Inconsistent Representation of Thiamine's Role in 2-Oxoacid Dehydrogenase Complexes

[Devlin-Moyer]

Current behavior:

In #524, when resolving the duplicate representations of the pyruvate dehydrogenase (PDH) and 2-oxoglutarate dehydrogenase (OGDH) complexes, we decided to keep the sets of reactions that explicitly show the involvement of thiamine in the catalytic mechanism (see this comment in particular for the rationale). The reactions representing the catalytic activities of the 2-oxoadipate dehydrogenase (OADH) and branched-chain ketoacid dehydrogenase (BCKDH) complexes do not show the involvement of thiamine, despite the fact that all four complexes use thiamine in exactly the same way (sources for BCKDH and OADH):

Complex	ID	Reaction	Genes
PDH	MAR08746	H+ + pyruvate + thiamin-PP --> 2-(alpha-hydroxyethyl)thiamine-diphosphate + CO2	(PDHA1 and PDHB) or (PDHA2 and PDHB)
PDH	MAR20069	2-(alpha-hydroxyethyl)thiamine-diphosphate + lipoamide --> S-acetyldihydrolipoamide + thiamin-PP	(PDHA1 and PDHB and DLAT) or (PDHA2 and PDHB and DLAT)
PDH	MAR06412	CoA + S-acetyldihydrolipoamide --> acetyl-CoA + dihydrolipoamide	PDHX and DLAT
PDH	MAR06409	H+ + lipoamide + NADH <=> dihydrolipoamide + NAD+	DLD
OGDH	MAR04209	AKG + H+ + thiamin-PP --> 3-carboxy-1-hydroxypropyl-ThPP + CO2	OGDH or DHTKD1
ODGH	MAR06413	3-carboxy-1-hydroxypropyl-ThPP + lipoamide --> S-succinyldihydrolipoamide + thiamin-PP	OGDH or DHTKD1
OGDH	MAR06414	CoA + S-succinyldihydrolipoamide <=> dihydrolipoamide + succinyl-CoA	DLST
OGDH	MAR06409	H+ + lipoamide + NADH <=> dihydrolipoamide + NAD+	DLD
OADH	MAR04599	2-oxoadipate + H+ + lipoamide --> CO2 + S-glutaryldihydrolipoamide	(OGDH and DLST) or (DHTKD1 and DLST)
OADH	MAR06415	CoA + S-glutaryldihydrolipoamide --> dihydrolipoamide + glutaryl-CoA	DLST
OADH	MAR06409	H+ + lipoamide + NADH <=> dihydrolipoamide + NAD+	DLD
BCKDH	MAR06416	3-methyl-2-oxobutyrate + H+ + lipoamide --> CO2 + S-(2-methylpropanoyl)-dihydrolipoamide	BCKDHB and TMEM91 and BCKDHA
BCKDH	MAR06417	CoA + S-(2-methylpropanoyl)-dihydrolipoamide <=> dihydrolipoamide + isobutyryl-CoA	DBT
BCKDH	MAR06409	H+ + lipoamide + NADH <=> dihydrolipoamide + NAD+	DLD
BCKDH	MAR06419	2-oxo-3-methylvalerate + H+ + lipoamide --> CO2 + S-(2-methylbutanoyl)-dihydrolipoamide	BCKDHB and TMEM91 and BCKDHA
BCKDH	MAR06420	CoA + S-(2-methylbutanoyl)-dihydrolipoamide --> 2-methylbutyryl-CoA + dihydrolipoamide	DBT
BCKDH	MAR06409	H+ + lipoamide + NADH <=> dihydrolipoamide + NAD+	DLD
BCKDH	MAR06421	4-methyl-2-oxopentanoate + H+ + lipoamide --> CO2 + S-(3-methylbutanoyl)-dihydrolipoamide	BCKDHB and TMEM91 and BCKDHA
BCKDH	MAR06422	CoA + S-(3-methylbutanoyl)-dihydrolipoamide --> dihydrolipoamide + isovaleryl-CoA	DBT
BCKDH	MAR06409	H+ + lipoamide + NADH <=> dihydrolipoamide + NAD+	DLD
BCKDH	MAR03800	2-oxobutyrate + CoA + NAD+ --> CO2 + NADH + propanoyl-CoA	BCKDHB and DLD and DBT and BCKDHA

(MAR06409 appears multiple times because DLD is a subunit of all of these complexes; see #529)

Expected feature/value/output:

All reactions representing the activities of 2-ketoacid dehydrogenase complexes should represent the role of thiamine in the catalytic mechanism in the same way. This would entail adding several new reactions to parallel MAR08746 and MAR04209 for the OADH and BCKDH reactions. MAR03800 glosses over the role of lipoic acid in the catalytic mechanism of BCKDH, so I'm also proposing changes to take care of that inconsistency.

