# HISTORY
24 Mar 2016: Updated by: TOUCHUP-v1.15
14 Mar 2016: Updated by: TOUCHUP-v1.12

# molecular_function
20120411: root_PTN000028575 has function glutathione transferase activity (GO:0004364) 
20121012: root_PTN000028575 has function glutathione peroxidase activity (GO:0004602) 
20110118: node_PTN000028640 has function leukotriene-C4 synthase activity (GO:0004464) 
20120411: Euteleostomi_PTN000028662 has LOST/MODIFIED function glutathione transferase activity (GO:0004364) 
20121012: Euteleostomi_PTN000028662 has LOST/MODIFIED function glutathione peroxidase activity (GO:0004602) 
20110118: Euteleostomi_PTN000028662 has LOST/MODIFIED function leukotriene-C4 synthase activity (GO:0004464) 

# cellular_component
20121012: node_PTN000741656 is found in nuclear envelope (GO:0005635) 
20121012: node_PTN000741656 is found in endoplasmic reticulum (GO:0005783) 

# biological_process
20130430: node_PTN000028640 participates in leukotriene biosynthetic process (GO:0019370) 

# WARNINGS - THE FOLLOWING HAVE BEEN REMOVED FOR THE REASONS NOTED

# NOTES
general information:
- http://en.wikipedia.org/wiki/Leukotriene
- PMID: 10091672: Homologues are identified in plants, fungi, and bacteria, demonstrating this superfamily to be generally occurring. The MAPEG family consists of six human proteins; demonstrate common structural characteristics typical of membrane proteins. Two of the members are crucial for leukotriene biosynthesis, and three are cytoprotective exhibiting glutathione S-transferase and peroxidase activities.
The GST activity adn peroxidase activities are most likely ancestral, since leukotrienes are apparently only found in vertebrates and participate in the inflammatory response. Thus, the leukotriene biosynthetic activities are derived and apparently due to cooption since they play both these roles in the pathway (HPETE -> HETE activity PMID:14637132-- note this should be reannotated to be more specific, and L4Csynthase).
PMID 15794756 also a review of the family
See http://ajrccm.atsjournals.org/content/161/Supplement_1/S147.full for an overview of the leukotriene synthesis pathway. Many of these genes are only in vertebrates, so we will only propagate this process to the vertebrate LCA.
Duplications: essentially none in the MGST3 clade, three duplicates in vertebrates MGST2 (ancestral), ALOX5AP, LTC4S. ALOX5AP localizes ALOX5 to the same complex as LTC4S, and is a required activator. ALOX5AP apparently does not have a catalytic role in this process (it is probably an adaptor/scaffold protein, see PMID:15084748-- note this is localized to the outer nuclear membrane), though it may in other processes. LTC4S and MGST2 catalyze the same rxn in leukotriene synthesis, one apparently includes a different regulatory interaction.
MF:
-propagate GO:0004602 glutathione transferase activity to root: found in both major clades and concluded by reviews above
- propagate glutathione peroxidase to root: found in both major clades and also concluded by reviews above
- contributes to ALOX5 activity for ALOX5AP is not correct; should be protein binding; this clade does not have either conserved Arg required for proton donation (R 31 and R 104 in Swiss-Prot Q16873, for example), so annotate as losing catalytic activity
-propagate GO:0004464 leukotriene-C4 synthase activity to duplication node that includes Alox5ap, LTC4S and MGST2 as this is found in LTC4S and MGST2, assume lost in Alox5ap clade (no known catalytic role in the process)
- PMID:14637132 shows Rat Mgst3 doesn?t have leukotriene-C4 synthase activity
While PMID:9278457 shows human MGST3 has leukotriene-C4 synthase activity
both in vitro experiment.
Assume lost in rat, based on current annotations but do not annotate
PMID: 14637132
human MGST2 and MGST3 both possess LTC4 synthase activity [13,14] and recent studies have shown that the main, if not the only, LTC4 producing enzyme in
human umbilical vein endothelial cells is MGST2, indicating that this enzyme plays a role in transcellular biosynthesis of LTC4 in the vascular wall [15,16]. Both MGST2 and MGST3 were also found to display peroxidase activity and catalyze the GSH-dependent reduction of 5-hydroperoxy-8,11,14-cis-6-trans-eicosatetraenoic acid (5-HPETE) to 5-hydroxy-8,11,14-cis- 6-trans-eicosatetraenoic acid (5-HETE), which may have an impact on the overall synthesis of LTA4 [17].
rat MGST3 lacks LTC4 synthase in spite of the presence of the conserved Arg/Tyr catalytic pair.
- Human, please consider add annotation to Mgst3 using PMID:9278457
CC:
- Propagate GO:0005783 endoplasmic reticulum to eukaryotic LCA: this appears in all eukaryotic clades; do not propagate microsome because it is an artifact of breaking up the ER. However it seems like it should actually be outer nuclear membrane (see above), but since these are contiguous this is OK for now.
- Also propagate GO:0031965 nuclear envelope for eukaryotic LSCA (contiguous so conceivably not exclusive)
- PMID:9092565 human MGST2 GO:0005886 plasma membrane, please consider update to microsome and membrane fraction.
- PMID:18461660 Rat Mgst2 GO:0005737 cytoplasm annotation, please consider update to microsome and membrane fraction.
BP:
- Do not propagate glutathione biosynthetic process since this is not for making glutathiones, it's for using them as electron carriers
- Do not propagate response to terms
- Propagate GO:0019370 leukotriene biosynthetic process to duplication node including MGST2, ALOX5P and LTC4S clades as this is found in all of them and it is consistent with evolution of other families in the pathway as being only in vertebrates.
- Do not propagate GO:0002540 leukotriene production involved in inflammatory response because this is the same as biosynthetic process, and the leukotriene biosynth process should be a part_of inflammatory response process.
LN, 18 Jan 2011
PDT, 12 Oct 2012

# 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).