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Table 1 Representative modules and cyclical EFMs

From: Discovery of substrate cycles in large scale metabolic networks using hierarchical modularity

Module ID

Metabolic function(s)

Representative cyclical EFM

Newman

Figure 2A: #144976

Cholesterol synthesis

r1136: 4alpha-Methylzymosterol-4-carboxylate (r) + NADP+(r) ↔ 3-Keto-4-methylzymosterol(r) + NADPH(r).

Yes

Lipoprotein synthesis

r1137: NAD+(r) + 4alpha-Methylzymosterol-4-carboxylate (r) ↔ NADH(r) + CO2(r) + 3-Keto-4-methylzymosterol(r)

Figure 2B: #143830

TCA cycle

r0829: Succinate(c) + Sulfate(m) ↔ Succinate(m) + Sulfate(c)

No

Mitochondria-cytosol exchange

r0831: Malate(c) + Pi(m) ↔ Malate(m) + Pi(c)

r0931: Isocitrate(m) + Malate(c) ↔Isocitrate(c) + Malate(m)

r0915: Citrate(c) + Succinate(m) ↔ Citrate(m) + Succinate(c)

r0917: Citrate(c) + Isocitrate(m) ↔ Citrate(m) + Isocitrate(c)

Figure 2C: #143829

β-Oxidation

r0223: 2-Methyl-3-oxopropanoate(m) + CoA(m) + NAD+(m) → Propanoyl-CoA(m) + CO2(m) + NADH(m)

Yes

Glutamate and proline metabolism

r0414: ATP(m) + Propanoyl-CoA(m) + HCO3-(m) → ADP(m) + Pi(m) + Methylmalonyl-CoA(m)

Ketone body synthesis

r0571: Methylmalonyl-CoA(m) + H2O(m) ↔ Methylmalonate(m) + CoA(m)

TCA Cycle

r0643: 2-Methyl-3-oxopropanoate(m) + NAD+(m) + H2O(m) ↔ Methylmalonate(m) + NADH(m)

Figure 2D: #142886

NADH(c) metabolism

r0267: CMP-N-acetylneuraminate(c) + O2(c) + NADH(c) ↔ CMP-NeuNGc(c) + NAD+(c) + H2O(c)

No

r0269: CTP(n) + N-Acetylneuraminate(n) ↔ PPi(n) + CMP-N-acetylneuraminate(n)

r0400: NAD+(c) + O2(c) + N-Acetylneuraminate(c) ↔ NeuNGc(c) + NADH(c) + H2O(c)

r0668: NeuNGc(c) + CTP(c) ↔ PPi(c) + CMP-NeuNGc(c)

r1461: CMP-N-acetylneuraminate(c) ↔ CMP-N-acetylneuraminate(n)

r1462: N-Acetylneuraminate(c) ↔ N-Acetylneuraminate(n)

Figure 2E: #142887

Lipid biosynthesis

r0225: THF(c) + NADP+(c) ↔Dihydrofolate(c) + NADPH(c)

Yes

Folate metabolism

r0227: 10-Formyl-THF(c) + H2O(c) + NADP+(c) → THF(c) + CO2(c) + NADPH(c)

NADPH(c) metabolism

r0293: 5,10-Methylene-THF(c) + NADP+(c) ↔ 5,10-Methenyl-THF(c) + NADPH(c)

r0371: 5,10-Methenyl-THF(c) + H2O(c) ↔ 10-Formyl-THF(c)

r0501: dUMP(c) + 5,10-Methylene-THF(c) ↔ Dihydrofolate(c) + dTMP(c)

Figure 2F: #142411

Acyl-CoA activation in cytosol

r0066: ATP(c) + Acetate(c) + CoA(c) → AMP(c) + PPi(c) + Acetyl-CoA(c)

No

Lipoprotein synthesis

r0485: Glucosamine-6P(c) + Acetyl-CoA(c) → CoA(c) + N-Acetylglucosamine-6P(c)

r0486: N-Acetylglucosamine-6P(c) + H2O(c) ↔ Glucosamine-6P(c) + Acetate(c)

Figure 2G: #141811

Sugar metabolism

r0487: Fructose-1,6PP(c) + H2O(c) → Fructose-6P(c) + Pi(c)

No

Amino acid metabolism

r0736: ATP(c) + Fructose-6P(c) → ADP(c) + Fructose-1,6PP(c)

Protein synthesis

r0129: GSH(c) + H2O(c) ↔ Glutamate(c) + Cys-Gly(c)

r0131: ATP(c) + gamma-Glutamyl-cysteine(c) + Glycine(c) → ADP(c) + Pi(c) + GSH(c)

r0212: ATP(c) + Glutamate(c) + Cysteine(c) → ADP(c) + Pi(c) + gamma-Glutamyl-cysteine(c)

r0214: H2O(c) + Cys-Gly(c) ↔ Cysteine(c) + Glycine(c)

  1. The first column lists the corresponding panel in Figure 2 and module ID (referenced in Additional file 1: ‘Modules’ for complete reaction list). The second column lists conventional textbook metabolic pathways/functions associated with reactions contained in the module. The third column provides a sample cyclical EFM identified for a given module. The fourth column indicates whether or not the cyclical EFM was identified when the network was partitioned using Newman’s connectivity-based modularity metric.