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Redox of Alpha-Tocopheryl (Hydroxy)Quinone #611

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Devlin-Moyer opened this issue Jun 6, 2023 · 7 comments · May be fixed by #945
Open
7 tasks done

Redox of Alpha-Tocopheryl (Hydroxy)Quinone #611

Devlin-Moyer opened this issue Jun 6, 2023 · 7 comments · May be fixed by #945
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@Devlin-Moyer
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Devlin-Moyer commented Jun 6, 2023 •
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While looking into FAD/ubiquinone reactions in #607, I came across these two reactions that involve ubiquinone and don't have any genes associated with them:
MAR03047: alpha-tocopheryl hydroquinone [c] + ubiquinone [c] ⇔ alpha-tocopheryl quinone [c] + ubiquinol [c]
MAR06500: alpha-tocopheryl hydroquinone [c] + ubiquinone [m] ⇔ alpha-tocopheryl quinone [c] + ubiquinol [m]

According to this paper, Complexes I and III of the electron transport chain can use alpha-tocopheryl quinone in place of ubiquinone, but ubiquinone/ol and alpha-tocopheryl (hydro)quinone cannot directly oxidize or reduce each other, so MAR06500 should be replaced by new reactions that look like MAR06921 and MAR06918 with ubiquinone/ol replaced with alpha-tocopheryl (hydro)quinone. Since there is not currently a version of either alpha-tocopheryl (hydro)quinone metabolite in [m], and these would be the only mitochondrial reactions they would participate in, it seems like overkill to add [c] to [m] transport reactions for both metabolites, so I'm just suggesting that the new reactions replacing MAR06500 involve both [c] and [m] metabolites, since that would not be functionally different from adding the transport reactions and mitochondrial metabolites.

  • Remove MAR06500 or replace it with one of the following reactions:
  • Add a new reaction to represent reduction of alpha-tocopheryl quinone by Complex I: 5 H+ [m] + NADH [m] + alpha-tocopheryl quinone [c] ⇒ 4 H+ [i] + NAD+ [m] + alpha-tocopheryl hydroquinone [m], GPR: ENSG00000004779 and ENSG00000023228 and ENSG00000065518 and ENSG00000090266 and ENSG00000099795 and ENSG00000109390 and ENSG00000110717 and ENSG00000115286 and ENSG00000119013 and ENSG00000119421 and ENSG00000125356 and ENSG00000128609 and ENSG00000130414 and ENSG00000131495 and ENSG00000136521 and ENSG00000139180 and ENSG00000140990 and ENSG00000145494 and ENSG00000147123 and ENSG00000147684 and ENSG00000151366 and ENSG00000158864 and ENSG00000160194 and ENSG00000164258 and ENSG00000165264 and ENSG00000166136 and ENSG00000167792 and ENSG00000168653 and ENSG00000170906 and ENSG00000174886 and ENSG00000178127 and ENSG00000183648 and ENSG00000184752 and ENSG00000184983 and ENSG00000186010 and ENSG00000189043 and ENSG00000198695 and ENSG00000198763 and ENSG00000198786 and ENSG00000198840 and ENSG00000198886 and ENSG00000198888 and ENSG00000212907 and ENSG00000213619 and ENSG00000267855, reference: PMID:16569397
  • Add a new reaction to represent reduction of alpha-tocopheryl quinone by Complex III: 2 H+ [m] + 2 ferricytochrome C [m] + alpha-tocopheryl quinone [c] ⇒ 4 H+ [i] + 2 ferrocytochrome C [m] + alpha-tocopheryl hydroquinone [c], GPR: ENSG00000010256 and ENSG00000127540 and ENSG00000140740 and ENSG00000156467 and ENSG00000164405 and ENSG00000169021 and ENSG00000173660 and ENSG00000179091 and ENSG00000184076 and ENSG00000198727, reference: PMID:16569397

That same paper also mentioned that the cytochrome b5 reductases (CYB5R1/2/3/4/L) can reduce either either ubiquinone or alpha-tocopheryl quinone using NADH in the cytosol, and I also found this paper that mentioned that CBR1 (ENSG00000159228) can do the same but with NADPH and not NADH, and this paper that found that NQO1 (ENSG00000181019) can use either NADPH or NADH to reduce either ubiquinone or alpha-tocopheryl quinone (both CBR1 and NQO1 are cytosolic according to Uniprot).

