Short- and medium-chain fatty acids don't have hydrolysis rxns

[pranasag]

Current behavior:

Hi everyone,
after the fix #557/discussion in #527, the Human-GEM v1.16 cannot produce free C4-C11 fatty acids (the ATP-generating reaction was the only route to get free FAs from their CoA-bound forms). Acyl-CoA hydrolysis reactions for C12 and longer FAs exist already.

Expected feature/value/output:

We would need cytosolic reactions for C4-, C6-, C8-, C10-, and C11-CoA hydryolysis in the same spirit as for C12 MAR00189: H2O[c] + acyl-CoA[c] => CoA[c] + H+[c] + free fatty acid[c].

[haowang-bioinfo]

interesting

We would need cytosolic reactions for C4-, C6-, C8-, C10-, and C11-CoA hydryolysis in the same spirit as for C12 MAR00189: H2O[c] + acyl-CoA[c] => CoA[c] + H+[c] + free fatty acid[c].

what are the gene(s) that are involved in these hydrolysis reactions?

[pranasag]

Good question. Currently, almost all reactions in the Acyl-CoA hydrolysis subsystem have the same GPR association (ENSG00000097021 or ENSG00000119673 or ENSG00000136881 or ENSG00000177465 or ENSG00000184227 or ENSG00000205669) - these are different isoforms of acyl-CoA thioesterase.

I initially thought that defining new reactions with just use the same GPR string will suffice, I think other entries also need a bit of curation. From a quick look to respective UniProt entries, some of these enzymes are known to have higher specificity for [very] long-chain fatty acids, and ACOT4 is even labelled as peroxisomal isoform in UniProt, thus should not be associated to the cytoplasmic acyl-CoA hydrolysis reactions.

[haowang-bioinfo]

Good question. Currently, almost all reactions in the Acyl-CoA hydrolysis subsystem have the same GPR association (ENSG00000097021 or ENSG00000119673 or ENSG00000136881 or ENSG00000177465 or ENSG00000184227 or ENSG00000205669) - these are different isoforms of acyl-CoA thioesterase.

good

I initially thought that defining new reactions with just use the same GPR string will suffice, I think other entries also need a bit of curation. From a quick look to respective UniProt entries, some of these enzymes are known to have higher specificity for [very] long-chain fatty acids, and ACOT4 is even labelled as peroxisomal isoform in UniProt, thus should not be associated to the cytoplasmic acyl-CoA hydrolysis reactions.

it does appear so. Maybe begin with sorting out cytoplasmic acyl-CoA hydrolysis reactions first, please go ahead proposing an implementation plan

[pranasag]

Hi there,
With some input from Christoff Odendaal/Christoff1993 I have summarized what I found in literature in this .csv file. The main points are:

• Suggested new reactions for short-chain acyl-CoA hydrolysis, reaction IDs to be assigned
• For existing cytosolic reactions, GPRs were reviewed based to the localization of the ACOTs and their known specificity towards different carbon chain lengths
• Ditto for the GPRs of the peroxisomal reactions
• Suggest adding two genes that are not currently in the model THEM4 and THEM5

As you could see in the .csv summary, many ACOTs localize to mitochondria as well. Thus a potential next step in curation would be to add analogous hydrolysis reactions for mitochondrial acyl-CoAs.

[haowang-bioinfo]

@pranasag sorry for late response - very nice and thorough investigation. Please go ahead to make the changes!

Gene	Ensembl ID	subcellular Localization	Known activity
ACOT1	ENSG00000184227	Cytosol	C12-C20
ACOT12	ENSG00000172497	Cytosol	Preferentially acetyl-CoA; activity towards butyryl- and hexanoyl-CoA known
ACOT2	ENSG00000119673	Mitochondria	long chain acyl CoAs (C14-C20)
ACOT4	ENSG00000177465	Peroxisome	glutaryl-CoA and long chain saturated acyl-CoAs
ACOT6	ENSG00000205669	Cytosol, peroxisome	phytanoyl-CoA and pristanoyl-CoA (long- and branched-chain)
ACOT7	ENSG00000097021	Cytosol, mitochondria	acyl-CoAs with chain-lengths of C8-C18
ACOT8	ENSG00000101473	Peroxisome	C2-C20, not active >C20
ACOT9	ENSG00000123130	Mitochondria	N/D
BAAT	ENSG00000136881	Cytosol, peroxisome	Bile acids + long-chain acyl-CoAs
ACOT13	ENSG00000112304	Cytosol, mitochondria	C12-C18
ACOT15/THEM5	ENSG00000196407	Mitochondria	C18
THEM4	ENSG00000159445	Cytosol, mitochondria, cell membrane	C14-C18

• the evidence table was extracted as above (good job!)
• new reactions can be assigned with ids from highest number and in +1 incremental order, e.g. MAR20201, MAR20202, ...

[haowang-bioinfo]

fixed by #715 and #717