Fig. 1

Metabolic features of hPSCs. hPSCs consume glucose for glycolysis, nucleotide synthesis, nonessential amino acid synthesis, and hexosamine biosynthesis. The hexosamine pathway produces UDP-GlcNAc, which serves as a substrate for protein O-GlcNAcylation. The entry of pyruvate into the TCA cycle is inhibited by reduced activity of PDH by PDK. Pyruvate is reduced to lactate to replenish nicotinamide adenine dinucleotide (NAD⁺) to maintain glycolytic activity. Pyruvate, which enters the mitochondrial matrix, is converted to acetyl-CoA and is utilized for citrate production. In hPSCs, the TCA cycle enzyme aconitase 2 is downregulated and conversion into αKG is limited. Citrate transported to the cytosol is converted back to acetyl-CoA, which is used for histone acetylation, de novo fatty acid synthesis, and hexosamine biosynthetic pathway. Fatty acids are utilized for various complex lipids, including glycosphingolipids. To replenish the latter part of the TCA cycle (i.e., αKG to oxaloacetate), hPSCs consume glutamine. Glutamine also plays a key role in glutathione synthesis, the hexosamine biosynthetic pathway, and the serine synthesis pathway. α-KG is required for histone and DNA demethylation. mPSCs consume threonine to produce SAM, but because threonine dehydrogenase is a pseudogene in hPSCs, hPSCs consume methionine to produce SAM. SAM is used for histone methylation. αKG, α-ketoglutarate; ACO2, aconitase 2; F6P, fructose 6-phosphate; FASN, fatty acid synthase; G6P, glucose 6-phosphate; Gln, glutamine; Glu, glutamate; Glucosamine-6-P, glucosamine-6-phosphate; Gly, glycine; GSH, glutathione; hCys, homocysteine; LDH, lactate dehydrogenase; Met, methionine; meTHF, 5,10-methylenetetrahydrofolate; mTHF, 5-methyltetrahydrofolate; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; PKM2, pyruvate kinase M2; PSAT1, phosphoserine aminotransferase 1; R5P, ribose 5-phosphate; SAH, S-adenosyl homocysteine; SAM, S-adenosyl methionine; Ser, serine; TCA cycle, tricarboxylic acid cycle; THF, tetrahydrofolic acid; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine