Table 1 Host and host-microbe model predictions in agreement with literature.

ATP:Dephospho Coenzyme A 3-Phosphotransferase (EC:2.7.1.24) and Pantothenate 4-Phosphotransferase (EC:2.7.1.33)

These enzymes catalyze the reactions leading to Coenzyme A synthesis, the latter being the acyl carrier participating in various metabolic pathways⁶⁰, and therefore being significant in cancer metabolism. The related enzyme-catalyzed reactions showed increased flux in the CRC model.

Carnitine O-Palmitoyltransferase (EC:2.3.1.21), Enoyl Coenzyme A Hydratase (EC:1.3.8.7), and Enoyl Coenzyme A Reductase (EC:1.3.1.38)

These enzymes catalyze the reactions of fatty acid oxidation metabolic pathways, and their activity is significantly heightened in colon carcinogenesis^61,62. The related enzyme-catalyzed reactions also showed increased flux values in the CRC metabolic, thus, being consistent with the literature findings.

Isopentenyl-Diphosphate D-Isomerase (EC:5.3.3.2)

This enzyme participates in the mevalonate-isoprenoid biosynthetic (MIB) pathway, which is crucial to CRC metabolism⁶³. Interestingly, the CRC metabolic model computational analysis also reported an increased flux through the related enzyme-catalyzed reaction.

Folylpolyglutamate Synthetase (EC:6.3.2.17)

The enzyme is required for the synthesis of folate derivatives (1-C carriers), the excess of which promotes CRC carcinogenesis⁶⁴. The CRC metabolic model showed increased flux value through the related enzyme-catalyzed reactions.

2-Methylpropanoyl Coenzyme A:Oxygen 2, 3-Oxidoreductase (EC:1.3.99.2) and ‘3-Methylbutanoyl Coenzyme A: (Acceptor) 2, 3-Oxidoreductase (EC:1.3.99.12)

These enzymes catalyze the degradation of BCAAs, the major degradation product being acetyl CoA, which is essentially required for fatty acid synthesis⁶⁵, a metabolic process elevated in CRC cells. The related enzyme-catalyzed reactions in the CRC microbe integrated model also showed increased flux values.

L-Alanine:2-Oxoglutarate Aminotransferase (EC:2.6.1.2)

This enzyme catalyzes the formation of pyruvate and glutamate, the two being important substrates for various major metabolic pathways⁶⁶, and hence relevant to cancer pathogenesis. Computationally, the CRC–microbe integrated model captured the increased activity of this enzyme through increased flux.

17-Beta-Hydroxysteroid Dehydrogenase (EC:1.1.1.35) and Steryl-Sulfatase (EC:3.1.6.2)

These enzymes participate in the steroid biosynthesis (estradiol) metabolic pathway, wherein increased serum levels of estradiol have been reported in colon cancer⁶⁷. The CRC–microbe model also showed increased flux values through the related enzyme-catalyzed reactions.

Arachidonate 5-Lipoxygenase (EC:1.13.11.34)

The enzyme catalyzes the intermediate steps in the synthesis of leukotrienes, and its activity is reported to be elevated in colon cancer cells⁶⁸. The CRC–microbe integrated model captured increased flux for the related enzyme-catalyzed reaction.