GPRs for Mitochondrial 2-enoyl-CoA Hydration Reactions

[Devlin-Moyer]

Current Behavior:

All of these reactions represent hydration of a 2-enoyl-CoA in mitochondria and have GPRs of HADHA and EHHADH and ECHS1 (ENSG00000084754 and ENSG00000113790 and ENSG00000127884):

ID	Reaction	Chain Length	Appropriate GPR
MAR03219	H2O [m] + trans,cis-2,13-docosadienoyl-CoA [m] --> 3(S)-hydroxy-13-cis-docosenoyl-CoA [m]	22	HADHA
MAR03108	(2E)-docosenoyl-CoA [m] + H2O [m] --> 3-hydroxydocosanoyl-CoA [m]	22	HADHA
MAR03171	(2E)-heneicosenoyl-CoA [m] + H2O [m] --> 3-hydroxyheneicosanoyl-CoA [m]	21	HADHA
MAR03449	H2O [m] + trans-2-cis,cis,cis-8,11,14-eicosatetraenoyl-CoA [m] --> 3(S)-hydroxy-dihomo-gamma-linolenoyl-CoA [m]	20	HADHA
MAR03241	H2O [m] + trans,cis-2,13-eicosadienoyl-CoA [m] --> 3(S)-hydroxy-13-cis-eicosenoyl-CoA [m]	20	HADHA
MAR03223	H2O [m] + trans,cis-2,11-eicosadienoyl-CoA [m] --> 3(S)-hydroxy-11-cis-eicosenoyl-CoA [m]	20	HADHA
MAR03112	(2E)-eicosenoyl-CoA [m] + H2O [m] --> 3-hydroxyeicosanoyl-CoA [m]	20	HADHA
MAR01272	5(S),12(R)-dihydroxy-eicosa-2,8-trans-6,14-cis-tetraenoyl-CoA [m] + H2O [m] --> 3(S),5(S),12(R)-trihydroxy-eicosa-8-trans-6,14-cis-trienoyl-CoA [m]	20	HADHA
MAR01255	(18E)-20-oxo-20-CoA-LTB4 [m] + H2O [m] --> 20-CoA-20-oxo-18r-hydroxy-LTB4 [m]	20	HADHA
MAR01206	5-oxo-12(S)-hydroxy-eicosa-(2E,8E,10E,14Z)-tetraenoyl-CoA [m] + H2O [m] --> 3(S),12(S)-dihydroxy-5-oxo-eicosa-(8E,10E,14Z)-trienoyl-CoA [m]	20	HADHA
MAR01163	5-oxo-12(R)-hydroxy-eicosa-(2E,8E,10E,14Z)-tetraenoyl-CoA [m] + H2O [m] --> 3(S),12(R)-dihydroxy-5-oxo-eicosa-(8E,10E,14Z)-trienoyl-CoA [m]	20	HADHA
MAR03175	(2E)-nonadecenoyl-CoA [m] + H2O [m] --> 3-hydroxynonadecanoyl-CoA [m]	19	HADHA
MAR03453	(2E,6Z,9Z,12Z)-octadecatetraenoyl-CoA [m] + H2O [m] --> 3(S)-hydroxy-(6Z,9Z,12Z)-octadecatrienoyl-CoA [m]	18	HADHA
MAR03277	H2O [m] + trans,cis,cis-2,9,12-octadecatrienoyl-CoA [m] --> (3S)-3-hydroxylinoleoyl-CoA [m]	18	HADHA
MAR03245	H2O [m] + trans,cis-octadeca-2,11-dienoyl-CoA [m] --> (S)-3-hydroxy-11-cis-octadecenoyl-CoA [m]	18	HADHA
MAR03227	H2O [m] + trans,cis-octadeca-2,9-dienoyl-CoA [m] --> (S)-3-hydroxyoleyleoyl-CoA [m]	18	HADHA
MAR03116	(2E)-octadecenoyl-CoA [m] + H2O [m] --> 3-hydroxyoctadecanoyl-CoA [m]	18	HADHA
MAR03179	(2E)-heptadecenoyl-CoA [m] + H2O [m] --> 3-hydroxyheptadecanoyl-CoA [m]	17	HADHA
MAR03281	H2O [m] + trans,cis,cis-2,7,10-hexadecatrienoyl-CoA [m] --> (3S)-3-hydroxy-cis,cis-palmito-7,10-dienoyl-CoA [m]	16	HADHA
MAR03252	H2O [m] + trans,cis-hexadeca-2,9-dienoyl-CoA [m] --> (S)-3-hydroxypalmitoleoyl-CoA [m]	16	HADHA
MAR03231	H2O [m] + trans,cis-hexadeca-2,7-dienoyl-CoA [m] --> (S)-3-hydroxy-7-hexadecenoyl-CoA [m]	16	HADHA
MAR03122	(2E)-hexadecenoyl-CoA [m] + H2O [m] --> (S)-3-hydroxyhexadecanoyl-CoA [m]	16	HADHA
MAR01219	3(S),8(S)-dihydroxy-(6E,10Z)-hexadecadienoate [m] <=> 8(S)-hydroxy-hexadeca-(2E,6E,10Z)-trienoate [m] + H2O [m]	16	HADHA
MAR01177	8(R)-hydroxy-hexadeca-(2E,6E,10Z)-trienoate [m] + H2O [m] --> 3(S),8(R)-dihydroxy-(6E,10Z)-hexadecadienoate [m]	16	HADHA
