Table 1. Proline axis: regulatory effects on metabolic reprogramming and epigenetics .

Pathway	Enzyme	Regulation	Metabolic Effect	Clinical, Cellular Findings Epigenetic Mechanism
Degradative	PRODH (POX)	Upregulated by p53;35-37,42 Increased by AMPK43,44 under glucose deprivation and/or hypoxia	ROS39–40 Increased α-KG;41 Decreased glycolysis Decreased Ox. Phos (Hancock, unpublished results)	Apoptosis39-41 Blockade Cell Cycle41 Stem cell pluripotency68,69 Ins/IGF1 prosurvival signaling dependent on proline metabolism70,71
		Decreased by miR-23b*45 and c-MYC46		permissive effect on cell proliferation46
		Mutations in PRODH51	Hyperprolinemia51	Neuropsychiatric disorders
Synthetic	P5CS	Induced by c-MYC46	Proline inreased Involved in c-MYC- stimulation of glycolysis (Warburg Effect) (Liu et al., unpublished results)	necessary for c-MYC stimulated proliferation;46 essential for T-cell activation53
		Inborn error59	Hypoprolinemia, Hypoornithinemia Hypoammonemia59	Neurodegeneration, mental deficiency, neuropathy connective tissue disorder59
	PYCR1	Induced by c-MYC46	As for P5CS (Liu et al., unpublished results)	As for P5CS (Liu et al., unpublished results) Knockdown in xenograft tumors inhibits tumor growth25
		Inborn error56	More sensitive to peroxide56	Multiple genetic defects Cutis laxa, progeroid56