Proposed Changes:

• Create a new metabolite to represent 2-(4-carboxy-1-hydroxybutyl)thiamine diphosphate
• Create a new reaction: 2-oxoadipate (MAM00670m) + thiamin-PP (MAM02984m) + H⁺ (MAM02039m) -> 2-(4-carboxy-1-hydroxybutyl)thiamine diphosphate + CO₂ (MAM01596m), GPR: OGDH or DHTKD1 (ENSG00000105953 or ENSG00000181192)
• Replace 2-oxoadipate (MAM00670m) with 2-(4-carboxy-1-hydroxybutyl)thiamine diphosphate, replace CO₂ (MAM01596m) with thiamin-PP (MAM02984m), and remove H⁺ in MAR04599
• Create a new metabolite to represent 2-(2-methyl-1-hydroxypropyl)thiamine diphosphate
• Create a new reaction: 3-methyl-2-oxobutyrate (MAM00824m) + thiamin-PP (MAM02984m) + H⁺ (MAM02039m) -> 2-(2-methyl-1-hydroxypropyl)thiamine diphosphate + CO₂ (MAM01596m), GPR: BCKDHA and BCKDHB (ENSG00000248098 and ENSG00000083123)
• Replace 3-methyl-2-oxobutyrate (MAM00824m) with 2-(2-methyl-1-hydroxypropyl)thiamine diphosphate, replace CO₂ (MAM01596m) with thiamin-PP (MAM02984m), and remove H⁺ in MAR06416
• Create a new metabolite to represent 2-(2-methyl-1-hydroxybutyl)thiamine diphosphate
• Create a new reaction: 2-oxo-3-methylvalerate (MAM00669m) + thiamin-PP (MAM02984m) + H⁺ (MAM02039m) -> 2-(2-methyl-1-hydroxybutyl)thiamine diphosphate + CO₂ (MAM01596m), GPR: BCKDHA and BCKDHB (ENSG00000248098 and ENSG00000083123)
• Replace 2-oxo-3-methylvalerate (MAM00669m) with 2-(2-methyl-1-hydroxybutyl)thiamine diphosphate, replace CO₂ (MAM01596m) with thiamin-PP (MAM02984m), and remove H⁺ in MAR06419
• Create a new metabolite to represent 2-(3-methyl-1-hydroxybutyl)thiamine diphosphate
• Create a new reaction: 4-methyl-2-oxo-pentanoate (MAM01013m) + thiamin-PP (MAM02984m) + H⁺ (MAM02039m) -> 2-(3-methyl-1-hydroxybutyl)thiamine diphosphate + CO₂ (MAM01596m), GPR: BCKDHA and BCKDHB (ENSG00000248098 and ENSG00000083123)
• Replace 4-methyl-2-oxo-pentanoate (MAM01013m) with 2-(3-methyl-1-hydroxybutyl)thiamine diphosphate, replace CO₂ (MAM01596m) with thiamin-PP (MAM02984m), and remove H⁺ in MAR06421
• Create a new metabolite to represent 2-(1-hydroxypropyl)thiamine diphosphate
• Create a new metabolite to represent S-propanoyldihydrolipoamide
• Change MAR03800 to: 2-oxobutyrate (MAM00671m) + thiamin-PP (MAM02984m) + H⁺ (MAM02039m) -> 2-(1-hydroxypropyl)thiamine diphosphate + CO₂ (MAM01596m), GPR: BCKDHA and BCKDHB (ENSG00000248098 and ENSG00000083123)
• Create a new reaction: 2-(1-hydroxypropyl)thiamine diphosphate + lipoamide (MAM02393m) -> S-propanoyldihydrolipoamide + thiamin-PP (MAM02984m), GPR: BCKDHA and BCKDHB and DBT (ENSG00000248098 and ENSG00000083123 and ENSG00000137992)
• Create a new reaction: S-propanoyldihydrolipoamide + CoA (MAM01597m) -> propanoyl-CoA (MAM02774m) + dihydrolipoamide (MAM01701m), GPR: DBT (ENSG00000137992)

[JonathanRob]

Very clearly presented - I agree with the suggested changes!

[Devlin-Moyer]

fixed in #753