MAR03183	(2E)-pentadecenoyl-CoA [m] + H2O [m] --> 3-hydroxypentadecanoyl-CoA [m]	15	HADHA
MAR03285	H2O [m] + trans-2-cis,cis-5,8-tetradecatrienoyl-CoA [m] --> 3(S)-hydroxy-(5Z,8Z)-tetradecadienoyl-CoA [m]	14	HADHA
MAR03260	H2O [m] + trans,cis-myristo-2,7-dienoyl-CoA [m] --> cis-(3S)-hydroxytetradec-7-enoyl-CoA [m]	14	HADHA
MAR03235	H2O [m] + trans,cis-myristo-2,5-dienoyl-CoA [m] --> cis-(3S)-hydroxytetradec-5-enoyl-CoA [m]	14	HADHA
MAR03129	(2E)-tetradecenoyl-CoA [m] + H2O [m] --> (S)-3-hydroxytetradecanoyl-CoA [m]	14	HADHA
MAR01224	6(S)-hydroxy-tetradeca-(2E,8Z)-dienoate [m] + H2O [m] --> 3(S),6(S)-dihydroxy-tetradec-(8Z)-enoate [m]	14	HADHA
MAR01182	6(R)-hydroxy-tetradeca-(2E,8Z)-dienoate [m] + H2O [m] --> 3(S),6(R)-dihydroxy-tetradec-(8Z)-enoate [m]	14	HADHA
MAR03187	(2E)-tridecenoyl-CoA [m] + H2O [m] --> 3-hydroxytridecanoyl-CoA [m]	13	HADHA
MAR03290	H2O [m] + trans,cis-lauro-2,6-dienoyl-CoA [m] --> (3S)-3-hydroxydodec-cis-6-enoyl-CoA [m]	12	HADHA or ECHS1
MAR03136	(2E)-dodecenoyl-CoA [m] + H2O [m] --> (S)-3-hydroxydodecanoyl-CoA [m]	12	HADHA or ECHS1
MAR03191	(2E)-undecenoyl-CoA [m] + H2O [m] --> 3-hydroxyundecanoyl-CoA [m]	11	HADHA or ECHS1
MAR03143	(2E)-decenoyl-CoA [m] + H2O [m] --> (S)-hydroxydecanoyl-CoA [m]	10	HADHA or ECHS1
MAR03523	4(R),8-dimethyl-trans-2-nonenoyl-CoA [m] + H2O [m] --> 3(S)-hydroxy-4(R),8-dimethyl-nonanoyl-CoA [m]	9	HADHA or ECHS1
MAR03195	(2E)-nonenoyl-CoA [m] + H2O [m] --> 3-hydroxynonanoyl-CoA [m]	9	HADHA or ECHS1
MAR03150	(2E)-octenoyl-CoA [m] + H2O [m] --> (S)-hydroxyoctanoyl-CoA [m]	8	HADHA or ECHS1
MAR03528	2,6-dimethyl-trans-2-heptenoyl-CoA [m] + H2O [m] --> 3(S)-hydroxy-2(S),6-dimethyl-heptanoyl-CoA [m]	7	HADHA or ECHS1
MAR03199	(2E)-heptenoyl-CoA [m] + H2O [m] --> 3-hydroxyheptanoyl-CoA [m]	7	HADHA or ECHS1
MAR03157	(2E)-hexenoyl-CoA [m] + H2O [m] --> (S)-hydroxyhexanoyl-CoA [m]	6	HADHA or ECHS1
MAR03532	4-methyl-trans-2-pentenoyl-CoA [m] + H2O [m] --> 3(S)-hydroxy-4-methyl-pentanoyl-CoA [m]	5	ECHS1
MAR03203	(2E)-pentenoyl-CoA [m] + H2O [m] --> 3-hydroxypentanoyl-CoA [m]	5	ECHS1
MAR03785	H2O [m] + tiglyl-CoA [m] --> (S)-3-hydroxy-2-methylbutyryl-CoA [m]	4	ECHS1
MAR03164	crotonyl-CoA [m] + H2O [m] --> (S)-3-hydroxybutyryl-CoA [m]	4	ECHS1
MAR04735	acrylyl-CoA [m] + H2O [m] <=> 3-hydroxypropionyl-CoA [m]	3	ECHS1
MAR03753	H2O [m] + methacrylyl-CoA [m] --> 3-hydroxyisobutyryl-CoA [m]	3	ECHS1

Expected behavior:

EHHADH is localized to peroxisomes, so it should not be associated with any of these reactions. While HADHA and ECHS1 are both localized to mitochondria, ECSH1 generally acts on substrates with shorter chains than HADHA, although there is some overlap. While most papers I could find were pretty vague about exactly what the range of substrates each enzyme could act on was, the best I've managed to come up with are these papers that say that ECSH1 can act on substrates with chain lengths of up to 12, and HADHA can act on substrates with chain lengths of at least 6. I have proposed new GPRs for each of these reactions that reflect these chain length preferences.

