Problematic Leukotriene Degradation Reactions

[Devlin-Moyer]

While working on #634, I noticed MAR01227 and MAR01185: these appear in between a bunch of reactions that clearly represent β-oxidation of fatty acids, but this chemistry does not correspond to any steps or combination of steps of β-oxidation (or α-, or ω-oxidation):

MAR01185: 4(R)-hydroxy-dodec-(6Z)-enoate [m] + CoA [m] ⇒ (2E)-dodecenoyl-CoA [m] + H+ [m] + O2 [m]
MAR01227: 4(S)-hydroxy-dodec-(6Z)-enoate [m] + CoA [m] ⇒ (2E)-dodecenoyl-CoA [m] + H+ [m] + O2 [m]

Also those oxygen molecules seem to be coming from the ketone groups on the hydroxydodecenoates, which seems dubiously real. If instead 4(R/S)-hydroxy-docec-(6Z)-enoate went through one round of normal β-oxidation (see these papers), that would look like:

1. 4(R/S)-hydroxy-dodec-(6Z)-enoyl-CoA + FAD -> 4(R/S)-hydroxy-dodec-(2Z,6Z)-dienoyl-CoA + FADH₂ catalyzed by ACAD9, ACADL, or ACADM (sources: 1, 2, 3)
2. 4(R/S)-hydroxy-dodec-(2Z,6Z)-dienoyl-CoA + H₂O -> 3(S),4(R)-dihydroxy-dodec-(6Z)-dienoyl-CoA catalyzed by HADHA
3. 3(S),4(R/S)-dihydroxy-dodec-(6Z)-dienoyl-CoA + NAD⁺ -> 3-oxo-4(R/S)-hydroxy-dodec-(6Z)-dienoyl-CoA + H⁺ catalyzed by HADHA
4. 3-oxo-4(R/S)-hydroxy-dodec-(6Z)-dienoyl-CoA + CoA -> 2(R/S)-hydroxy-dec-(4Z)-enoyl-CoA + acetyl-CoA catalyzed by HADHB or SCP2

But then there's a problem: 2-hydroxy-acyl-CoAs cannot undergo β-oxidation, so if one is formed as an intermediate during β-oxidation, HACL1 or ILVBL converts the 2-hydroxy-acyl-CoA into an aldehyde with one fewer carbon than the 2-hydroxyacyl-CoA while releasing a formyl-CoA, then ALDH3A2 converts that aldehyde into a carboxylic acid (source), which can then be turned into an acyl-CoA by an acyl-CoA syntheases and resume “normal” β-oxidation. None of these enzymes are localized to mitochondria: HACL1 is in peroxisomes, ILVBL is in the E.R., and ALDH3A2 can be in either peroxisomes or the E.R. I'm proposing a series of reactions that takes the E.R. route and rejoins the ordinary β-oxidation pathway at (2E)-nonenoyl-CoA (MAM00056m):

5. 2(R/S)-hydroxy-dec-(4Z)-enoyl-CoA + H₂O -> 2(R/S)-hydroxy-dec-(4Z)-enoate [m] + CoA + H⁺ catalyzed by ACOT2, ACOT8, ACOT9, ACOT11, or ACAA2 (sources: 1, 2, 3, 4)
6. 2(R/S)-hydroxy-dec-(4Z)-enoate [m] -> 2(R/S)-hydroxy-dec-(4Z)-enoate [c]
7. 2(R/S)-hydroxy-dec-(4Z)-enoate [c] -> 2(R/S)-hydroxy-dec-(4Z)-enoate [r]
8. 2(R/S)-hydroxy-dec-(4Z)-enoate + ATP + CoA -> 2(R/S)-hydroxy-dec-(4Z)-enoyl-CoA + AMP + PP_i catalyzed by SLC27A4 (sources: figure 3 of this paper and table 2 of this paper)
9. 2(R/S)-hydroxy-dec-(4Z)-enoyl-CoA -> 3Z-nonenal + formyl-CoA by ILVBL
10. 3Z-nonenal + NAD⁺ + H₂O -> 3Z-nonenoate [r] + NADH + 2 H⁺ catalyzed by ALDH3A2
11. 3Z-nonenoate [r] -> 3Z-nonenoate [c]
12. 3Z-nonenoate [c] -> 3Z-nonenoate [m]
13. 3Z-noneoate [m] + ATP + CoA -> 3Z-nonenoyl-CoA + AMP + PP_i catalyzed by ACSM1 (source)
14. 3Z-nonenoyl-CoA -> 2E-nonenoyl-CoA catalyzed by ECI1

