Duplicate 2-oxoadipate dehydrogenase reactions

[Devlin-Moyer]

Current behavior:

MAR04239: 2-oxoadipate + CoA + NAD+ --> CO2 + glutaryl-CoA + NADH, GPR: DLD and OGDH and DLST
is the same as the net reaction of the following three reactions:
MAR04599: 2-oxoadipate + H+ + lipoamide --> CO2 + S-glutaryldihydrolipoamide, GPR: OGDH or DHTKD1 or OGDHL
MAR06415: CoA + S-glutaryldihydrolipoamide --> dihydrolipoamide + glutaryl-CoA, GPR: DLST
MAR06409: H+ + lipoamide + NADH <=> dihydrolipoamide + NAD+, GPR: DLD

Expected feature/value/output:

Following the same rationale as #524, #529, and #660:

• MAR04239 should be removed for being a duplicate of MAR04599 + MAR06415
• The GPR of MAR04599 should be changed to (OGDH and DLST) or (DHTKD1 and DLST), since the lipoamide it uses is bound to DLST (source) and OGDHL doesn't appear to catalyze this reaction (source)
  • Add PMID:28757203 to the list of references for MAR04599
• Remove OGDHL from the GPR of MAR04209 and MAR06413, since OGDHL doesn't appear to catalyze these reactions (source)

[haowang-bioinfo]

yes, it seems reasonable to remove MAR04239

regarding the change to GPR of MAR04599, can you please paste the direct evidence from that source

[Devlin-Moyer]

So that paper I cited in the original comment never super directly states that DLST is lipoylated, but this one does, right at the beginning:

Lipoic acid (LA) is an essential cofactor of major mitochondrial enzyme complexes (Figure S1), including the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases, namely [...] 2-oxoadipate dehydrogenase (2-OADH, lysine catabolism). This cofactor is covalently bound to a conserved lysine residue of the E2 subunits of PDHc, BCKDHc, 2-OADH, and α-KGDHc as well as the H protein of GCS.

Figure S1:

I just updated my proposed changes to include adding this paper as a reference for MAR04599

[haowang-bioinfo]

2-oxoadipate dehydrogenase (2-OADH, lysine catabolism). This cofactor is covalently bound to a conserved lysine residue of the E2 subunits of PDHc, BCKDHc, 2-OADH, and α-KGDHc as well as the H protein of GCS

maybe there are multiple aliases names, just to be sure, which of these is DLST?

[Devlin-Moyer]

DLST is the E2 subunit of both the 2-OADH (2-OxoAdipate DeHydrogenase) and α-KGDHc (α-KetoGlutarate DeHydrogenase) complexes

[haowang-bioinfo]

This cofactor is covalently bound to a conserved lysine residue of the E2 subunits of PDHc, BCKDHc, 2-OADH, and α-KGDHc as well as the H protein of GCS

according this description, DLST (E2 subunit of both the 2-OADH) should be part of the GPR of MAR04599.

Now the proposed GPR (OGDH or DHTKD1 or OGDHL) and DLST reflects that MAR04599 is catalyzed by a complex with E1 and E2 subunits, this seems fine. For the three paralogues of E1, please double check if OGDHL should be included or not.

[Devlin-Moyer]

From this paper:

The activity with OG increased only upon transfection of OGDH, while the activity with OA increased upon transfection of DHTKD1 and/or OGDH (Fig. 3A and Supplementary Material, Fig. S3B and C). [...] Transient transfection of OGDHL or MRPS36 did not increase 2-oxo acid dehydrogenase activity in HEK-293 cell lysates using either OA or OG substrates.

So perhaps OGDHL should be removed from MAR04599 as well as MAR04209 and MAR06413, since it seems to have no measurable impact on catalysis of either reaction. I noticed that Uniprot only associates OGDHL with the dehydrogenation of 2-oxoglutarate "by similarity", and the above paper is the only one I can find that directly assess catalytic activity of OGDHL independently of OGDH; most of the others I can find that mention OGDHL implicitly treat it as functionally equivalent to OGDH.

[haowang-bioinfo]

thanks for the investigation - yes, OGDHL can only be associated with the dehydrogenation of 2-oxoglutarate "By similarity", according to Uniprot. No evidence for MAR04599, MAR04209, and MAR06413, even "By similarity"

[haowang-bioinfo]

it might worth revisiting the removal of OGDHL altogether from MAR04599, MAR04209 and MAR06413; such an implementation in #725 led to its removal from Human-GEM completely and this might be an overkill

it appears that OGDHL should still be kept for MAR04209 and MAR06413, given the Uniprot annotation as 2-oxoglutarate dehydrogenase-like with matched substrate (2-oxoglutarate) and cofactor (thiamine diphosphate).

sorry for the mistake I made before

[Devlin-Moyer]

As I mentioned earlier, this paper found that

Transient transfection of OGDHL or MRPS36 did not increase 2-oxo acid dehydrogenase activity in HEK-293 cell lysates using either OA or OG substrates.

where OA = 2-oxoadipate and OG = 2-oxoglutarate
and once again, Uniprot's only references for associating OGDHL with the OGDH reaction is "by similarity" (the two papers it cites at the very beginning only establish OGDHL's role in signalling pathways, not as an enzyme)

[haowang-bioinfo]

So the Uniprot assignment of OGDHL "by similarity" is actually overridden by the experimental validation in this paper. Then probably it's fine to remove OGDHL entirely now

[haowang-bioinfo]

Transient transfection of OGDHL or MRPS36 did not increase 2-oxo acid dehydrogenase activity in HEK-293 cell lysates using either OA or OG substrates.

The paper is relatively new, maybe this info should be updated to Uniprot somehow. How did you trace to it specifically @Devlin-Moyer ?

[Devlin-Moyer]

pretty sure I just searched for something along the lines of "OGDHL catalytic activity" on Google Scholar; nothing fancy

[haowang-bioinfo]

pretty sure this should be turned into routines processed regularly by bots

[haowang-bioinfo]

fixed by #725