Cellular metabolism signaling

Cellular metabolism integrates glucose uptake and glycolysis, mitochondrial TCA/OXPHOS, glutamine and fatty-acid carbon routes, and branches such as the pentose phosphate pathway and nucleotide biosynthesis. AMPK and mTORC1 sense energy and nutrient availability; HIF programs bias glycolysis under hypoxia. Metabolic reprogramming couples to growth signaling, immune niches, and therapy resistance in cancer and chronic inflammation.

1. Key targets

Core nodes

  • GLUT / HK / PFK / PKM

    Glucose capture and flux control; isoforms like PKM2 route intermediates and can moonlight (context-dependent).

  • PDH / TCA / ETC

    Pyruvate entry and acetyl-CoA supply; ETC couples ATP generation with ROS and biosynthetic precursors.

  • GLS / IDH / ACLY / FASN

    Glutamine anaplerosis, α-KG/2-HG axes, citrate–acetyl-CoA shunt, and lipogenesis.

Sensing & integration

  • AMPK: rising AMP/ADP, Ca2+, LKB1, etc.
  • mTORC1: amino acids, glucose, growth factors, Rag/Rheb
  • HIF1A: PHD–VHL–proteasome regulation

Outputs & transport

  • LDH–lactate–MCT: NAD+ cycling and acidification
  • NADPH: PPP, ME, one-carbon branches (model-dependent)

Supplement: metabolism-related targets (gene symbols)

Below the overview, HGNC symbols group glycolysis/glucose capture, pyruvate & TCA, OXPHOS & PPP, FAO & lipogenesis, glutamine anaplerosis & amino-acid transport, AMPK/mTOR/HIF sensing, and lactate/NAD balance. Validate isozymes, complex subunits, and model context with databases and papers.

Glucose uptake & glycolysis

Glucose uptake & hexokinases

GLUT isoforms and HK isozymes gate glucose capture and flux entry.

SLC2A1, SLC2A2, SLC2A3, SLC2A4, HK1, HK2, HK3, GPI, PFKM, PFKL, PFKP, ALDOA, ALDOB, ALDOC

Core glycolytic enzymes (flux & branching)

PKM isoforms couple to lactate/biosynthetic branching.

TPI1, GAPDH, PGK1, PGAM1, PGAM2, ENO1, ENO2, ENO3, PKM, PKLR, PDK1, PDK2, PDK3, PDK4

PDH & TCA cycle

PDH complex & acetyl-CoA entry

PDHA1, PDHA2, PDHB, DLAT, DLD, PDHX, PDPR, PDP1, PDP2

Tricarboxylic acid (TCA) cycle

CS, ACO1, ACO2, IDH1, IDH2, IDH3A, IDH3B, IDH3G, OGDH, DLST, SUCLG1, SUCLG2, SUCLA2, SDHA, SDHB, SDHC, SDHD, FH, MDH1, MDH2, PC, PCK1, PCK2

OXPHOS & PPP / one-carbon

OXPHOS (ETC / ATP synthase representatives)

Many subunits; representative genes for common readouts.

NDUFS1, NDUFS3, UQCRC2, CYCS, COX4I1, COX5A, ATP5F1A, ATP5F1B, ATP5F1C, SLC25A1, SLC25A5

PPP & one-carbon / folate (representative)

NADPH/nucleotide precursors; intersects folate cycle.

G6PD, PGD, TALDO1, TKT, RPIA, RPE, MTHFD1, MTHFD2, SHMT1, SHMT2, DHFR, TYMS

Fatty-acid oxidation & lipogenesis

Fatty acid oxidation (mitochondrial β-oxidation entry)

CPT1A, CPT1B, CPT1C, CPT2, ACADVL, ACADM, HADHA, HADHB, EHHADH, ACADS, ACAA2

Fatty-acid & lipid biosynthesis

ACLY, ACACA, ACACB, FASN, SCD, ELOVL6, AGPAT1, GPAM, DGAT1, DGAT2, LPIN1

Glutaminase, anaplerosis & SLC transporters

Glutaminase & anaplerosis

GLS, GLS2, GLUD1, GLUD2, GOT1, GOT2, GPT, GPT2, MDH1, MDH2

SLCs: glucose, lactate, amino acids (representative)

SLC2A1, SLC16A1, SLC16A3, SLC16A7, SLC1A5, SLC7A5, SLC7A11, SLC38A1, SLC38A2

AMPK, mTOR & HIF

LDH & malic enzymes

LDH & malic enzymes (NADH/NADPH)

LDHA, LDHB, LDHC, ME1, ME2, ME3, MDH1, MDH2

2. Suggested experimental readouts

Combine flux (OCR/ECAR), stable-isotope tracing, and targeted proteomics; document dose, time, and cell-density dependence for metabolic probes.

