iron assimilation and transport

[ValWood]

We have a term "iron assimilation" which always bothers me.

We have to use it for the transmembrane transport of iron when it needs to be reduced before uptake. This means that this transporter is not annotated as part of transmembrane transport unless you make an additional annotation.

I'm not sure that we need this term at all.

Can't we just call this "iron ion transmembrane transport" to me the reductase is part of the transmembrane transport process?...in the same way that other activities like https://www.pombase.org/gene/SPCC965.06 (reductase) https://www.pombase.org/gene/SPBC27B12.07 (we don't know how) https://www.pombase.org/gene/SPAC1F8.02c cell-surface heme aquisition protein

What do you think? does that seem odd?

[RLovering]

I agree, I had a student working on iron transport and he never identified this term :)

[pgaudet]

Useful references: https://www.sciencedirect.com/science/article/pii/S1367593113000203

[RLovering]

Hi I had a student who annotated iron homeostasis as regulation of this seems to be important in Cardiovascular disease.

His thesis has a summary:In order to understand cellular iron ion homeostasis, it is important to firstly review the mechanism by which iron is taken up by cells, as presented in figure 2. One of the main proteins involved in this process is transferrin, which circulates in the blood (Ganz, 2013). When blood plasma is in an iron-rich state, diferric transferrin (holotransferrin) binds to transferrin receptor 1 (TFRC) (Morgan and Laurell, 1963; Morgan and Appleton, 1969; Moos, 2002; Aisen, 2004; Ganz, 2013). The holotransferrin/TFRC assembly is then endocytosed into a clathrin-coated pit, assisted by AP2 (an adaptor protein complex) (Conner and Schmid, 2003) and internalises to an endosome (Aisen, 2004). The lowered pH in the endosome (~5.6) facilitates iron release from transferrin, which returns to the cell surface (Qian et al., 2002). The iron (in its ferrous form Fe2+) then crosses the endosomal membrane through DMT1 (Fleming et al., 1998). Iron in the cytosol is used as a cofactor for many chemical reactions, or stored as ferritin (Qian et al., 2002). (figure hopefully below).

Transferrin, P02787, which circulates in the blood I think is an Iron transporter.

If not what should it's MF be?

[ValWood]

Hi Ruth It's an "iron sulfur cluster carrier" https://www.ebi.ac.uk/QuickGO/term/GO:0140132 It isn't involved in "directed movement" so it isn't a "transporter" but it is a "carrier" part_of "iron sulfur cluster transport"

Val

[deustp01]

I don't think iron-sulfur works because it's plain Fe(2+) CHEBI:29033, not an iron-sulfur cluster (CHEBI:30408) that's involved here. Would it be useful to think of ferritin protein as having the same function with respect to extracellular iron as albumin does for extracellular bile acids and free fatty acids?

[ValWood]

Ah ok, some term under here though https://www.ebi.ac.uk/QuickGO/term/GO:0140104

[RLovering]

Hi so when I looked at the Transferrin, P02787 annotations we had not annotated it to a transporting function. (hooray). However when I tried to create the annotation GO:0140104 molecular carrier activity I was not able to do so because of : Restrictions This term should not be used for direct annotation. See comment below for further information. Comments https://github.com/geneontology/go-ontology/issues/14221 I tried to add more specific information but this was not allowed with Protein2GO. Does this mean that there are going to be individual terms for each type of molecular carrier? Or should I request metal ion carrier activity? Or should I request that curators can use GO:0140104 molecular carrier activity as long as they specify the location and the object carried.

Thanks for the help with this, it is obviously not my area and I don't want to get this wrong again.

Ruth

[ValWood]

Well, this raises a question

Currently metallochaperone and iron chaperone activity https://www.ebi.ac.uk/QuickGO/term/GO:0034986

are defined in terms of delivery to compartments. Perhaps this should be broadened for delivery to cells?

[ValWood]

Note that the BHF annotations to this term "iron chaperone activity" include frataxin, that would definitely be "iron sulfur cluster carrier"

(but a grouping term for iron-compound-containing carriers would be nice here for curators to find things)

[ValWood]

Ruth new terms may be needed. The terms existed before but the arrangement is very new...part of MF refactoring. v

[RLovering]

OK so I am completely blind it seems when looking at these terms.

