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ME1 and ME3 require NADP + and ME2 utilizes either NAD + or NADP + for their catalytic activities, thus NADPH can be produced by ME both directly and indirectly through the activity of the NNT that catalyzes the transfer of hydride ions from NADH to NADP + and produces NADPH in mitochondria

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However, the level of creatine synthesis in the embryonic nervous system is not sufficient for needs and so the developing brain requires maternally and peripherally synthesized creatine

However, in ME/CFS and dysautonomia, this vital switching mechanism becomes severely impaired, leaving patients unable to generate the rapid ATP required for basic daily activities