Processing Function Terms

Amelia Ireland

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’

The Proposal

• Move function terms representing steps in a process into the process ontology

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’

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’

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 + O2 = ent-kaur-16-en-19-ol + NADP+ + H2O

2. ent-kaur-16-en-19-ol + NADPH + O2 = ent-kaur-16-en-19-al + NADP+ + 2 H2O

3. ent-kaur-16-en-19-al + NADPH + O2 = ent-kaur-16-en-19-oate + NADP+ + H2O

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.

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’

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?

The ‘One Step’ Rule

One step… or many?

fructose-bisphosphate aldolase activity

http://www.bu.edu/aldolase/lab/aldolase/intro/mechanism.html

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?

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’

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

‘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

‘Clean’ Functions

Notch signaling pathway ; GO:0007219

Notch binding ; GO:0005112

Delta binding ; GO:new

Notch receptor processingGO:0007220 (process term)

Notch signaling pathway

Delta binding

Notch binding

Notch receptor processing

‘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)

‘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

‘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

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’

Proposed Solution

• Move terms representing events into the process ontology

Catalytic activities

• Terms would be rehomed under ‘metabolism’

metabolism hydrolase activity isomerase activity ligase activity lyase activity oxidoreductase activity transferase activity

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

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?

Catalytic activities

• Reactions in more than one pathway

arginase activity arginase activity during arginine catabolism to glutamate

arginase activity during arginine catabolism to pyruvate

Binding

• Binding terms could be rehomed under ‘metabolism’

metabolism amine metabolism

amine binding binding

amine binding

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

…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

…and the rest

• Reinstate some obsoletes Cell adhesion molecule --> cell adhesion receptor binding during cell-cell adhesion

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

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.

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?

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

Processed Functions

Notch signaling pathway ; GO:0007219

Process: Notch binding ; GO:0005112function: ligand

process: Delta binding ; GO:newfunction: receptor

Processed Functions

arginine catabolism to glutamate ; GO:0019544

arginase activityenzyme

ornithine-oxo-acid transaminase

activityenzyme

1-pyrroline-5-carboxylate

dehydrogenase activity enzyme

MetaCyc:ARGASEDEG-PWY arginine degradation I (arginase pathway)

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

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