Metabolic control of methylation and acetylation

Abstract

Methylation and acetylation of DNA and histone proteins are the chemical basis for epigenetics. From bacteria to humans, methylation and acetylation are sensitive to cellular metabolic status. Modification rates depend on the availability of one-carbon and two-carbon substrates (S-adenosylmethionine, acetyl-CoA, and in bacteria also acetyl-phosphate). In addition, they are sensitive to demodification enzyme cofactors (α-ketoglutarate, NAD(+)) and structural analog metabolites that function as epigenetic enzyme inhibitors (e.g., S-adenosylhomocysteine, 2-hydroxyglutarate). Methylation and acetylation likely initially evolved to tailor protein activities in microbes to their metabolic milieu. While the extracellular environment of mammals is more tightly controlled, the combined impact of nutrient abundance and metabolic enzyme expression impacts epigenetics in mammals sufficiently to drive important biological outcomes such as stem cell fate and cancer.

Figure 1

Metabolic pathways contributing to histone acetylation and deacetylation. Acetyl-CoA is the substrate of histone acetyltransferase (HATs). Glucose derived pyruvate and fatty acids feed into mitochondria to produce acetyl-CoA and subsequently citrate. Mitochondrial citrate can be exported and converted to cytosolic acetyl-CoA by citrate-ATP lyase (ACL). AKT activates ACL by phosphorylation. Alternatively, cytosolic acetyl-CoA can be generated from acetate, which is the primary production route under hypoxia. Two classes of enzymes remove the histone acetylation marks, HDACs and sirtuins. Sirtuins use NAD⁺ as the substrate for deacetylation, generating nicotinamide and O-acetyl-ADP-ribose as the products. Nicotinamide is a sirtuin inhibitor. Calorie restriction or supplementation of NAD biosynthetic precursors enhance NAD⁺ levels and thus sirtuin activity. Poly(ADP-ribose) polymerases (PARPs) use NAD⁺ as substrate and deplete NAD under DNA damage conditions. Other HDACs have no co-substrate requirement, but can be inhibited by β-hydroxybutyrate.

Figure 2

Metabolic pathways contributing to histone and DNA methylation and demethylation. Histone and DNA methyltransferases use SAM as substrate and produce SAH as product. SAH is a competitive inhibitor of the methyltransferases, therefore the SAM:SAH ratio dictates the activity of the transferases. SAH can be removed by S-adenosylhomocysteine hydrolase, producing homocysteine, which can be remethylated to form methionine. This set of reactions is called the methionine cycle. The remethylation uses methyl-THF and vitamin B12. Serine, glycine and (in mouse but not human) threonine can all contribute to the methyl-THF pool. S-adenosylmethionine synthetase converts methionine and ATP into SAM. DNA demethylation and most histone demethylation depend on both O₂ and α-ketoglutarate. Other dicarboxylic acids, such as succinate, fumarate and 2-hydroxyglutarate (2HG), are inhibitors of the α-ketoglutarate-dependent demethylases. Oncogenic mutations in isocitrate dehydrogenase (IDH1 R132H and IDH2 R172K) result in D-2HG production. Loss of succinate dehydrogenase or fumarase can similarly cause cancer due to accumulation of succinate and fumarate. All these mutations are oncogenic due to the inhibition of DNA and histone demethylation.