Duplicate Lipoic Acid Biosynthesis Pathways

[Devlin-Moyer]

Background

At the moment, octanoyl-[ACP] (MAM02643c) can become [protein]-N6-(lipoyl)lysine (MAM00209c) via either MAR06400 + MAR06401 or MAR06402 + MAR06403:

Reaction ID	Reaction	Genes
MAR06400	5 H+ [c] + 7 NADPH [c] + octanoyl-[ACP] [c] + 2 PAPS [c] + 2 SAM [c] --> 2 5-deoxyadenosine [c] + 6 H2O [c] + lipoyl-[ACP] [c] + 2 methionine [c] + 7 NADP+ [c] + 2 PAP [c]	LIAS or LIPT2 (ENSG00000121897 or ENSG00000175536)
MAR06401	apoA1 [c] + lipoyl-[ACP] [c] --> [ACP] [c] + [protein]-N6-(lipoyl)lysine [c]	LIPT2 (ENSG00000175536)
MAR06402	apoA1 [c] + octanoyl-[ACP] [c] --> [ACP] [c] + [protein]-N6-(octanoyl)lysine [c]	LIPT2 (ENSG00000175536)
MAR06403	[protein]-N6-(octanoyl)lysine [c] + 5 H+ [c] + 7 NADPH [c] + 2 PAPS [c] + 2 SAM [c] --> [protein]-N6-(lipoyl)lysine [c] + 2 5-deoxyadenosine [c] + 6 H2O [c] + 2 methionine [c] + 7 NADP+ [c] + 2 PAP [c]	LIAS (ENSG00000121897)

Problems

According to these papers, the lipoic acid biosynthesis starts with LIPT2 transferring an octanoyl residue from ACP to GCSH, and LIAS only converts that octanoyl residue into a lipoyl residue after the octanoyl has been moved off of ACP. Figure S1 from the first paper cited above illustrates this:

That paper also mentions that this whole process happens in mitochondria, and both sets of Human-GEM reactions happen entirely in the cytosol, but several of the metabolites involved do not currently exist in [m], and addressing that turns out to get rather complicated, so I’ve separated all that out into #684 and #685. For now, I’m just proposing that MAR06400 and MAR06401 be removed for being redundant with MAR06402 and MAR06403 and misrepresenting the timing of the ACP to GCSH octanoyl transfer mediated by LIPT2.

Proposed Changes:

• Merge annotations of MAR06400 into annotations for MAR06403
• Remove MAR06400 for being a less accurate version of MAR06403
• Merge annotations of MAR06401 into annotations for MAR06402
• Remove MAR06401 for being a less accurate version of MAR06402
• Remove now-isolated MAM02397c (lipoyl-[ACP])

[haowang-bioinfo]

yes the lipoic acid synthesis should be in mitochondria, to which the relevant modifications are well planned in #685

it's smart to take steps and begin with removing duplicates MAR06400 and MAR06401, please go ahead. Would suggest to double check protonation state of MAR06402 (Rhea:17665) and MAR06403 (Rhea:16585) for charge balancing while implementing

[haowang-bioinfo]

fixed in #707