Bridging epigenetics and metabolism

Figures & data

Figure 1. Proposed Parametabolic Regulation by NEAA Metabolism This cartoon is a representation of a generic parametabolic scheme. The conversion of A to B yields a non-essential amino acid and this step may be upregulated by cancer reprogramming. I₁ and I₂ are in a metabolic interlock with the conversion of S to M, which is then used for epigenetic modification of DNA or chromatin. For example, if A is serine and B is glycine, the reaction is coupled to the conversion of tetrahydrofolate (THF) to 5,10-methylene THF, which as 5-methyl THF, transfers methyl groups to homocysteine forming methionine. In the presence of ATP, S-adenosylmethionine is formed for DNA methylation. In another example, if pyrroline-5-carboxylate, A, is converted to proline, B, NADH, I_1, is oxidized to NAD⁺, I₂, which can accept acetyl groups hydrolyzed from histone lysines by sirtuins to form acetyl-ADP-ribose.

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 AMPK^43^,^44 under glucose deprivation and/or hypoxia	ROS39–40 Increased α-KG;^41 Decreased glycolysis Decreased Ox. Phos (Hancock, unpublished results)	Apoptosis^39^-^41 Blockade Cell Cycle^41 Stem cell pluripotency^68^,^69 Ins/IGF1 prosurvival signaling dependent on proline metabolism^70^,^71
		Decreased by miR-23b*^45 and c-MYC^46		permissive effect on cell proliferation^46
		Mutations in PRODH^51	Hyperprolinemia^51	Neuropsychiatric disorders
Synthetic	P5CS	Induced by c-MYC^46	Proline inreased Involved in c-MYC- stimulation of glycolysis (Warburg Effect) (Liu et al., unpublished results)	necessary for c-MYC stimulated proliferation;^46 essential for T-cell activation^53
		Inborn error^59	Hypoprolinemia, Hypoornithinemia Hypoammonemia^59	Neurodegeneration, mental deficiency, neuropathy connective tissue disorder^59
	PYCR1	Induced by c-MYC^46	As for P5CS (Liu et al., unpublished results)	As for P5CS (Liu et al., unpublished results) Knockdown in xenograft tumors inhibits tumor growth^25
		Inborn error^56	More sensitive to peroxide^56	Multiple genetic defects Cutis laxa, progeroid^56

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