fix: remove generic reactions

[BenjaSanchez]

Description of the issue:

Reaction r_4308 uses a generic phospholipid species, not specifying which type of phospholipid it is. As this creates confusion with the rest of the model, which has very specific details for each lipid, e.g. 1-phosphatidyl-1D-myo-inositol (1-16:1, 2-16:1), I would suggest removing that reaction until it can be formulated with more precise species. In any case, the reaction is blocked and both phospholipid species in it are dead-ends as they only appear in this reaction.

H2O [erm] + ATP [erm] + phospholipid [erm]  -> H+ [erm] + phosphate [erm] + phospholipid [gm] + ADP [erm]

@hongzhonglu what do you think?

I hereby confirm that I have:

• Tested my code with all requirements for running the model
• Done this analysis in the master branch of the repository
• Checked that a similar issue does not exist already

[hongzhonglu]

@BenjaSanchez Hi Ben, I agree that r_4308 should be removed.

[edkerk]

Other instances of generic reactions:

Generic lipid

rxnID	reaction name	equation
r_4225	Broad-range acid phosphatase DET1 (EC 3.1.3.-) (Decreased ergosterol transport protein 1)	ATP[c] + H2O[c] + sterols[e] <=> ADP[c] + H+[c] + phosphate[c] + sterols[c]
r_4251	CTP:phosphatidate cytidyltransferase	CTP[m] + phosphatidate[m] <=> diphosphate[m] + H+[m] + CDP-diacylglycerol[m]
r_4277	acyl-CoA:sn-glycerol-3-phosphate 1-O-acyltransferase	Acyl-CoA[er] + 1-acyl-sn-glycerol 3-phosphate[er] <=> coenzyme A[er] + 1,2-diacyl-sn-glycerol 3-phosphate[er]

---

R-group

rxnID	reaction name	equation
r_4199	Glutathione S-transferase 1 (EC 2.5.1.18) (GST-I)	RX[er] + glutathione[er] <=> HX[er] + R-S-glutathione[er]
r_4200	Glutathione S-transferase 1 (EC 2.5.1.18) (GST-I)	glutathione[c] + RX[c] <=> HX[c] + R-S-glutathione[c]
r_4201	Glutathione S-transferase 1 (EC 2.5.1.18) (GST-I)	glutathione[m] + RX[m] <=> HX[m] + R-S-glutathione[m]
r_4207	Glutathione S-transferase omega-like 2 (EC 2.5.1.18) (Extracellular mutant protein 4) (Glutathione-dependent dehydroascorbate reductase) (EC 1.8.5.1)	RX[p] + glutathione[p] <=> HX[p] + R-S-glutathione[p]

---

Generic protein

rxnID	reaction name	equation
r_4233	S-Adenosyl-L-methionine:protein-C-terminal-S-farnesyl-L-cysteine O-methyltransferase	S-adenosyl-L-methionine[c] + Protein C-terminal S-farnesyl-L-cysteine[c] <=> S-adenosyl-L-homocysteine[c] + Protein C-terminal S-farnesyl-L-cysteine methyl ester[c]
r_4239	L-arginyl-tRNA(Arg):protein arginyltransferase	Arg-tRNA(Arg)[c] + Protein[c] <=> H+[c] + tRNA(Arg)[c] + L-Arginyl-protein[c]
r_4240	Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3 (Oligosaccharyl transferase subunit STT3) (EC 2.4.99.18)	Protein asparagine[er] + G00008[er] <=> H+[er] + Dolichyl diphosphate[er] + G00009[er]
r_4258	[lipoyl-carrier protein]-L-lysine:lipoate ligase (AMP-forming)	ATP[c] + (R)-Lipoate[c] + Apoprotein[c] => AMP[c] + diphosphate[c] + Protein N6-(lipoyl)lysine[c]
r_4280	octanoyl-[acp]:protein N6-octanoyltransferase	octanoyl-ACP[m] + Apoprotein[m] <=> ACP1[m] + Protein N6-(octanoyl)lysine[m]
r_4281	lipoyl-[acp]:protein N6-lipoyltransferase	Apoprotein[m] + Lipoyl-[acp] [mitochondrion][m] <=> ACP1[m] + Protein N6-(lipoyl)lysine[m]
r_4323	protein N6-(octanoyl)lysine:sulfur sulfurtransferase	2 S-adenosyl-L-methionine[m] + Protein N6-(octanoyl)lysine[m] + 2 Sulfur donor[m] <=> 2 L-methionine[m] + Protein N6-(lipoyl)lysine[m] + 2 5'-Deoxyadenosine[m]
r_4325	Iron sulfur cluster assembly protein 2, mitochondrial (Iron sulfur cluster scaffold protein 2)	S-sulfanyl-[L-cysteine desulfurase] [mitochondrion][m] + [disordered-form [Fe-S] cluster scaffold protein] [mitochondrion][m] => S-sulfanyl-[cysteine desulfurase]-[disordered-form scaffold protein] complex [mitochondrion][m]
r_4340	D-amino-acid N-acetyltransferase HPA3 (DNT) (EC 2.3.1.36) (EC 2.3.1.48) (Histone and other protein acetyltransferase 3)	acetyl-CoA[c] + [protein]-L-lysine [cytoplasm][c] <=> coenzyme A[c] + H+[c] + [protein]-N(6)-acetyl-L-lysine [cytoplasm][c]