Proposed Changes:

• Create a new gene entry for ILVBL (ENSG00000105135)
• Create new metabolites for mitochondrial 4-hydroxy-dodec-(2Z,6Z)-dienoyl-CoA, formula: C33H50N7O18P3S4-, charge: -4
• Create new metabolites for mitochondrial 3(S),4-dihydroxy-dodec-(6Z)-dienoyl-CoA, formula: C33H52N7O19P3S4-, charge: -4
• Create new metabolites for mitochondrial 3-oxo-4-hydroxy-dodec-(6Z)-dienoyl-CoA, formula: C33H50N7O19P3S4-, charge: -4
• Create new metabolites for mitochondrial 2-hydroxy-dec-(4Z)-enoyl-CoA, formula: C31H48N7O18P3S4-, charge: -4
• Create new metabolites for mitochondrial 2-hydroxy-dec-(4Z)-enoate, formula: C10H17O3, charge: -1
• Create new metabolites for cytosolic 2-hydroxy-dec-(4Z)-enoate, formula: C10H17O3, charge: -1
• Create new metabolites for E.R. 2-hydroxy-dec-(4Z)-enoate, formula: C10H17O3, charge: -1
• Create new metabolites for E.R. 2-hydroxy-dec-(4Z)-enoyl-CoA, formula: C31H48N7O18P3S4-, charge: -4
• Create a new metabolite for E.R. (3Z)-nonenal, formula: C9H16O, charge: 0
• Create a new metabolite for E.R. (3Z)-nonenoate, formula: C9H15O2, charge: -1
• Create a new metabolite for cytosolic (3Z)-nonenoate, formula: C9H15O2, charge: -1
• Create a new metabolite for mitochondrial (3Z)-nonenoate, formula: C9H15O2, charge: -1
• Create a new metabolite for mitochondrial (3Z)-nonenoyl-CoA, formula: C30H46N7O17P3S4-, charge: -4
• Edit MAR01227 to be MAM00936m + MAM02630m -> 4(R)-hydroxy-dodec-(2Z,6Z)-dienoyl-CoA + MAM02041m, GPR: ENSG00000115361 or ENSG00000117054 or ENSG00000177646
• Edit MAR01185 to be MAM00935m + MAM02630m -> 4(S)-hydroxy-dodec-(2Z,6Z)-dienoyl-CoA + MAM02041m, GPR: ENSG00000115361 or ENSG00000117054 or ENSG00000177646
• Create a new reaction 4(R)-hydroxy-dodec-(2Z,6Z)-dienoyl-CoA + MAM02040m -> 3(S),4(R)-dihydroxy-dodec-(6Z)-dienoyl-CoA, GPR: ENSG00000084754
• Create a new reaction 4(S)-hydroxy-dodec-(2Z,6Z)-dienoyl-CoA + MAM02040m -> 3(S),4(S)-dihydroxy-dodec-(6Z)-dienoyl-CoA, GPR: ENSG00000084754
• Create a new reaction 3(S),4(R)-dihydroxy-dodec-(6Z)-dienoyl-CoA + MAM02552m -> 3-oxo-4(R)-hydroxy-dodec-(6Z)-dienoyl-CoA + MAM02553m + MAM02039m, GPR: ENSG00000084754
• Create a new reaction 3(S),4(S)-dihydroxy-dodec-(6Z)-dienoyl-CoA + MAM02552m -> 3-oxo-4(S)-hydroxy-dodec-(6Z)-dienoyl-CoA + MAM02553m + MAM02039m, GPR: ENSG00000084754
