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Mitochondrial Nucleotide Transporters #694

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Devlin-Moyer opened this issue Aug 22, 2023 · 7 comments
Closed
41 tasks done

Mitochondrial Nucleotide Transporters #694

Devlin-Moyer opened this issue Aug 22, 2023 · 7 comments
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@Devlin-Moyer
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Devlin-Moyer commented Aug 22, 2023

According to this paper (specifically Figure 4 and Table 1 from that paper), SLC25A33 (ENSG00000171612) and SLC25A36 (ENSG00000114120) can transport pyrimidine (d)NTPs, (d)NDPs, and (d)NMPs from the cytosol into the mitochondria. To be specific:

Reaction Appropriate GPR
CTP [c] + CDP [m] <-> CTP [m] + CDP [c] ENSG00000114120
CTP [c] + CMP [m] <-> CTP [m] + CMP [c] ENSG00000114120
CTP [c] + dCTP [m] <-> CTP [m] + dCTP [c] ENSG00000114120
CTP [c] + dCDP [m] <-> CTP [m] + dCDP [c] ENSG00000114120
CTP [c] + dCMP [m] <-> CTP [m] + dCMP [c] ENSG00000114120
CTP [c] + GTP [m] <-> CTP [m] + GTP [c] ENSG00000114120
CTP [c] + GDP [m] <-> CTP [m] + GDP [c] ENSG00000114120
CTP [c] + GMP [m] <-> CTP [m] + GMP [c] ENSG00000114120
CTP [c] + dGTP [m] <-> CTP [m] + dGTP [c] ENSG00000114120
CTP [c] + dGDP [m] <-> CTP [m] + dGDP [c] ENSG00000114120
CTP [c] + dGMP [m] <-> CTP [m] + dGMP [c] ENSG00000114120
CTP [c] + ITP [m] <-> CTP [m] + ITP [c] ENSG00000114120
CTP [c] + IDP [m] <-> CTP [m] + IDP [c] ENSG00000114120
CTP [c] + IMP [m] <-> CTP [m] + IMP [c] ENSG00000114120
CTP [c] + UTP [m] <-> CTP [m] + UTP [c] ENSG00000114120 or ENSG00000171612
CTP [c] + UDP [m] <-> CTP [m] + UDP [c] ENSG00000114120
CTP [c] + UMP [m] <-> CTP [m] + UMP [c] ENSG00000114120
CTP [c] + dUTP [m] <-> CTP [m] + dUTP [c] ENSG00000114120
CTP [c] + dUDP [m] <-> CTP [m] + dUDP [c] ENSG00000114120
CTP [c] + dUMP [m] <-> CTP [m] + dUMP [c] ENSG00000114120
UTP [c] + CDP [m] <-> UTP [m] + CDP [c] ENSG00000171612
UTP [c] + dCTP [m] <-> UTP [m] + dCTP [c] ENSG00000171612
UTP [c] + dCDP [m] <-> UTP [m] + dCDP [c] ENSG00000171612
UTP [c] + GTP [m] <-> UTP [m] + GTP [c] ENSG00000171612
UTP [c] + GDP [m] <-> UTP [m] + GDP [c] ENSG00000171612
UTP [c] + dGTP [m] <-> UTP [m] + dGTP [c] ENSG00000171612
UTP [c] + dGDP [m] <-> UTP [m] + dGDP [c] ENSG00000171612
UTP [c] + ITP [m] <-> UTP [m] + ITP [c] ENSG00000171612
UTP [c] + dTTP [m] <-> UTP [m] + dTTP [c] ENSG00000171612
UTP [c] + dTDP [m] <-> UTP [m] + dTDP [c] ENSG00000171612
UTP [c] + UDP [m] <-> UTP [m] + UDP [c] ENSG00000171612
UTP [c] + dUTP [m] <-> UTP [m] + dUTP [c] ENSG00000171612
CTP [c] <-> CTP [m] ENSG00000114120 or ENSG00000171612
GTP [c] <-> GTP [m] ENSG00000114120 or ENSG00000171612
dTTP [c] <-> dTTP [m] ENSG00000171612
UTP [c] <-> UTP [m] ENSG00000114120 or ENSG00000171612

The only one of those reactions that is already represented in Human-GEM is MAR08301: dTTP [c] ⇒ dTTP [m], but it is irreversible has no genes associated with it; it should be made reversible and have its GPR set to ENSG00000171612.

There are also MAR07823: dCTP [c] ⇒ dCTP [m], MAR07926: dGTP [c] ⇒ dGTP [m], and MAR09019: CDP [c] ⇒ CDP [m], none of which have any associated genes. Adding all of the reactions in the table above would allow all three of these metabolites to be exchanged and actually have evidence supporting their existence, so I think MAR07823, MAR07926, and MAR09019 should be removed. Similarly, I think MAR04843: GDP [c] + GTP [m] ⇔ GDP [m] + GTP [c] should also be removed in favor of the reactions in the above table; it is currently associated with ALDH1A3, ALDH3A1, and ALDH3B2, but none of those known to exchange GTP and GDP between the cytosol and mitochondria. The only reference associated with MAR04843 just shows that GTP, GDP, and GMP can be transported into mitochondria from their surroundings and does not identify which gene(s) is/are responsible or even whether this transport is antiport, symport, or uniport.