Proposed changes:

• Change GPR of MAR03219 to ENSG00000084754
• Change GPR of MAR03108 to ENSG00000084754
• Change GPR of MAR03171 to ENSG00000084754
• Change GPR of MAR03449 to ENSG00000084754
• Change GPR of MAR03241 to ENSG00000084754
• Change GPR of MAR03223 to ENSG00000084754
• Change GPR of MAR03112 to ENSG00000084754
• Change GPR of MAR01272 to ENSG00000084754
• Change GPR of MAR01255 to ENSG00000084754
• Change GPR of MAR01206 to ENSG00000084754
• Change GPR of MAR01163 to ENSG00000084754
• Change GPR of MAR03175 to ENSG00000084754
• Change GPR of MAR03453 to ENSG00000084754
• Change GPR of MAR03277 to ENSG00000084754
• Change GPR of MAR03245 to ENSG00000084754
• Change GPR of MAR03227 to ENSG00000084754
• Change GPR of MAR03116 to ENSG00000084754
• Change GPR of MAR03179 to ENSG00000084754
• Change GPR of MAR03281 to ENSG00000084754
• Change GPR of MAR03252 to ENSG00000084754
• Change GPR of MAR03231 to ENSG00000084754
• Change GPR of MAR03122 to ENSG00000084754
• Change GPR of MAR01219 to ENSG00000084754
• Change GPR of MAR01177 to ENSG00000084754
• Change GPR of MAR03183 to ENSG00000084754
• Change GPR of MAR03285 to ENSG00000084754
• Change GPR of MAR03260 to ENSG00000084754
• Change GPR of MAR03235 to ENSG00000084754
• Change GPR of MAR03129 to ENSG00000084754
• Change GPR of MAR01224 to ENSG00000084754
• Change GPR of MAR01182 to ENSG00000084754
• Change GPR of MAR03187 to ENSG00000084754
• Change GPR of MAR03290 to ENSG00000084754 or ENSG00000127884
• Change GPR of MAR03136 to ENSG00000084754 or ENSG00000127884
• Change GPR of MAR03191 to ENSG00000084754 or ENSG00000127884
• Change GPR of MAR03143 to ENSG00000084754 or ENSG00000127884
• Change GPR of MAR03523 to ENSG00000084754 or ENSG00000127884
• Change GPR of MAR03195 to ENSG00000084754 or ENSG00000127884
• Change GPR of MAR03150 to ENSG00000084754 or ENSG00000127884
• Change GPR of MAR03528 to ENSG00000084754 or ENSG00000127884
• Change GPR of MAR03199 to ENSG00000084754 or ENSG00000127884
• Change GPR of MAR03157 to ENSG00000084754 or ENSG00000127884
• Change GPR of MAR03532 to ENSG00000127884
• Change GPR of MAR03203 to ENSG00000127884
• Change GPR of MAR03785 to ENSG00000127884
• Change GPR of MAR03164 to ENSG00000127884
• Change GPR of MAR04735 to ENSG00000127884
• Change GPR of MAR03753 to ENSG00000127884

[JHL-452b]

It looks great to remove EHHADH. And I agree with your suggestion about ECSH1 and HADHA as some databases have similar description.

The Proposed changes tips gived above may be ENSG0000012788 or ENSG00000084754, and no other genes should appear. That's a small problem need to be noticed. (•̀ᴗ• ) ̑̑

In addition, 3-hydroxyacyl-CoA dehydrogenase from mitochondrial membranes should be a complex, HADHA can be used as an α subunit, and I suggest HADHB as a β subunit. So, the GPR of the above reaction should replace ENSG00000084754 with ENSG00000084754 and ENSG00000138029

[Devlin-Moyer]

oh whoops I did the classic click and drag spreadsheet thing where it increments the number for each cell; I will fix that

I didn't include HADHB in the GPRs following the rationale here, where we set the GPRs of reactions catalyzed by enzyme complexes such that each reaction was only associated with the specific subunits of the larger complex that directly catalyzed that reaction and left out the genes encoding all the other subunits of the same complex. HADHB is only responsible for the 3-ketoacyl-CoA activity of the HADHA/HADHB complex.

[JHL-452b]

Agree with your reply. I think the evidence you provided is enough to support that HADHB isn't responsible for 2,3-enoyl-CoA hydratase and the 3-hydroxyacyl-CoA dehydrogenase activities. So, there is no need for the GPR of the above reaction to be replaced.

[Devlin-Moyer]

fixed by #808