---

Generic sulfur

rxnID	reaction name	equation
r_4173	L-cysteine:sulfur-acceptor sulfurtransferase	(sulfur carrier)-H[m] + L-cysteine[m] <=> L-alanine[m] + (sulfur carrier)-SH[m]
--	--	--
r_4252	Thiamine thiazole synthase (Thiazole biosynthetic enzyme)	L-glycine[c] + NAD[c] + Sulfur donor[c] <=> 3 H2O[c] + nicotinamide[c] + ADP-5-ethyl-4-methylthiazole-2-carboxylate[c]
r_4324	octanoyl-[acp]:sulfur sulfurtransferase	octanoyl-ACP[m] + 2 S-adenosyl-L-methionine[m] + 2 Sulfur donor[m] <=> 2 L-methionine[m] + Lipoyl-[acp] [mitochondrion][m] + 2 5'-Deoxyadenosine[m]

---

Various

rxnID	reaction name	equation
r_4215	Cys-Gly metallodipeptidase DUG1 (EC 3.4.13.-) (Deficient in utilization of glutathione protein 1) (GSH degradosomal complex subunit DUG1)	H2O[c] + R-S-Cysteinylglycine[c] <=> L-glycine[c] + S-Substituted L-cysteine[c]
r_4229	Monocarboxylic acid amide amidohydrolase	H2O[c] + Monocarboxylic acid amide[c] <=> ammonium[c] + Carboxylate[c]
r_4246	Alpha-mannosidase (EC 3.2.1.24) (Alpha-D-mannoside mannohydrolase)	H2O[v] + alpha-D-mannoside[v] => alpha-D-mannopyranose[v] + non glycosylated sugar acceptor[v]

[hongzhonglu]

Some generic reactions can be changed into more detailed reactions if we know the detailed functions of the enzymes. So be careful when we delete some generic reactions.

[edkerk]

Good point @hongzhonglu, but I'd argue that protein-modifying enzymes are still outside the scope of a purely metabolic model, which is what yeast-GEM represents. So should we then remove the reactions labelled as Generic protein in the table above?

Regardless what we decide for the protein-modifying reactions, I think @hongzhonglu makes a fair argument that future knowledge might allow to curate these generic reactions to specific metabolites. In the meanwhile: would it be better to block these reactions (UB and LB = 0), to prevent any possibility of them being involved in some unrealistic loops? For instance r_4252 and r_4324 (Generic sulfer) are now strictly coupled as they are the only reactions using the Sulfur donor[c] metabolite.

• Keep Generic protein reactions?
• Block reactions with generic reactants?

[BenjaSanchez]

For now, blocking these reactions sounds like a good plan to me, maybe also mentioning in the corresponding notes the reason why?