Abstract
Following the Lejeune work, researchers focused on a potential anomaly within the folate-mediated one-carbon metabolism (FOCM). Here, we present a FOCM model modified from a previous work with the incorporation of the enzyme cystathionine beta-synthase (CBS), whose encoding gene is located on Hsa21, coupled with the methionine input rate. Systematic perturbation of FOCM enzyme activity rates has been performed to explore possible in silico configurations to simulate the DS condition. The perturbed vs. unperturbed model-derived ratio concentrations of tetrahydrofolate, 5-formyl-tetrahydrofolate, 5-methyl-tetrahydrofolate, S-adenosyl-homocysteine, and S-adenosyl-methionine were compared with the known literature through various statistical approaches. After investigating public transcriptomic databases, the FTS (formate-tetrahydrofolate ligase) perturbation achieved the best overall score. Although the FTS encoding gene (MTHFD1) is not located on Hsa21, it was found to be overexpressed in the DS condition. In addition, an interesting correlation emerged with the PTG (phosphoribosylglycinamide formyltransferase) perturbation and the corresponding encoding gene (GART), located on Hsa21 and notably over-expressed in the DS condition. The model thus identifies key enzyme activities that warrant further investigation.