orthlogs, sphingo/ lipid metabolism

[ValWood]

@dexink

• SPBC660.17 - Schizosaccharomyces specific protein, uncharacterized
  -> YGR016W (ER protein), from jackhmmr. Need t double check if more broadly conserved

• (lcb3 removed)/ SPAC23A1.05
  is currently annotated as "serine palmitoyltransferase subunit A Lcb3 (where from ?) FIXED is S. cerevisiae tsc3 orthlog YBR058C-A (NOT lcb3 )

• add GO ISO to sphingolipid metabolism and SPOTs complex

[ValWood]

still need to look for

• LIP1 https://www.yeastgenome.org/locus/S000004913
  unable to find via jackhmmer.

[dexink]

Not to mention the rest of the pathway that we hadn't gotten to yet by the end of yesterday

[ValWood]

There are not so many missing orthologs
#3245
The main question is whether all of the annotations are correct.

[ValWood]

Also to look for:

• S. cerevisiae YPC1/YDC1 ortholog established that this is unlikely to be present
• S. cerevisiae CSG2 ortholog
• S. cerevisiae LDB16 ortholog

[dexink]

RE: YPC1/YDC1, definition
UniProt lists two in their database with a precursory search, one per each name (YPC1 and YDC1)

• both are annotated as being largely transmembraneous
• KEGG orthologs are negative for S. pombe
• KEGG does list the two as paralogs of one-another (ENSEMBL corroborates this)
• Both entries in ENSEMBL specifically list them as not having orthologs across all relevant species of Schizosaccharomyces (YDC1, bottom; YPC1, bottom)

[ValWood]

In my old losses file.
These are proteins which are relatively highly conserved and would be unlikely to be very divergent and difficult to detect.

YPC1 YBR183W paralog YDC1 (conserved in human ACER3) (no compara) ceramide
YDC1 YPL087W paralog YPC1 (conserved in human ACER3) (no compara) ceramide
DPL1 YDR294C (from Compara) sphingolipid

So I agree these are gene loss in fission yeast YPC1 /YDC1

[dexink]

RE: CSG2, definition
Purportedly part of a heterodimer via UniProt with either CSH1 or SUR1
Interesting, this is not corroborated by the listed binary interactions on the same entry page

KEGG orthologs is negative for S. pombe
UniProt page reads the following for the function in S. cerevisiae, which links ceramide biosynthesis to inositol derivatives: "Required for calcium regulation. May regulate calcium accumulation by a non-vacuole organelle. Also regulates the activity of CSH1 and SUR1 during mannosyl phosphorylinositol ceramide synthesis."

Inositol metabolic pathways may need better resolving; potential for replacement of other central metabolism that is missing in S. pombe (?)

Still looking for homolog of CSG2 in S. pombe

[dexink]

Possibly interesting:
STRING network for SPCC1450.15.1 (pig-F/3-ketosphinganine reductase fusion protein) links ceramide biosynthesis to tryptophan biosynthesis, mTor, the erf2-erf4 complex, and a chaperonin-containing t-complex:
Network (no textmining, no co-expression; 2nd shell = no more than 30 interactors)

Nodes that may be of particular interest are SPCC320.14 (a racemase) and SPBC119.09c, a purported member of the SPOTS complex for which Pombase has its characterization status listed as "biological role inferred". Even more interesting, the latter node, as shown in the network, is linked directly to SPAC23A1.05, the protein that we determined had somehow been misannotated at some point as "lcb3"(!). (Recall that we were able to determine that the true S. cerevisiae Lcb3 ortholog in S. pombe was actually SPAC823.11 (currently annotated as "sgp1" in Pombase); it is also in the network and is clustered, as would be expected, with the other nodes linked to ceramide biosynthesis)

Do we think that SPAC23A1.05 was misannotated as Lcb3 because of an observed link to the other proteins we've confirmed as being involved in ceramide biosynthesis, and so in the past had been mistaken for one of the remaining players missing from the S. pombe pathway compared to that in S. cerevisiae?

Ultimately, it's possible that we may want to add a D-tryptophan (or D-amino acid) pathway to the list of possible alternative routes of tryptophan degradation in S. pombe. Thoughts?

[dexink]

To add to the interest in the misannotated "lcb3" protein, Sgp1 (SPAC823.11), it appears to be a regulatory target of Sre1, a regulator of sterol biosynthesis (relates to issues #1324 & #3244 )

Other interesting targets of Sre1 (under hypoxic conditions) include:

• SPAC186.08c (our mysterious L-lactate dehydrogenase)
• SPAC9.02c (polyamine N-acetyltransferase)
• several S. pombe-/fungal-specific proteins
• some unknowns (including a "conserved unknown" aldo/keto reductase, SPBC215.11c)
• "implied in cellular detox" proteins SPBC21C3.15c and SPBC23G7.10c
• an inner membrane transporter, SPCC613.02, for which only an S. japonicus ortholog is listed in Pombase

[dexink]

RE: D-Tryptophan and Tryptophan degradation
Another reaction is listed for this molecule in MetaCyc that I did not notice before; there are promiscuous amino acid-utilizing reactions that feed into ceramide/Sphingolipid metabolism pathways:

[ValWood]

SPBC119.09c, SPAC23A1.05 and SPAC823.11 should be updated tomorrow.
I will check. I had already done it but not committed.

[ValWood]

Ultimately, it's possible that we may want to add a D-tryptophan (or D-amino acid) pathway to the list of possible alternative routes of tryptophan degradation in S. pombe.

yes if this looks like the route. We can begin to model this in Noctua training session.

[ValWood]

CLosing this one as all should be addressed went he pathways are built