# HISTORY 07 May 2016: Updated by: TOUCHUP-v1.18 24 Mar 2016: Updated by: TOUCHUP-v1.15 14 Mar 2016: Updated by: TOUCHUP-v1.14 07 May 2016: Updated by: TOUCHUP-v1.18 # molecular_function 20110225: node_PTN000168392 has function carboxylic ester hydrolase activity (GO:0052689) 20110614: Bilateria_PTN000168538 has function receptor activity (GO:0004872) 20110614: Bilateria_PTN000168538 has function neurexin family protein binding (GO:0042043) 20141029: Bilateria_PTN001356861 has function cholinesterase activity (GO:0004104) 20141029: Deuterostomia_PTN000168437 has function acetylcholinesterase activity (GO:0003990) # cellular_component 20141029: node_PTN000169064 is found in extracellular space (GO:0005615) 20110614: Bilateria_PTN000168538 is found in synapse (GO:0045202) 20110614: Bilateria_PTN000168538 is found in integral component of plasma membrane (GO:0005887) 20110614: Bilateria_PTN000168538 is found in cell surface (GO:0009986) 20141029: Deuterostomia_PTN000168437 is found in neuromuscular junction (GO:0031594) 20141029: Bilateria_PTN000168538 is NOT found in extracellular space (GO:0005615) # biological_process 20110614: Bilateria_PTN000168538 participates in synapse assembly (GO:0007416) 20141029: Bilateria_PTN000168538 participates in modulation of synaptic transmission (GO:0050804) 20141029: Bilateria_PTN000168538 participates in neuron cell-cell adhesion (GO:0007158) 20141029: Deuterostomia_PTN000168437 participates in acetylcholine catabolic process (GO:0006581) # WARNINGS - THE FOLLOWING HAVE BEEN REMOVED FOR THE REASONS NOTED # NOTES Fast-pass curation of PTHR11559, the CARBOXYLESTERASE family Phylogeny This family contains 266 members, 166 of which are RefGenome proteins. There are a lot of polytomies near the leaves, probably due to the existence of many sequence variants, especially in the non-RefGenome organisms. Branch lengths are, generally, very short. The root (AN0) is trifurcated into AN1, a clade of Ache and Bche proteins (more below); degenerate clade AN137; and the very large clade AN142. AN1: Ignoring the 3 unannotated outgroups from fungi to bacteria, AN1 reduces to AN4, a metazoan clade with a worm/fly outgroup ("ace" proteins) and a chordate duplication. However, 1 chordate clade, AN6, is completely unannotated and consists primarily of a cluster of urchin proteins. On the other hand, AN45 has a fish outgroup and 2 paralogous tetrapod clades, Ache (AN72) and Bche (AN49), with no further duplications. AN142 has an unannotated bacterial outgroup (AN803) and a duplication at AN143. AN144 stretches from plants to humans; there is a 4-way polytomy of the vertebrates at AN149 and leading to the NLGN1, -2, and -3 clades, plus a clade fo several Tg proteins. The other branch of AN142, AN322, reduces to a dicty outgroup, a very large worm/fly outgroup, and 2 paralogous vertebrate clades: AN345 ("CEL" proteins) and AN374. The latter has very few annotations, mostly in the mammalian Ces2/Ces6 clade (AN395) and in the rodent clade AN478. Most of the effort in this family will be on the Ache/Bche clade AN1. MF -Most of the annotations to catalytic activities fall under GO:0004091 "carboxylesterase activity." By triangulation, propagate this to AN0. -While awaiting an is_a link between GO:0004104 "cholinesterase activity" and GO:0003990 "acetylcholinesterase activity" (see questions, below), propagate both 4104 and 3990 to AN1 based on multiple annotations to both. If and when 3990 is_a 4104 is confirmed, 3990 will subsume 4104. -Note that 4104 has as an exact synonym "butyrylcholinesterase activity." This is because butyrylcholine is not a naturally-occurring compound. (See http://en.wikipedia.org/wiki/Butyrylcholine.) So-called butyrylcholinesterases are actually non-specific cholinesterases acting on a variety of acyl choline compounds, including acetylcholine. Therefore, there is no need for a new term for "butyrylcholinesterase activity." -All the choline binding terms have been covered. -Outside AN1, annotation is too sparse to make reliable inferences. -To go with the MF annotations, propagate the BP's GO:0019695 "choline metabolic process" and GO:0008291 "acetylcholine metabolic process" to AN1. Should there be an is_a relationship here, too? (See below.) -catalytic activity has been lost in the neuroligin/Tg clade, so annotate a NOT here. Neuroligins bind neurexins, which are only present in animals (see PTHR10127), so neurexin binding and associated locations and functions are annotated to the animal MRCA of this clade even though there are other members. -neurexin-like functions (and associated locations and processes) have apparently been lost in Tg, so annotate these NOTs. Unfortunately there are no hormone activity annotations for Tg so cannot give a MF to this clade. CC -Propagate GO:0005886 "plasma membrane" to AN1 based on annotations in vertebrate Ache clade and in fly Ace. There may be more specific "synapse" terms to use for Ache, so look for those. NOT/IRD 5886 to Bche clade based on paralogy and branch length. Also, human BCHE is secreted (see UniProt), and mouse and rat Bche are found in the ER (en route to secretion). Propagate GO:0005788 "endoplasmic reticulum lumen" and GO:0005615 "extracellular space" to