MOONLIGHTING FUNCTIONS OF METABOLIC ENZYMES AND METABOLITES IN
CANCER
REVIEW
* Altered metabolism at the molecular level, which has long been described in a variety of cancer cells,
allows them to thrive through environmental challenges, including nutrient-scarce conditions, limited
oxygen supply, immune attack, and/or clinical interventions.
* Metabolic changes can be achieved not only by modulation of conventional activities of key enzymes,
but also by regulation of their non-canonical roles, referred to as “moonlighting” functions.
* These metabolic enzymes and related metabolites provide multi-functional hubs to ensure the
plasticity and adaptation of both normal and cancer cells.
Glycolysis
o Converts glucose to pyruvate via series of intermediate metabolites, forming ATP and NADH.
o Growing number of glycolytic enzymes have been observed in cell nuclei and are involved in
transcriptional regulation by directly binding to DNA or functioning as transcription cofactors.
o Aldose is an enzyme splitting FBF into dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-
phosphate. Nuclear aldolase A plays an important role in cell division through its interaction with F-
actin and WASP family proteins that govern the polymerization of actin filaments.
o Aldolase B suppresses hepatocellular carcinogenesis through moonlighting interactions with multiple
protein targets, including glucose-6-phosphate dehydrogenase, phosphorylated Akt, and insulin
receptor.
o PGAM1 inhibition results in marked depletion of the
deoxyribonucleotide triphosphate nucleoside (dNTP)
pool, interfering with DNA synthesis and homologous
recombination (HR) repair.
o Pyruvate kinase catalyses an irreversible step in
glycolysis under physiologic conditions that generates
pyruvate from phosphoenolpyruvate and harbours
multiple posttranslational modifications in diverse
context.
o Hypoxia has been reported to induce the prolyl-
hydroxylation of PKM2, which interacts with nuclear
hypoxia-inducible factors (HIFs) to augment the
expression of multiple glycolytic genes in cancer
cells.
o Lactate dehydrogenase A (LDHA), converting
pyruvate to lactate and oxidizing NADH to NAD+, is
frequently overexpressed in a variety of cancer types.
phosphorylation at Y10 activates LDHA, promoting
cancer cell invasion, anoikis resistance, and tumour
metastasis.
Gluconeogenesis
o It converts non-carbohydrate substrates (like lactates, pyruvate, and glycerol) to free glucose.
o FBP1 enzyme expression is uniformly depleted in clear cell renal cell carcinoma and hepatocellular
carcinoma.
, o In renal tumours, FBP1 directly interacts with HIF’s “inhibitory domain” in the nucleus and blocks
HIF function, thereby suppressing cancer cell proliferation and glucose metabolism independent of its
catalytic activity.
o In human hepatocellular carcinoma where PCK1 is markedly depleted, accumulation of the PCK1
substrate oxaloacetate activates checkpoint kinase 2 to promote cancer cell proliferation, reinforcing
the functional importance of PCK1 metabolic activity.
TCA Cycle
o It oxidizes acetyl-CoA derived from carbohydrates, lipids, and proteins, resulting in CO 2 production
by mitochondria, providing the reducing equivalent NADH and an array of metabolic precursors.
o The compartmentalized activities of PDC (pyruvate dehydrogenase complex) generate building blocks
for lipid structures and regulate lipogenic gene expression to foster prostate tumorigenesis.
o L-2HG is markedly elevated in activated T cells, increasing HIF stability and promoting anti-tumour
immunity.
o Germline mutations in SDH and FH are tightly associated with hereditary leiomyomatosis and renal
cell cancer or rare neuroendocrine tumors.
Pentose Phosphate Pathway
o PPP is a metabolic branch stemming from glycolysis, generating NADPH and ribose 5-phosphate.
o Ru-5-P (nucleotide synthesis) inhibits AMPK by dissembling the LKB1 complex, promoting
lipogenesis and tumour growth.
o Together, 6PGD and G6PD in the PPP control dynamic AMPK signalling through opposite, non-
canonical functions.
Additional Carbohydrate Metabolism
o High doses of fructose may overwhelm intestinal fructose absorption and make contact with gut
microbiota.
o Colon cancer rely on ALDOB and fructose metabolism to fuel gluconeogenesis, the PPP, and the TCA
cycle to support their metastatic behaviour.
Lipid Metabolism
o Deregulated lipid metabolism is closely related to rapid cancer cell growth and tumour progression.
o High-fat diets may also increase the level of circulating acetoacetate, which significantly promotes
BRAF V600E-positive melanoma cell growth in vivo.
o Upon fatty acid synthase depletion, malonyl-CoA build-up leads to the malonylation and suppression
of mTORC1 in endothelial cells and impaired angiogenesis.
o De novo sphingolipid biosynthesis is mainly catalysed by serine palmitoyltransferases, which
surprisingly generate non-canonical deoxysphingolipids upon serine deprivation to mitigate tumour
growth.
Amino Acid Metabolism
o Amino acid metabolism is markedly re-programmed in
cancer.
o Glutamine is the most naturally abundant nonessential
amino acid in the human body, and actively taken up
and converted to glutamate by glutamate by glutaminase
in a variety of cancer cells.
