Exploring metabolism flexibility in complex organisms through quantitative study of precursor sets for system outputs

Abdou-Arbi, Oumarou; Lemosquet, Sophie; Milgen, Jaap Van; Siegel, Anne; Bourdon, Jérémie

doi:10.1186/1752-0509-8-8

Table 9 Effect of long-chain fatty acids (LCFA) oxidization in the triacarboxylic acid (TCA) cycle over model analysis

From: Exploring metabolism flexibility in complex organisms through quantitative study of precursor sets for system outputs

Main properties of the simplex vertices, assuming constant ATP-production,
with different ratios of LCFA oxidized in TCA
	Dataset	% of FA	Model	Example of	Combinatorics					Validation
		oxidated	name	maximized	of pathways
		in TCA		function
					R ₁₉	R ₁₅	R ₁₄	R ₈	R ₆₄	R ₆₃	R ₁₃
					NADPH	OAA →G3P	OAA →PYR	G3P →G6P	Peptide	Peptide	Pyr→ OAA
					oxidation				hydrolysis	synthesis
	(Ctrl)	0%				1831				125	1835	Non relevant flux values for R ₁₃, R ₆₄
	(Ctrl)	10%				2451				125	2455
	(CN)	0%	B	v ₁₅- v ₁₉	0	795	0	0	0	150	803
		10%				1489					1497
		20%				2357					2365
		25%				2878					2886
	(HB)	10%				6173				150	6145
	(HB)	20%				7115					7086
		25%				7675					7646
	(Ctrl)	0%					1831			125	1835	Non relevant flux values for R ₁₃, R ₆₄
	(Ctrl)	10%					2451			125	2455
	(CN)	0%	F	v ₁₄- v ₁₉	0	0	795	0	0	150	803
		10%					1489				1497
		20%					2357				2365
		25%					2878				2886
	(HB)	10%					6173			150	6145
	(HB)	20%					7115			150	7086
		25%					7675				7646
	(Ctrl)	0%						3662		125	4	Non relevant flux values for R ₈, R ₆₄
	(Ctrl)	10%						4902		125	4
	(CN)	0%	D	v ₈- v ₁₉	0	0	0	1590	0	150	8
		10%	D		0	0	0	2978	0
		20%						4714
		25%						5756
	(HB)	10%						12289
		20%	D1	v ₈- v ₁₉- v ₁₄		29	0	14172
		25%			0			15292	0	150	0
		10%						12289
		20%	D2	v ₈- v ₁₉- v ₁₅		0	29	14172
		25%						15292
	(Ctrl)	0%							305	430	4	Glucose is the unique precursor of lactose synthesis (AIO)
		10%							409	533	4
	(CN)	0%	H	v ₆₄- v ₁₉	0	0	0	0	133	283	8
		10%	H	v ₆₄- v ₁₉	0	0	0	0	248	398
		20%							393	543
		25%							480	630
	(HB)	10%	H1	v ₆₄- v ₁₉- v ₁₄	0	29	0	0	1024	1174	0	Non relevant flux values for R ₆₃
		20%							1181	1331
		25%							1274	1424
		10%	H2	v ₆₄- v ₁₉- v ₁₅		0	29		1024	1174
		20%							1181	1331
		25%							1274	1424
	(Ctrl)	0%			669	1714				125	1718	Non relevant flux values for R ₁₃, R ₆₄
		10%			694	2330				125	2334
	(CN)	0%	A	v ₁₅ + v ₁₉		791	0	0	0	150	799
		10%	A	v ₁₅ + v ₁₉	22	1485	0	0	0	150	1493
		20%			22	2353					2361
	(HB)	10%			1216	5961				150	5932
		20%				6902					6873
Extreme flux distributions within the set of plausible solutions		25%				7462					7433
	(Ctrl)	0%			694		1714			125	1718
		10%					2330				2334
	(CN)	0%	E	v ₁₄ + v ₁₉	22	0	791	0	0	150	799
		10%	E	v ₁₄ + v ₁₉		0	1485	0	0		1493
		20%					2353				2361
		25%					2874				2882	Non relevant flux values for R ₁₃, R ₆₄
	(HB)	10%	E1	v ₁₄ + v ₁₉	1216	32	5929	0	0	150	5932
		20%	E1	v ₁₄ + v ₁₉	1216	32	6902				6873
		25%			1216	32	7462				6920
		10%					6008				5979
		20%	E2	v ₁₄ + v ₁₉- 50v ₁₅	946	0	6949				6920
		25%					7509				7481
	(Ctrl)	0%			694			3428		125	4
		10%			694			4659		125
	(CN)	0%	C	v ₈ + v ₁₉	22	0	0	1583	0	150	8
		10%	C	v ₈ + v ₁₉		0	0	2971	0		8
		15%						4706
		20%						5749
	(HB)	10%	C1	v ₈ + v ₁₉	1216	32	0	11858			3
		20%						13840
		25%						14961	0	150
		10%	C2	v ₈ + v ₁₉- 50v ₁₅	946	0	29	11958			0	Non relevant flux values for R ₈, R ₆₄
		20%						13840
		25%						14961
	(Ctrl)	0%			694				286	410	4	Glucose is the unique precursor of lactose synthesis (AIO)
		10%			694				388	513	4
	(CN)	0%	G	v ₆₄ + v ₁₉	22	0	0	0	132	282	8
		10%	G	v ₆₄ + v ₁₉		0	0	0	248	398
		20%							392	542
		25%							479	629
	(HB)	10%	G1	v ₆₄ + v ₁₉	1216	32	0	0	989	1139	3	Non relevant flux values for R ₆₃, R ₆₄
		20%	G1	v ₆₄ + v ₁₉	1216	32	0		1145	1295	3
		25%							1238	1388
		10%	G2	v ₆₄ + v ₁₉- 50v ₁₅	946	0	29		996	1146	0
		20%	G2	v ₆₄ + v ₁₉- 50v ₁₅	946	0			1146	1296	0
		25%							1247	1397
Litterature-based upperbounds for fluxes								≤ 591	Non-zero	Lower than	≤ 266 mmol/h/half
							mmol/	[28, 31]	whole body	udder [33]
							h/half udder [33]		protein synthesis [29]

To study the impact of the variability of FA oxidation, a ratio of long-chain FA (10%, 20%, 25%) was introduced in the TCA cycle. For datasets (CN), (Ctrl) and (HB) which were compatible with a given ratio of LCFA oxidation, extreme flux distributions and AIO coefficients variability were studied. Our main conclusions are robust to the introduction of LCFA oxidation (Table 8). Interestingly, as shown in (Table 9), the structure of the simplex generated by the (HB) diet is more complicated than the (Ctrl) and (CN) treatments, with 13 vertices for all hypotheses. This is due to the fact that R ₁₅ is highly constrained by measurements, so that this flux cannot vanish when R ₁₄ is optimized or when R ₁₉ is maximized. All the vertices for the (HB)-simplex contradict knowledge-based literature.

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ISSN: 1752-0509

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