There are also a large number of reactions that exchange (d)NTPs and (d)NDPs catalyzed by SLC15A19 that should all be removed, but I address that in #695.

Proposed Changes

  • Create new gene entries for ENSG00000171612 (name: SLC25A33) and ENSG00000114120 (name: SLC25A36)
  • Make MAR08301 reversible and change its GPR to ENSG00000171612
  • Remove MAR07823
  • Remove MAR07926
  • Remove MAR09019
  • Remove MAR04843
  • Create new reaction CTP [c] + CDP [m] <-> CTP [m] + CDP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + CMP [m] <-> CTP [m] + CMP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + dCTP [m] <-> CTP [m] + dCTP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + dCDP [m] <-> CTP [m] + dCDP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + dCMP [m] <-> CTP [m] + dCMP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + GTP [m] <-> CTP [m] + GTP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + GDP [m] <-> CTP [m] + GDP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + GMP [m] <-> CTP [m] + GMP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + dGTP [m] <-> CTP [m] + dGTP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + dGDP [m] <-> CTP [m] + dGDP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + dGMP [m] <-> CTP [m] + dGMP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + ITP [m] <-> CTP [m] + ITP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + IDP [m] <-> CTP [m] + IDP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + IMP [m] <-> CTP [m] + IMP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + UTP [m] <-> CTP [m] + UTP [c], GPR: ENSG00000114120 or ENSG00000171612
  • Create new reaction CTP [c] + UDP [m] <-> CTP [m] + UDP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + UMP [m] <-> CTP [m] + UMP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + dUTP [m] <-> CTP [m] + dUTP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + dUDP [m] <-> CTP [m] + dUDP [c], GPR: ENSG00000114120
  • Create new reaction CTP [c] + dUMP [m] <-> CTP [m] + dUMP [c], GPR: ENSG00000114120
  • Create new reaction UTP [c] + CDP [m] <-> UTP [m] + CDP [c], GPR: ENSG00000171612
  • Create new reaction UTP [c] + dCTP [m] <-> UTP [m] + dCTP [c], GPR: ENSG00000171612
  • Create new reaction UTP [c] + dCDP [m] <-> UTP [m] + dCDP [c], GPR: ENSG00000171612
  • Create new reaction UTP [c] + GTP [m] <-> UTP [m] + GTP [c], GPR: ENSG00000171612
  • Create new reaction UTP [c] + GDP [m] <-> UTP [m] + GDP [c], GPR: ENSG00000171612
  • Create new reaction UTP [c] + dGTP [m] <-> UTP [m] + dGTP [c], GPR: ENSG00000171612
  • Create new reaction UTP [c] + dGDP [m] <-> UTP [m] + dGDP [c], GPR: ENSG00000171612
  • Create new reaction UTP [c] + ITP [m] <-> UTP [m] + ITP [c], GPR: ENSG00000171612
  • Create new reaction UTP [c] + dTTP [m] <-> UTP [m] + dTTP [c], GPR: ENSG00000171612
  • Create new reaction UTP [c] + dTDP [m] <-> UTP [m] + dTDP [c], GPR: ENSG00000171612
  • Create new reaction UTP [c] + UDP [m] <-> UTP [m] + UDP [c], GPR: ENSG00000171612
  • Create new reaction UTP [c] + dUTP [m] <-> UTP [m] + dUTP [c], GPR: ENSG00000171612
  • Create new reaction CTP [c] <-> CTP [m], GPR: ENSG00000114120 or ENSG00000171612
  • Create new reaction GTP [c] <-> GTP [m], GPR: ENSG00000114120 or ENSG00000171612
  • Create new reaction UTP [c] <-> UTP [m], GPR: ENSG00000114120 or ENSG00000171612
@feiranl
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feiranl commented Oct 9, 2023

@Devlin-Moyer these rxns mentioned in the beginning are missing in the tasks/actions.

rxn grRule
CTP [c] <-> CTP [m] ENSG00000114120 or ENSG00000171612
GTP [c] <-> GTP [m] ENSG00000114120 or ENSG00000171612

@Devlin-Moyer
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oops, looks like I forgot those; I'll add them to the list of new reactions to add

@Devlin-Moyer Devlin-Moyer mentioned this issue Oct 17, 2023
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@haowang-bioinfo
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haowang-bioinfo commented Oct 18, 2023

@Devlin-Moyer very nice findings!

it has been nearly 10 years since the publication of this paper, are there any new isoenzymes of these transporters reported recently?

@Devlin-Moyer
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Devlin-Moyer commented Oct 18, 2023

not that I can tell; the only more recent papers that mention either gene that I can find were looking for something else and happened to find that one or both was over- or under-expressed in response to some perturbation.

@haowang-bioinfo
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not that I can tell; the only more recent papers that mention either gene were looking for something else and happened to find that one or both was over- or under-expressed in response to some perturbation.

good to know this. I assume it was found manually, if it's possible to get it done by script automatically?

@Devlin-Moyer
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yea all the papers I've found for all my issues were ones I found manually, either by directly searching on Google Scholar or looking at references on Uniprot pages for specific proteins; I have no thoughts or experience on any sort of automated paper-finding script

@haowang-bioinfo
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fixed in #709

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