• Create a new reaction 3-oxo-4(R)-hydroxy-dodec-(6Z)-dienoyl-CoA + MAM01597m -> 2(R)-hydroxy-dec-(4Z)-enoyl-CoA [m] + MAM02041m, GPR: ENSG00000138029
• Create a new reaction 3-oxo-4(S)-hydroxy-dodec-(6Z)-dienoyl-CoA + MAM01597m -> 2(S)-hydroxy-dec-(4Z)-enoyl-CoA [m] + MAM02041m, GPR: ENSG00000138029
• Create a new reaction 2(R)-hydroxy-dec-(4Z)-enoyl-CoA + MAM02040m -> 2(R)-hydroxy-dec-(4Z)-enoate + MAM01597m + MAM02039m, GPR: ENSG00000119673 or ENSG00000101473 or ENSG00000123130 or ENSG00000162390 or ENSG00000167315, references: PMID:20470824;PMID:22897136;PMID:25478839
• Create a new reaction 2(S)-hydroxy-dec-(4Z)-enoyl-CoA + MAM02040m -> 2(S)-hydroxy-dec-(4Z)-enoate + MAM01597m + MAM02039m, GPR: ENSG00000119673 or ENSG00000101473 or ENSG00000123130 or ENSG00000162390 or ENSG00000167315, references: PMID:20470824;PMID:22897136;PMID:25478839
• Create a new reaction 2(R)-hydroxy-dec-(4Z)-enoate [m] -> 2(R)-hydroxy-dec-(4Z)-enoate [c]
• Create a new reaction 2(S)-hydroxy-dec-(4Z)-enoate [m] -> 2(S)-hydroxy-dec-(4Z)-enoate [c]
• Create a new reaction 2(R)-hydroxy-dec-(4Z)-enoate [c] -> 2(R)-hydroxy-dec-(4Z)-enoate [r]
• Create a new reaction 2(S)-hydroxy-dec-(4Z)-enoate [c] -> 2(S)-hydroxy-dec-(4Z)-enoate [r]
• Create a new reaction 2(R)-hydroxy-dec-(4Z)-enoate [r] + MAM01371r+ MAM01597r -> 2(R)-hydroxy-dec-(4Z)-enoyl-CoA + MAM01334r + MAM02759r, GPR: ENSG00000167114, references: PMID:28289220
• Create a new reaction 2(S)-hydroxy-dec-(4Z)-enoate [r] + MAM01371r + MAM01597r -> 2(S)-hydroxy-dec-(4Z)-enoyl-CoA + MAM01334r + MAM02759r, GPR: ENSG00000167114, references: PMID:28289220
• Create a new reaction 3-oxo-4(R)-hydroxy-dodec-(6Z)-dienoyl-CoA -> (3Z)-nonenal + MAM01836r, GPR: ENSG00000105135, references: PMID:28289220
• Create a new reaction 3-oxo-4(S)-hydroxy-dodec-(6Z)-dienoyl-CoA -> (3Z)-nonenal + MAM01836r, GPR: ENSG00000105135, references: PMID:28289220
• Create a new reaction (3Z)-nonenal + MAM02552r + MAM02040r -> (3Z)-nonenoate [r] + MAM02553r + 2 MAM02039r, GPR: ENSG00000072210, references: PMID:28289220
• Create a new reaction (3Z)-nonenoate [r] -> (3Z)-nonenoate [c]
• Create a new reaction (3Z)-nonenoate [c] -> (3Z)-nonenoate [m]
• Create a new reaction (3Z)-nonenoate [m] + MAM01597m + MAM01371m -> (3Z)-nonenoyl-CoA + MAM01334m + MAM02759m, GPR: ENSG00000166743 , references: PMID:27351777
• Create a new reaction (3Z)-nonenoyl-CoA -> MAM00056m, GPR: ENSG00000167969