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192 Part IV: Molecular and Cellular Hematology Chapter 14: Metabolism of Hematologic Neoplastic Cells 193

glucose Figure 14–1. Central metabolic pathways involv-
ribose ing glycolysis, glutaminolysis, and the tricarboxylic
lipid acid (TCA) cycle. Glucose is shown metabolized to
glycerol-3P
nucleotides glycine serine 3 PG pyruvate, which can be converted to lactate, alanine,
or acetyl-coenzyme A (acetyl-CoA). Upstream of
fatty acid pyruvate, glucose carbons are shunted toward the
lactate pyruvate alanine
pentose phosphate pathway for ribose synthesis,
malonyl-CoA glycine, and glycerol synthesis. Acetyl-CoA (2-carbon
unit) combines with oxaloacetate (4-carbon) to form
acetyl-CoA citrate (6-carbon), which is subsequently metab-
aspartate oxaloacetate citrate acetyl CoA olized in the TCA cycle to generate isocitrate, α-
malate TCA Cycle isocitrate ketoglutarate, and other intermediates as depicted.
Glutamine is shown to enter the TCA cycle via α-
fumarate ketoglutarate, after being converted to glutamate.
a ketoglutarate
succinate Glucose gives rise to glycerol and citrate, which
contributes 2-carbon units for fatty acid synthesis,
succinyl CoA glutamate and contributes to lipid synthesis. Glutamine and
glucose are depicted to contribute to nucleotide
synthesis.
glutamine

Pyruvate, derived from glucose through glycolysis, from malate contribute to protein synthesis or glucosamine or nucleobase biosyn-
through malic enzyme or from alanine through transamination, could thesis by donating its nitrogen. Glutamine is further imported into the
enter the mitochondria through specific transporters and be converted mitochondrion and converted to glutamate by glutaminase (GLS) with
to acetyl-coenzyme A (CoA) by pyruvate dehydrogenase (PDH) (see the release of ammonia. Glutamate is converted to α-ketoglutarate by
Fig. 14–1). PDH activity can be attenuated by phosphorylation, medi- either glutamate dehydrogenase (primarily in nongrowth states) or
10
ated by PDH kinase (PDK), which is activated by hypoxia to divert aminotransferases (GOT or glutamate pyruvate transaminase [GPT]).
glucose carbons away from the TCA cycle toward lactate production. In this manner, glutamine serves as a major growth substrate for grow-
Under aerobic conditions, acetyl-CoA combines with oxaloacetate ing cells. Hence, the TCA cycle is a metabolic roundabout that uses
coming from a complete turn of the TCA cycle to produce citrate, which carbons from glucose, glutamine, and fatty acids to generate carbon
can be extruded into the cytoplasm to participate in lipid synthesis or skeletons for biosynthesis, NADH for the production of ATP, or α-
which can be converted to isocitrate in the TCA cycle. Isocitrate is fur- ketoglutarate for catalyzing key oxygenase reactions.
ther oxidized to α-ketoglutarate by isocitrate dehydrogenase (IDH) with Oxidation of glucose, glutamine, and fatty acids produces energy
the production of either nicotinamide adenine dinucleotide (NADH) or for growing cells. On the other hand, synthesis of fatty acids and other
nicotinamide adenine dinucleotide phosphate (NADPH) and release of building blocks require the reductive power of NADPH for bond for-
a carbon dioxide molecule. There are three IDH isozymes with IDH1 mation. NADPH is produced from several well-characterized pathways,
being located in the cytosol, while IDH2 and IDH3 are in the mitochon- including the pentose phosphate pathway, malic enzyme, IDH, and the
drion. NADH in the mitochondrion contributes to the high-energy folate pathway. Glucose-6-phosphate dehydrogenase (G6PD) is well-
15
electrons that drive production of ATP through the electron transport known for its role in oxidation of G6P to 6-phosphogluconolactone and
chain. NADPH produced by cytosolic IDH1 or mitochondrial IDH2 the concurrent reduction of NADP+ to NADPH, which contribute to an
could participate in reductive biosynthesis of fatty acids or nucleobases. antioxidant state through maintaining reduced glutathione. Specifically,
In addition to being a key TCA cycle intermediate at the crossroads loss of G6PD function is associated with severe hemolytic anemia in
of several metabolic pathways, a-ketoglutarate (or oxoglutarate) serves patients who inherit hypomorphic alleles of G6PD (see Chap. 47). Malic
as a cofactor for many important oxygenases, such as those involved enzyme mediates the oxidation of malate to pyruvate using nicotin-
in the hydroxylation and degradation of the hypoxia inducible factors amide adenine dinucleotide phosphate (NADP+), which is reduced to
(HIFs), modification of ribosomes, or those involved in demethylation NADPH. IDH1 oxidizes isocitrate to α-ketoglutarate with the produc-
of DNA and histones. 11,12 Notably, glutamine can enter the TCA cycle tion of NADPH from NADP+. Lastly, it was recently documented that
at this junction. α-Ketoglutarate is further oxidized by oxoglutarate the folate pathway plays a major role in NADPH production through
15
dehydrogenase (OGDH) to produce succinyl-CoA and carbon dioxide. the oxidation of methylene-tetrahydrofolate (THF) to formyl-THF.
Succinyl-CoA, which is also used for heme synthesis, is then converted The largest consumer of NADPH, on the other hand, involves fatty acid
to succinate with the production of a guanosine-5′-triphosphate (GTP) synthesis with reduction of glutathione following closely behind. Thus
from guanosine-5′-diphosphate (GDP). Succinate is then converted to production of NADPH is critical for both biosynthesis and for redox
fumarate by succinate dehydrogenase (SDH), which is mutated in cer- homeostasis.
tain familial cancer syndromes. Fumarate hydratase (FH), which is also
mutated in cancer syndromes, converts fumarate to malate that is, in SIGNAL TRANSDUCTION:
turn, converted to oxaloacetate. Oxaloacetate can serve as a substrate
for glutamate oxaloacetate transaminase (GOT) for the production of ONCOGENES, TUMOR SUPPRESSORS
aspartate for nucleotide synthesis, or it can further cycle forward into AND METABOLISM
the TCA cycle by combining with acetyl-CoA to form citrate, thus com-
pleting the TCA (citric acid or Krebs) cycle (see Fig. 14–1). Growth factors and nutrients drive the growth and proliferation of
Glutamine also serves as a key metabolic substrate for growing cells (Fig. 14–2 and Chap. 17). Growth factor engagement of a (usu-
cells (see Fig. 14–1). Glutamine is imported by membrane transport- ally dimeric) growth factor receptor triggers allosteric alterations
ers, such as SLC1A5 or ASCT2. 13,14 Once in the cytosol, glutamine can that lead to autophosphorylation, in the case of the receptor tyrosine

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