CANCER
REVIEW
* Altered metabolism at the molecular level, which has long been described in a variety of cancer cells,
allows them to thrive through environmental challenges, including nutrient-scarce conditions, limited
oxygen supply, immune attack, and/or clinical interventions.
* Metabolic changes can be achieved not only by modulation of conventional activities of key enzymes,
but also by regulation of their non-canonical roles, referred to as “moonlighting” functions.
* These metabolic enzymes and related metabolites provide multi-functional hubs to ensure the
plasticity and adaptation of both normal and cancer cells.
Glycolysis
o Converts glucose to pyruvate via series of intermediate metabolites, forming ATP and NADH.
o Growing number of glycolytic enzymes have been observed in cell nuclei and are involved in
transcriptional regulation by directly binding to DNA or functioning as transcription cofactors.
o Aldose is an enzyme splitting FBF into dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-
phosphate. Nuclear aldolase A plays an important role in cell division through its interaction with F-
actin and WASP family proteins that govern the polymerization of actin filaments.
o Aldolase B suppresses hepatocellular carcinogenesis through moonlighting interactions with multiple
protein targets, including glucose-6-phosphate dehydrogenase, phosphorylated Akt, and insulin
receptor.
o PGAM1 inhibition results in marked depletion of the
deoxyribonucleotide triphosphate nucleoside (dNTP)
pool, interfering with DNA synthesis and homologous
recombination (HR) repair.
o Pyruvate kinase catalyses an irreversible step in
glycolysis under physiologic conditions that generates
pyruvate from phosphoenolpyruvate and harbours
multiple posttranslational modifications in diverse
context.
o Hypoxia has been reported to induce the prolyl-
hydroxylation of PKM2, which interacts with nuclear
hypoxia-inducible factors (HIFs) to augment the
expression of multiple glycolytic genes in cancer
cells.
o Lactate dehydrogenase A (LDHA), converting
pyruvate to lactate and oxidizing NADH to NAD+, is
frequently overexpressed in a variety of cancer types.
phosphorylation at Y10 activates LDHA, promoting
cancer cell invasion, anoikis resistance, and tumour
metastasis.
Gluconeogenesis
o It converts non-carbohydrate substrates (like lactates, pyruvate, and glycerol) to free glucose.
o FBP1 enzyme expression is uniformly depleted in clear cell renal cell carcinoma and hepatocellular
carcinoma.
, o In renal tumours, FBP1 directly interacts with HIF’s “inhibitory domain” in the nucleus and blocks
HIF function, thereby suppressing cancer cell proliferation and glucose metabolism independent of its
catalytic activity.
o In human hepatocellular carcinoma where PCK1 is markedly depleted, accumulation of the PCK1
substrate oxaloacetate activates checkpoint kinase 2 to promote cancer cell proliferation, reinforcing
the functional importance of PCK1 metabolic activity.
TCA Cycle
o It oxidizes acetyl-CoA derived from carbohydrates, lipids, and proteins, resulting in CO 2 production
by mitochondria, providing the reducing equivalent NADH and an array of metabolic precursors.
o The compartmentalized activities of PDC (pyruvate dehydrogenase complex) generate building blocks
for lipid structures and regulate lipogenic gene expression to foster prostate tumorigenesis.
o L-2HG is markedly elevated in activated T cells, increasing HIF stability and promoting anti-tumour
immunity.
o Germline mutations in SDH and FH are tightly associated with hereditary leiomyomatosis and renal
cell cancer or rare neuroendocrine tumors.
Pentose Phosphate Pathway
o PPP is a metabolic branch stemming from glycolysis, generating NADPH and ribose 5-phosphate.
o Ru-5-P (nucleotide synthesis) inhibits AMPK by dissembling the LKB1 complex, promoting
lipogenesis and tumour growth.
o Together, 6PGD and G6PD in the PPP control dynamic AMPK signalling through opposite, non-
canonical functions.
Additional Carbohydrate Metabolism
o High doses of fructose may overwhelm intestinal fructose absorption and make contact with gut
microbiota.
o Colon cancer rely on ALDOB and fructose metabolism to fuel gluconeogenesis, the PPP, and the TCA
cycle to support their metastatic behaviour.
Lipid Metabolism
o Deregulated lipid metabolism is closely related to rapid cancer cell growth and tumour progression.
o High-fat diets may also increase the level of circulating acetoacetate, which significantly promotes
BRAF V600E-positive melanoma cell growth in vivo.
o Upon fatty acid synthase depletion, malonyl-CoA build-up leads to the malonylation and suppression
of mTORC1 in endothelial cells and impaired angiogenesis.
o De novo sphingolipid biosynthesis is mainly catalysed by serine palmitoyltransferases, which
surprisingly generate non-canonical deoxysphingolipids upon serine deprivation to mitigate tumour
growth.
Amino Acid Metabolism
o Amino acid metabolism is markedly re-programmed in
cancer.
o Glutamine is the most naturally abundant nonessential
amino acid in the human body, and actively taken up
and converted to glutamate by glutamate by glutaminase
in a variety of cancer cells.
