SLC15A19 Is Not A Nucleotide Transporter

[Devlin-Moyer]

While working on #694, I noticed a large number of transport reactions that transport (d)NTPs and (d)NDPs between the cytosol and mitochondria that are associated with SLC25A19 (ENSG00000125454). There is a warning at the top of the Uniprot page for SLC25A19 that says that, while it was initially claimed to be a mitochondrial nucleotide transporter, it was eventually shown to only be capable of transporting thiamine diphosphate.

All but 2 of the 56 reactions currently associated with SLC25A19 transport (d)NTPs and (d)NDPs between the cytosol and mitochondria, and I believe they should all be removed, since other existing reactions and the new ones proposed in #694 will ensure that all (d)NTPs and (d)NDPs can still move between the [c] and [m] compartments.

The two reactions that don’t involve nucleotides are MAR04933: AKG [e] + Na+ [e] ⇒ AKG [c] + Na+ [c] and MAR05047: Pi [l] ⇒ Pi [c]. MAR04933 is nearly identical to MAR05992, which uses 3 sodium ions instead of 1 and is associated with SCL13A3, which is actually known to catalyze that reaction according to Uniprot, so I think MAR04933 should be removed. MAR05047 appears to be the only way for inorganic phosphate to move from the lysosome to the cytosol, so I think it should be kept but have SLC25A19 removed from its GPR. As far as I can tell, people have known that phosphate is exported from human lysosomes since at least 1991 (source), but never determined which protein is responsible — this paper from 2021 cited that 1991 paper and no others when it mentioned lysosomal phosphate transport.

Proposed Changes

• Remove ENSG00000125454 from GPR of MAR05047
• Remove MAR04933 for being a duplicate of MAR05992
• Remove MAR06332
• Remove MAR06333
• Remove MAR06334
• Remove MAR06335
• Remove MAR06336
• Remove MAR06337
• Remove MAR06338
• Remove MAR06339
• Remove MAR06340
• Remove MAR06341
• Remove MAR06342
• Remove MAR06343
• Remove MAR07804
• Remove MAR07806
• Remove MAR07808
• Remove MAR07810
• Remove MAR07812
• Remove MAR07814
• Remove MAR07815
• Remove MAR07816
• Remove MAR07818
• Remove MAR07820
• Remove MAR07822
• Remove MAR07824
• Remove MAR07825
• Remove MAR07826
• Remove MAR07827
• Remove MAR07828
• Remove MAR07829
• Remove MAR07830
• Remove MAR07831
• Remove MAR07832
• Remove MAR07833
• Remove MAR07834
• Remove MAR07835
• Remove MAR07836
• Remove MAR07837
• Remove MAR07838
• Remove MAR07839
• Remove MAR07840
• Remove MAR07841
• Remove MAR07842
• Remove MAR07843
• Remove MAR07844
• Remove MAR07845
• Remove MAR07846
• Remove MAR07847
• Remove MAR07848
• Remove MAR07849
• Remove MAR07850
• Remove MAR07851
• Remove MAR07852
• Remove MAR07853
• Remove MAR07854

[haowang-bioinfo]

could it be good enough to turn the GPRs of these reactions into blank?

[Devlin-Moyer]

Maybe, but I feel like that would be inconsistent with how we resolved issues like #568, #569, #570, and #679. Those all identified reactions that transported the same metabolite between the same compartments that misrepresented how certain transporters worked, and we either removed or edited the reactions that did not correspond to the activity of a known transporter, rather than just removing the GPRs but keeping those reactions. Also, as I mentioned in the initial comment, the new reactions proposed in #694 would allow transport of all of the metabolites involved in all of these reactions to move between the same compartments, and we have evidence to support that those particular reactions are actually mediated by a specific transporter, while we have no evidence that any of the reactions I mentioned here actually reflect the activities of any known transport proteins.