FIGURE 5

Glucose utilization pathways that provide or consume ATP. (A) Schematic of key aspects of the glycolytic pathway of glucose utilization for energy metabolism and major branch points that can divert carbon for other uses, including NADPH generation, storage of glucosyl units in glycogen, neuromodulator, and amino acid and nucleotide biosynthesis. The most important reactions for generation of energy are glycolysis (pyruvate/lactate formation from glucose), shown in light brown and occurring in all cell types, and glycogenolysis (pyruvate/lactate formation from glycogen), shown in light green, which occurs only in astrocytes, due to the astrocyte-specific expression of the enzyme glycogen phosphorylase, which releases a glucosyl unit from glycogen as G1P. The energetically most important biosynthetic reactions are synthesis of glycogen from glucose (glycogenesis) shown in brown and green and from pyruvate/lactate (gluconeogenesis) shown in pink, brown, and green. Gluconeogenesis is also astrocyte-specific, because only astrocytes express fructose-1, 6-bisphosphatase, which generates F6P from fructose-1, 6-bisphosphate (F1, 6P) and PC, which generates oxaloacetate (OAA) from pyruvate. The latter reaction is followed by formation of phosphoenolpyruvate (PEP) by decarboxylation of OAA; this sequence is necessary to form PEP from pyruvate, an energetically unfavorable reaction. Biosynthesis of serine/glycine (shown in olive) is also an astrocyte-specific process due to preferential expression of 3-phosphoglycerate dehydrogenase (Yamasaki et al., 2001). Both neurons and astrocytes form alanine and ribose-5-phosphate (R5P), the latter in the pentose shunt pathway (upper left corner), linked to NADPH production needed for operation of glutathione peroxidase and oxidation of monoamine transmitters. The MAS, indicated by red, transfers malate formed in the cytosol from oxaloacetate during conversion of NADH to NAD⁺ into mitochondria. PDH-mediated formation of acetyl CoA, which is also shown in red, initiates oxidative degradation of pyruvate in the mitochondria. Red and blue text for ATP indicates energy production and utilization, respectively. (B) Major reactions and net ATP yields or net ATP consumption of major pathways derived from the glycolytic pathway are indicated in color-coded boxes that correspond to the color-coded pathways in panel A. For simplicity, the scheme indicates the energy yields (ATP) and NAD(P)H production or utilization based on metabolism of 1 glucose to form one ribulose-5-P, two lactate/pyruvate, or 2 serine; a similar representation illustrates the energy and cofactors required for gluconeogenic conversion of two moles of lactate into one free (G6P) or glycogen-bound glucosyl unit. Glc, glucose; P, phosphate; G6P, glucose-6-P; 6PG, 6-P-gluconate; R5P, ribulose-5-P; GSH, reduced form of glutathione; GSSG, oxidized form of glutathione; F6P, fructose-6-P; F1, 6-P, fructose-1, 6-bisphosphate; GAP, glyceraldehyde-3-P; DHAP, dihydroxyacetone-P; 3PG, 3-P-glycerate; 2PG, 2-P-glycerate; PEP, phosphoenolpyruvate; Pyr, pyruvate; Lac, lactate; Ala, alanine; OAA, oxaloacetate; 3P-HyPyr, 3-P-hydoxypyruvate; Glu, glutamate; KG, -ketoglutarate; 3P-L-Ser, 3P-L-serine; L-ser, L-serine; D-ser, D-serine; Gly, glycine; C1, one carbon fragment used for methyl donor reactions.