Added to frataxin, "iron sulfur cluster carrier. But it also seems to just bind iron (ferrous 2+) and is involved in heme biosynthesis. So I will leave the iron chaperone activity annotation.

wrt Transferrin, P02787 it does 'assist in the delivery of Fe3+ to the endosome via binding to the transferrin receptor. So maybe the definition of GO:0034986 iron chaperone activity: Assists in the delivery of iron ions to target proteins or compartments. is OK?

I will add this term to this record now, I have found a couple of papers that refer to transferrin as a metallochaperone eg https://pubs.acs.org/doi/abs/10.1021/acs.inorgchem.7b00372?journalCode=inocaj

Thanks

Ruth

[ValWood]

I did not know until today that iron could be endocytosed, although @pgaudet mentioned it last week, I was still convinced that endocytosis was only regulating transporter localization...

[dianeoinglis]

Siderophores are secondary metabolites produced by fungi and some bacteria that bind iron in the environment and are then taken into a cell by transport. This process is often referred to as 'iron assimilation' in siderophore literature. Diane

[deustp01]

I'm not expert at all here but at a glance it looks like frataxin binds Fe ions and enables their delivery to the place where sulfur is also independently being delivered and where iron-sulfur complexes form as a result, so frataxin function has a role in iron-sulfur assembly process but does not bind or transport the complex: http://www.uniprot.org/citations/12785837 - "Holo frataxin ... mediate[s] the transfer of iron from holo frataxin to nucleation sites for [2Fe-2S] cluster formation on ISU." So a iron sulfur cluster carrier annotation looks wrong.

[RLovering]

Thank you Peter. This makes sense, I have deleted the "iron sulfur cluster carrier" and "iron sulfur cluster binding" terms.

[pgaudet]

For specific forms of iron, I will rename simply 'iron import' (the iron form should be captured in the MF annotation):

• GO:0098707 ferrous iron import across plasma membrane -> iron import across plasma membrane
• GO:0098706 ferric iron import across cell outer membrane -> iron import across cell outer membrane

[RLovering]

Hi Pascale

if you are getting rid of the iron specific form terms will you also get rid of terms like GO:0072512 trivalent inorganic cation transport, otherwise we would need to annotate to this term and to the iron transport term?

Thanks

Ruth

[pgaudet]

Hi Ruth,

Yes, the plan is to get rid of the specific form of iron in the BP, only keeping them in the MF. Does that make sense ?

I will commit what I have done so far. There are 4 types of iron transport:

• transmembrane
• endocytic
• siderophore-mediated
• reductive iron assimilation (in which Fe3+ is converted into Fe2+ and then transported by TM transport).

Does that seem OK to you ?

Thanks, Pascale

@Antonialock I think you have also looking into this.

[ValWood]

@Antonialock has been looking at iron sulphur cluster biosynthesis

[pgaudet]

Changes:

• [x] Change label GO:0033212 iron assimilation to iron import into cell
• [x] Merge GO:0033216 ferric iron import into GO:0006826 iron ion transport #16408
• [x] Merge GO:1903988 'ferrous iron export across plasma membrane' into 'GO:1903414 iron cation export' change label to 'iron ion export across plasma membrane' #16416
• [x] Change label GO:0033214 iron assimilation by chelation and transport to siderophore-dependent iron import into cell
• [x] Change label GO:0033215 iron assimilation by reduction and transport to reductive iron assimilation
• [x] Merge GO:0033213 iron assimilation by capture and transport (0 annotations) into GO:0033214 siderophore-dependent iron import into cell
• [x] Merge GO:0098707 ferrous iron import across plasma membrane into GO:0098711 iron ion import across plasma membrane
• [x] Change label GO:1904438 regulation of ferrous iron import across plasma membrane to regulation of iron import across plasma membrane
• [x] Change label GO:1904439 negative regulation of ferrous iron import across plasma membrane to negativeregulation of iron import across plasma membrane
• [x] Change label GO:1904440 positive regulation of ferrous iron import across plasma membrane to positiveregulation of iron import across plasma membrane

[pgaudet]

Here are the changes I made: (updated to include the number of annotations)