Bche clade (AN49). Expand 5788 and 5615 to include Ache clade, too; actually, expand to AN47 to include the fish, as well. Actually, drop the 5886 annotation, which is too vague to describe a secreted protein that hangs out in the extracellular space, but still look for synapse-type terms. -Synapse-type terms to propagate to Ache clade: GO:0009986 : cell surface (actually more consistent with annotations above than synapses, but still OK) GO:0031594 : neuromuscular junction GO:0042734 : presynaptic membrane GO:0045211 : postsynaptic membrane also: GO:0030424 : axon GO:0030425 : dendrite That covers the main properties of the Ache and Bche clades. BP -In addition to the propagations in MF, propagate GO:0006581 "acetylcholine catabolic process" to AN1 to specificity that the metabolic process in question is catabolic. -Do not propagate IMP's to cellular functions, such as GO:0045212 "neurotransmitter receptor biosynthetic process" and GO:0001919 "regulation of receptor recycling" from mouse Ache. -Neuro development: --Propagate GO:0048666 "neuron development" and GO:0007416 "synapse assembly" to the Ache clade based on rat. --Also propagate GO:0050770 "regulation of axonogenesis" and GO:0048814 "regulation of dendrite morphogenesis" to AN1 from rat. (Note: this drops the "positive" restriction on the primary annotation.) -Don't bother with "response to" various chemicals annotations, which are covered by "synaptic transmission" and would take a long time to dissect. That covers the main themes of BP for the Ache and Bche clades. =Questions for ontology curators= ==Molecular Function== *'''Question: '''Shouldn't GO:0003990 "acetylcholinesterase activity" be a child of GO:0004104 "cholinesterase activity"? (SF# 3220868) **GO:0004104 "cholinesterase activity" is defined as "Catalysis of the reaction: an acylcholine + H2O = choline + a carboxylic acid anion." ***Acylcholine (CHEBI:35287) is defined as "A choline ester formed from choline and a carboxylic acid." **GO:0003990 "acetylcholinesterase activity" is defined as "Catalysis of the reaction: acetylcholine + H2O = choline + acetate." ***Acetylcholine (CHEBI:15355) "is an ester of acetic acid and choline..." **Since acetic acid is a carboxylic acid, acetylcholine is an acylcholine. **'''Curator answer: '''"I just checked with ChEBI. I think the [above] is true, but not the [BP assertion below], as long as cholinesterase really does only work on acylcholines. A choline ester is not a choline in ChEBI, so the latter is not true. [We] are starting to work through the GO-ChEBI misalignements. We will put this one at the top of the list." ***http://wiki.geneontology.org/index.php/Chemical_terms_in_GO ***2011-08-11: Moved: GO:0003990 "acetylcholinesterase activity" is_a GO:0004104 "cholinesterase activity *'''Question: '''GO:0017171 "serine hydrolase activity" is defined as "Catalysis of the hydrolysis of a substrate by a catalytic mechanism that involves a catalytic triad consisting of a serine nucleophile ..." In other words, the definition specifies a reaction mechanism. Is this a valid use of GO? **'''Curator answer: '''I think it's a valid way to define a function. Most of the other catalytic activities are defined based on the EC definition of catalysis of , which is why you see so many in that type of format. However, this does not mean that definitions of functions based on mechanism are not equally valid. -TB ==Biological Process== *'''Question: '''Similar to the MF annotations above, shouldn't GO:0008291 "acetylcholine metabolic process" be a child of GO:0019695 "choline metabolic process"? (SF# 3220868) **'''Curator answer: '''Probably not. See above. ***2011-08-11: In CHEBI, acetylcholine is not a choline but a choline ester. Choline ester has functional parent choline. So I don't think that 8291 should be a child of 19695. Both GOCHE and ChEBI reflect the correct chemical parentage and do not need to be edited. MSL, 10 March 2011 Answers to questions updated 22 March 2011, MSL PDT, 2011 June 14 MSL, 26 Aug 2011: Updated answers based on SF item Oct 2014 - Recuration MF - Butyrylcholinesterase is annotated to have acetylcholinesterase activity, but it is a non-specific cholinesterase. CC - Many cytosol terms are based on staining. They are ER or Golgi, which seem to be not reliable. Not propagate. BP - Don't seem to be conserved throughout the tree. Also, majority of the terms are systems level indirect annotations. HM # REFERENCE Annotation inferences using phylogenetic trees The goal of the GO Reference Genome Project, described in PMID 19578431, is to provide accurate, complete and consistent GO annotations for all genes in twelve model organism genomes. To this end, GO curators are annotating evolutionary trees from the PANTHER database with GO terms describing molecular function, biological process and cellular component. GO terms based on experimental data from the scientific literature are used to annotate ancestral genes in the phylogenetic tree by sequence similarity (ISS), and unannotated descendants of these ancestral genes are inferred to have inherited these same GO annotations by descent. The annotations are done using a tool called PAINT (Phylogenetic Annotation and INference Tool).