci pore decreases in size and forces a Pi out of the cytoplasm. One step… or many?

12. Function Problems Function-process crossover  Function and process are not orthogonal  Functions appear in process and vice versa The ‘One Step Rule’  ‘Steps’ vary between terms ‘Clean’ and ‘dirty’ functions  Many functions don’t fit the def ‘elemental activities describing the actions of a gene product at the molecular level’ GO function is not what people mean when they talk about the ‘function of a protein’

13. Clean and Dirty Functions molecular function  Elemental activities, such as catalysis or binding, describing the actions of a gene product at the molecular level. A given gene product may exhibit one or more molecular functions. Two kinds of function term  “Clean”: steps in a process  “Dirty”: combination of two or more process, function or other attributes

14. ‘Clean’ Functions arginine catabolism to glutamate ; GO:0019544 arginase activity GO:0004053 ornithine-oxo-acid transaminase activity GO:0004587 1-pyrroline-5-carboxylate dehydrogenase activity GO:0003842 MetaCyc:ARGASEDEG-PWY arginine degradation I (arginase pathway) arginine catabolism to glutamate  arginase activity  ornithine-oxo-acid transaminase activity  1-pyrroline-5-carboxylate dehydrogenase activity

15. ‘Clean’ Functions Notch signaling pathway ; GO:0007219 Notch binding ; GO:0005112 Delta binding ; GO:new Notch receptor processing GO:0007220 (process term) Notch signaling pathway  Delta binding  Notch binding  Notch receptor processing

16. ‘Dirty’ Functions Not steps in a process Represent a combination of two or more attributes from function, component, process or other domain May be occurrents (events) or continuants (entities)

17. ‘Dirty’ Functions transcription factor activity  Any activity required to initiate or regulate transcription; includes the actions of both gene regulatory proteins as well as the general transcription factors.  i.e. a role in regulation of transcription or transcription initiation receptor activity  Combining with an extracellular or intracellular messenger to initiate a change in cell activity.  i.e. binding in a signaling pathway

18. ‘Dirty’ Functions ‘structural molecule activity’, ‘enzyme regulator activity’, ‘hormone activity’, ‘protein tag’ have similar problems Dirty functions represent a role or a class and cannot be linked to process terms using existing GO relationships

19. Function Problems Function-process crossover  Function and process are not orthogonal  Functions appear in process and vice versa The ‘One Step Rule’  ‘Steps’ vary between terms ‘Clean’ and ‘dirty’ functions  Many functions don’t fit the def ‘elemental activities describing the actions of a gene product at the molecular level’ GO function is not what people mean when they talk about the ‘function of a protein’

20. Proposed Solution Move terms representing events into the process ontology

21. Catalytic activities Terms would be rehomed under ‘metabolism’ metabolism  hydrolase activity  isomerase activity  ligase activity  lyase activity  oxidoreductase activity  transferase activity

22. Catalytic activities Individual reactions could be organised according to substances involved arginine metabolism  arginine biosynthesis  argininosuccinate lyase activity  D-nopaline dehydrogenase activity  arginine catabolism  arginase activity  arginine 2-monooxygenase activity

23. Catalytic activities Reactions could be put into pathways arginine catabolism  arginase catabolism to glutamate  1-pyrroline-5-carboxylate dehydrogenase activity  arginase activity  ornithine-oxo-acid transaminase activity Data from MetaCyc, FIGS, KEGG?

24. Catalytic activities Reactions in more than one pathway arginase activity  arginase activity during arginine catabolism to glutamate  arginase activity during arginine catabolism to pyruvate

25. Binding Binding terms could be rehomed under ‘metabolism’  metabolism  amine metabolism  amine binding  binding  amine binding

26. Binding Binding terms can now be linked with signaling pathways and other processes  Notch signaling pathway  Notch binding during Notch signaling pathway  Delta binding during Notch signaling pathway  Notch receptor processing

27. …and the rest Transporter activity  xxx transporter activity --> xxx transport  xxx permease activity --> permease-mediated xxx transport Receptor activity  ligand binding during signaling pathway Regulator activity  regulation

28. …and the rest Reinstate some obsoletes  Cell adhesion molecule --> cell adhesion receptor binding during cell-cell adhesion

29. Synonyms All moved terms will be given many synonyms in both process and function ‘style’  e.g. glucose dehydrogenase, glucose dehydrogenation  glucose carrier, carrier-mediated glucose transport

30. Brave New Function World Redefine function  Various dictionary definitions of function:  the special, normal, or proper physiologic activity of a gene product  the actions and activities assigned to or required or expected of a gene product  what a gene product is used for  the purpose, role, or function a gene product serves  The purpose or role a gene product serves in the normal physiologic activity of an organism. A gene product may have one or more functions.

31. Proposed Solution Keep ‘dirty’ terms representing combinations of function, process or other information in function New function def would allow us to add useful terms currently not allowed  toxin  ligand  other suggestions?

32. Brave New Function World  energy transducer  enzyme  motor  nutrient reservoir  signal  chemoattractant  chemorepellant  hormone  ligand  morphogen  protein tag  structural molecule  receptor  regulator  chaperone regulator  enzyme regulator  transcription regulator  translation regulator  transporter  toxin

33. Processed Functions Notch signaling pathway ; GO:0007219 Process: Notch binding ; GO:0005112 function: ligand process: Delta binding ; GO:new function: receptor

34. Processed Functions arginine catabolism to glutamate ; GO:0019544 arginase activity enzyme ornithine-oxo-acid transaminase activity enzyme 1-pyrroline-5-carboxylate dehydrogenase activity enzyme MetaCyc:ARGASEDEG-PWY arginine degradation I (arginase pathway)

35. Pros and Cons +reactions involving a certain substrate can all be homed underneath ‘xxx metabolism’ +reactions can be linked to pathways +greater precision in annotation +ontologies more consistent and ‘pure’ +less redundancy between process and function +GO function closer to colloquial interpretation

36. Pros and Cons -some adjustment needed by those accustomed to seeing binding and enzymatic reactions in function -may take some time to implement -no obsoletions 