  • Seahorse OCR/ECAR with oligomycin, FCCP, rotenone/antimycin controls
  • 13C6-glucose or 13C5-glutamine tracing for glycolysis/TCA/anaplerosis
  • Extracellular lactate, glucose uptake (e.g., 2-NBDG), ATP/ADP (method-sensitive)
  • p-AMPKα, p-ACC, p-S6K / p-S6 as mTORC1 readouts
  • HK2, PKM2, LDHA, GLS, ACLY, FASN, IDH1/2 with fractionation as needed

3. Major carbon-route modules compared

ModuleMain rolesTypical readoutsNotes
GlycolysisRapid ATP, biosynthetic intermediates, lactateECAR, 13C-lactate, HK2/PKM2Aerobic glycolysis does not imply absent OXPHOS.
TCA / OXPHOSEfficient ATP, precursors, NADH/FADH2OCR, 13C-glutamine TCA, TMREPyruvate/glutamine in medium strongly shape phenotypes.
PPPNADPH and nucleotide precursors6-AN (6-aminonicotinamide), 13C1-glucose branching traceDistinguish oxidative vs non-oxidative arms.
Fatty-acid oxidation / lipogenesisβ-oxidation ATP/NADH; de novo FA synthesis and membrane lipidsSeahorse FAO substrates, CPT1 probes (etomoxir—off-target caveats), FASN/p-ACCFAO dependence differs sharply across tumor vs liver models.
Glutamine anaplerosisα-KG entry to TCA; biosynthesis & redox balance13C5-glutamine tracing, GLS inhibition (BPTES/CB-839), GOT1/2Glutamine addiction is not universal across cell lines.

4. Tumor & niche: metabolic reprogramming

  • Nutrient competition: Under glucose/glutamine limitation, tumor and immune metabolic preferences co-evolve.
  • Lactate & acidity: MCT-mediated shuttling affects neighbor cell function and drug penetration.
  • Metabolic therapy resistance: Bypass enzymes, mitochondrial plasticity, or autophagy can compensate single-node inhibition.

Metabolism-related antibodies (curated)

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5. Product lines & on-site search

Primary & phospho antibodies

HK2, PFKL, ALDOA, PKM2, LDHA, GLUT1, MCT1/4, PDK1, PDH, IDH1/2, ACLY, FASN, GLS, AMPKα, p-AMPK, mTOR, p-S6K, p-S6, HIF1α—WB/IHC/IF/FC per clone.

Recombinant proteins / enzymes

Recombinant HK, LDH, glutaminase for in vitro assays or pulldowns (availability-dependent).

Assays & kits

Glucose uptake, lactate, ATP, NAD/NADH kits—follow datasheets and ethics.

6. Inhibitors & tool compounds (summary)

For research use; follow lab SOP and datasheets. Some entries are flux probes rather than therapeutics.

2-Deoxy-D-glucose (2-DG)

HK substrate analog; common glycolysis flux probe.

Oligomycin

ATP synthase inhibitor; Seahorse OCR control.

BPTES / CB-839

GLS inhibitors; glutamine-addicted models.

Etomoxir

CPT1/FAO probe (off-target caveats).

Metformin

Complex I–linked effects; AMPK-context studies.

Rapamycin / Torin1

mTORC1 inhibition; watch PI3K/Akt feedback.

Oxamate

LDH tool; lactate/NAD+ balance experiments.

AGI-5198 / Ivosidenib class

Mutant IDH1 inhibitors (project/regulatory dependent).

7. Pathway schematic

Cellular metabolism (simplified schematic)
Cellular metabolism pathway schematic
Legend
  1. Glucose import, glycolysis, pyruvate–lactate branch
  2. Mitochondrial TCA/OXPHOS couples ATP and ROS
  3. Glutamine anaplerosis and IDH nodes shape α-KG/2-HG
  4. AMPK and mTORC1 integrate nutrients and growth

8. Pathway biology overview

Metabolic networks are not isolated housekeeping—they intersect chromatin regulation, checkpoints, and immune receptor signaling; single proteins can moonlight between cytosolic and nuclear roles.

  • Tissue/cell type sets baseline flux—extrapolate cautiously across models
  • Culture conditions (serum, O2, substrates) dominate metabolic phenotypes

9. Related pathways on this site

Nervous systemCellular autophagyPI3K/Akt/mTORMAPK/ERKApoptosisAngiogenesisReceptor tyrosine kinaseEndocrine and HormoneJAK-STAT

10. External databases & modification resources

11. References

Classics in cancer metabolism

  • • Warburg O. (1956). Science. 123(3191):309-14.
  • • Vander Heiden MG, Cantley LC, Thompson CB. (2009). Science. 324(5930):1029-33.

Integration & reviews

  • • DeBerardinis RJ, Thompson CB. (2012). Cell. 148(6):1132-44.
  • • Martinez-Reyes I, Chandel NS. (2020). Nat Rev Mol Cell Biol. 21(12):710-27.