MAR01801 and MAR01808 already represent reduction of ubiquinone by NADPH (MAR01801) or NADH (MAR01808) in the cytosol, but are currently only associated with TXNRD1, which Uniprot thinks is only capable of reducing thioredoxin. So I think that the GPRs of MAR01801 and MAR01808 should be replaced with this new list of enzymes that can actually reduce cytosolic ubiquinone, MAR03407 should be edited to represent the reduction of alpha-tocopheryl (hydro)quinone by NADPH, and a new reaction should be created to represent its reduction by NADH:

  • Change GPR of MAR01801 to ENSG00000159228 or ENSG00000181019 and add PMID:7005231 and PMID:16569397 as references
  • Change GPR of MAR01808 to ENSG00000181019 or ENSG00000159348 or ENSG00000166394 or ENSG00000100243 or ENSG00000065615 or ENSG00000215883 and add PMID:16569397 and PMID:9271353 as references
  • Change MAR03047 to H+ [c] + NADPH [c] + alpha-tocopheryl quinone [c] ⇒ NADP+ [c] + alpha-tocopheryl hydroquinone [c], GPR: ENSG00000159228 or ENSG00000181019 and add PMID:7005231 and PMID:16569397 as references
  • Create new reaction H+ [c] + NADH [c] + alpha-tocopheryl quinone [c] ⇒ NAD+ [c] + alpha-tocopheryl hydroquinone [c], GPR: ENSG00000181019 or ENSG00000159348 or ENSG00000166394 or ENSG00000100243 or ENSG00000065615 or ENSG00000215883, references: PMID:16569397 and PMID:9271353
@haowang-bioinfo
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haowang-bioinfo commented Jun 7, 2023 •
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based on this issue, the redox of alpha-tocopheryl (hydroxy)quinone is associated to OXPHOS complexes. To save the time for evaluation, can you please just directly paste the text here from the references

@Devlin-Moyer
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From this paper:
Reduction of alpha-tocopheryl quinone (which this paper calls TQ1) to alpha-tocopheryl hydroxyquinone by Complex I:

The lack of succinate-dependent TQ1 reduction in the presence of antimycin A (vide infra) shows that electron transfer from endogenous UQH2 to exogenous TQ1 does not occur. Therefore, TQ1 is directly reduced by complex I.

Reduction of alpha-tocopheryl quinone to alpha-tocopheryl hydroxyquinone by Complex III:

From the lack of succinate-dependent TQ1 reduction in the presence of antimycin A we conclude, similar to above, that TQ1 interacts directly with the quinone reduction site (Qi pocket) of complex III. Reduction of short-chain UQ homologues and analogues by complex III has been observed before [46]. TQ1 binds to complex III with comparable affinity, but with only 1% reactivity with respect to UQ1 (Table 3).

Also I just realized that I confused Complexes II and III in the original set of suggested changes, so I fixed that (this paper showed that Complex II does not reduce alpha-tocopheryl quinone)

@Devlin-Moyer Devlin-Moyer mentioned this issue Jun 14, 2023
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@edkerk
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edkerk commented Jul 3, 2023

If TQ1 is directly reduced by complex I, should MAR06500 not also involve translocation of protons?

@Devlin-Moyer
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Oh so looking more closely at the paper I cited when I said that Complex I and Complex III could reduce TQ1, they specified that TQ1 is binding to the same site that ubiquinone usually binds to, so if we wanted to fully represent the mechanism here, MAR06500 should probably be edited to look like MAR06921 but with ubiquinone/ol replaced with alpha-tocopheryl (hydroxy)quinone, and then also add a new reaction that looks like MAR06918 but with ubiquinone/or replaced with alpha-tocopheryl (hydroxy)quinone. I can update my proposed changes & #644 accordingly if you think that sounds reasonable

@edkerk
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edkerk commented Jul 4, 2023

Sounds indeed reasonable! Regarding the number of protons being pumped, would that still be the same (4 for complex I and 4 for complex III), or would that depend on the redox potential of TQ1? I'm not sure, and I'm even less sure whether any useful data is available/can be deciphered. In that case, the default of 4 and 4 H+ seems like a reasonable estimate.

@Devlin-Moyer
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Yea I was planning on using the same number of protons as the existing ubiquinone versions, since I think it's already the case that the number of protons pumped per NADH oxidized is somewhat variable when ubiquinone is the final acceptor, and that Complex I does several electron transfer steps between FeS clusters elsewhere in the enzyme that drive at least part of the proton pumping before the final transfer to ubiquinone/alpha-tocopheryl quinone, which presumably have about the same potential differences whether ubiquinone of alpha-tocopheryl quinone is at the end

@Devlin-Moyer
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That inspired me to revisit the other papers I'd initially cited and I found that they all described enzymes that could reduce either ubiquinone or alpha-tocopheryl quinone, but using NAD(P)H and not each other, so I have substantially revised my proposed changes (I think I'm also gonna just close #644 since it is now completely different from these changes)

@Devlin-Moyer Devlin-Moyer linked a pull request Dec 24, 2024 that will close this issue
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@Devlin-Moyer Devlin-Moyer linked a pull request Dec 24, 2024 that will close this issue
Fix alpha-tocopheryl quinone redox reactions #945
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Fix alpha-tocopheryl quinone redox reactions SysBioChalmers/Human-GEM
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