Glucose 6 phosphate anomer in Pentose Phosphate Pathway (R-HSA-71336)

[sjm41]

As mentioned during the NY meeting:

• R-HSA-71336 (Pentose Phosphate Pathway) currently has input to first reaction as α-D-glucose 6-phosphate(2−) CHEBI:58225 (see R-HSA-70377.5 reaction)
• Corresponding RHEA:15841/EC:1.1.1.49 for that reaction uses the more generic D-glucopyranose 6-phosphate(2-) CHEBI:61548, from which we can assume that the enzyme can use either anomer (following my email exchange with Kristin Axelson on this issue) - which means the Reactome annotation is 'legal'
• The fly GO-CAM (662af8fa00000691) uses D-glucopyranose 6-phosphate(2-) CHEBI:61548 (because it uses the participant via RHEA)
• However, the corresponding GO BP (GO:0009051) uses the other anomer in the LD - has_primary_input CHEBI:58247 ! beta-D-glucose 6-phosphate(2-)

@rozaru mentioned that there's evidence that the glucose-6-phosphate dehydrogenase enzyme catalysing this reaction is specific (or has preference) for the beta anomer.
I've found a couple of papers supporting this:

• https://jofem.org/index.php/jofem/article/view/555/284284366 (from 2019) says that "yeast glucose-6-P dehydrogenase acts specifically on β-D-glucose-6-P only."
• https://www.jbc.org/article/S0021-9258(17)38615-5/pdf (from 1985) says that "beta-D-glucose 6-phosphate is metabolized preferentially to alpha-D-glucose 6-phosphate in the pentose cycle, whether in tumoral or normal islet cells."

Proposals:

• change the G6P on R-HSA-70377.5 to the more generic D-glucopyranose 6-phosphate(2-) CHEBI:61548 (to match RHEA) OR use the other anomer CHEBI:58247 ! beta-D-glucose 6-phosphate(2-) (to match literature)
• It might be best to change the input chemical on GO:0009051 to the more generic D-glucopyranose 6-phosphate(2-) CHEBI:61548 to match RHEA and thus accommodate the possibility that the alpha anomer might be used in some circumstances (or a low efficiency). This would also mirror how the D-glucose anomer is specified in the LD for the input chemical for glycolysis (GO:0061621 ).

[sjm41]

I'm going to go ahead and do this:

change the input chemical on GO:0009051 to the more generic D-glucopyranose 6-phosphate(2-) CHEBI:61548 to match RHEA and thus accommodate the possibility that the alpha anomer might be used in some circumstances (or a low efficiency). This would also mirror how the D-glucose anomer is specified in the LD for the input chemical for glycolysis (GO:0061621 ).

I checked with Rossana, and we don't know of any evidence that the alpha form of D-glucopyranose 6-phosphate(2-) is specifically/preferentially used by the mammalian/human G6P. I also checked the 3 PMIDs listed on R-HSA-71336, and don't easily see any discussion of the anomer used therein. So it does look like Reactome should either change to use the more generic D-glucopyranose 6-phosphate(2-) CHEBI:61548 (to match RHEA) OR use the other anomer CHEBI:58247 ! beta-D-glucose 6-phosphate(2-) (to match literature mentioned in my original post)

[sjm41]

geneontology/go-ontology#29188

[ukemi]

Added CHEBI:61548 to mouse model.