Term		annotations (Manual = EXP and children + TAS, NAS, IC)	Change
GO:0015682	ferric iron transport	6 Manual  & 20 ISS	MERGE INTO	GO:0006826	iron ion transport
GO:0015684	ferrous iron transport	11 Manual & 33 ISS	MERGE INTO	GO:0006826	iron ion transport
GO:0097286	iron ion import	3 manual (no manual ISS)	MERGE INTO	GO:0006826	iron ion transport
GO:0070627	ferrous iron import	2 EXP (no manual ISS)	MERGE INTO	GO:0033212	iron import into cell
GO:0042928	ferrichrome transport	17 EXP (no manual ISS)	RENAMED	ferrichrome import into cell
			CHANGED DEF	NEW: A process in which ferrichrome is transported into the cell by specific cell surface receptors. Ferrichromes are any of a group of growth-promoting Fe(III) chelates formed by various genera of microfungi. They are homodetic cyclic hexapeptides made up of a tripeptide of glycine (or other small neutral amino acids) and a tripeptide of an N'acyl-N4-hydroxy-L-ornithine. (OLD: The directed movement of a ferrichrome into, out of or within a cell, or between cells, by means of some agent such as a transporter or pore. Ferrichromes are any of a group of growth-promoting Fe(III) chelates formed by various genera of microfungi. They are homodetic cyclic hexapeptides made up of a tripeptide of glycine (or other small neutral amino acids) and a tripeptide of an N'acyl-N4-hydroxy-L-ornithine.)
GO:0015685	ferric-enterobactin transport		RENAMED	ferric-enterobactin import into cell
			CHANGED DEF	NEW: A process in which ferric-enterobactin, the iron-bound form of the siderophore enterobactin, is transported into the cell by specific cell surface receptors. (OLD: The directed movement of ferric-enterobactin into, out of or within a cell, or between cells, by means of some agent such as a transporter or pore.)
GO:0015686	ferric triacetylfusarinine C transport	RENAMED	ferric triacetylfusarinine C import into cell
GO:0015687	ferric-hydroxamate transport		RENAMED	ferric-hydroxamate import into cell
			CHANGED DEF	NEW: A process in which ferric-hydroxamate, the iron-bound form of the iron chelator hydroxamate, is transported into the cell by specific cell surface receptors. (OLD: The directed movement of ferric-hydroxamate into, out of or within a cell, or between cells, by means of some agent such as a transporter or pore.)
GO:0015688	iron chelate transport	4 EXP & 11 ISS	MERGE INTO	siderophore-dependent iron import into cell
GO:0033212	iron import into cell		CHANGED DEF	NEW: The directed movement of iron ions from outside of a cell into the cytoplasmic compartment. This may occur via transport across the plasma membrane or via endocytosis. (OLD: The directed movement of iron ions from outside of a cell into the cytoplasmic compartment. This may occur via transport across the plasma membrane or via endocytosis.)
GO:1900390	regulation of iron ion import	4 EXP	MERGE INTO	GO:0034756	regulation of iron ion transport
GO:1903874	ferrous iron transmembrane transport	1 EXP	MERGE INTO	GO:0034755	iron ion transmembrane transport
GO:1900400	regulation of iron ion import by regulation of transcription from RNA polymerase II promoter	RENAMED	regulation of iron ion import into cell by regulation of transcription from RNA polymerase II promoter
GO:1900393	regulation of iron ion transport by regulation of transcription from RNA polymerase II promoter	0 direct annotations	MERGE INTO	GO:1900400	regulation of iron ion import by regulation of transcription from RNA polymerase II promoter
GO:0100022	regulation of iron ion import by transcription from RNA polymerase II promoter	0 direct annotations	MERGE INTO	GO:0100021	regulation of iron ion transport by transcription from RNA polymerase II promoter

[pgaudet]

@ValWood @RLovering @hdrabkin @dsiegele Does that look right to you ?

Thanks; Pascale

[ValWood]

@Antonialock

[pgaudet]

@ValWood @RLovering @hdrabkin @dsiegele @Antonialock I would like to merge these changes today (since it's a lot; conflicts would be difficult to fix). Let me know if you'd like more time to check.

Thanks, Pascale

[dsiegele]

Hi Pascale, Your changes look OK to me. thank you! Debby

[hdrabkin]

Seems good

[ValWood]

Sounds Ok to me . @Antonialock ?

[Antonialock]

I don't feel confident enough to say that all the changes look ok. If it is helpful I don't have any objections.

[RLovering]

I have no objections, sorry to be late