Why pathways speed up or slow down

Cells tune glycolysis to energy demand and tissue state.

• Can speed upAMP and ADP

  Low-energy signals activate phosphofructokinase-1 (PFK-1) in many tissues.

• Can slow downATP and citrate

  High-energy and abundant-carbon signals restrain PFK-1.

• Can speed upFructose 2,6-bisphosphate

  In liver, this strong PFK-1 activator rises with insulin signaling and falls with glucagon signaling.

The liver adjusts glucose production during fasting; opposing pathways are coordinated.

• Can slow downAMP and fructose 2,6-bisphosphate

  Both inhibit fructose-1,6-bisphosphatase, a key gluconeogenic control point.

• Can speed upAcetyl-CoA

  Acetyl-CoA activates pyruvate carboxylase and signals fatty-acid oxidation.

• Depends on contextGlucagon in liver

  Fasting signaling lowers fructose 2,6-bisphosphate and favors glucose output; this is not a universal direct switch in every tissue.

The oxidative branch responds to the cell’s need for NADPH.

• Can speed upNADP+ availability

  NADP+ availability supports glucose-6-phosphate dehydrogenase activity and NADPH production.

• Can slow downNADPH

  NADPH product feedback restrains the first oxidative step.

• Depends on contextBiosynthetic demand

  Cells can route more glucose 6-phosphate through this pathway when reducing power or ribose is needed.

Phosphorylation coordinates glycogen breakdown and storage.

• Can speed upInsulin signaling

  In liver and muscle it favors glycogen synthase activity and storage after feeding.

• Can speed upGlucagon in liver; epinephrine in liver and muscle

  These signals favor glycogen breakdown. Muscle contraction also activates muscle glycogen use.

• Depends on contextOpposing enzyme states

  Glycogen synthase and glycogen phosphorylase are coordinated so synthesis and breakdown do not simply run full speed together.

The pyruvate dehydrogenase complex responds to fuel and energy status.

• Can slow downATP, NADH, and acetyl-CoA

  These products and high-energy signals favor inhibitory phosphorylation of the complex.

• Can speed upPyruvate, ADP, and calcium in working muscle

  These signals favor active pyruvate dehydrogenase and help match oxidation to demand.

• Depends on contextInsulin

  Insulin can promote pyruvate oxidation in selected tissues; effects depend on tissue and nutritional state.

The cycle’s rate follows cellular energy demand and mitochondrial signals.

• Can speed upADP and calcium in active muscle

  These signals can activate key control enzymes when ATP demand rises.

• Can slow downATP and NADH

  High-energy and reduced-cofactor signals restrain several control points.

• Depends on contextOxygen supply

  Oxygen is not consumed directly by TCA reactions, but the respiratory chain must reoxidize NADH and FADH2 for sustained cycling.

ADP availability is a major signal for mitochondrial ATP production.

• Can speed upADP and phosphate

  When ATP is used, ADP and phosphate availability can increase ATP synthesis and electron transport.

• Can slow downHigh ATP / low ADP

  Low demand slows ATP synthase and, in turn, electron transport.

• Depends on contextOxygen

  Oxygen accepts electrons at complex IV; limited oxygen constrains respiratory ATP production.

Fatty-acid entry into mitochondria is a major control point.

• Can slow downMalonyl-CoA

  Malonyl-CoA inhibits CPT1, limiting long-chain fatty-acid entry into mitochondria.

• Can speed upLow insulin and increased fatty-acid supply

  During fasting, adipose lipolysis supplies fatty acids to tissues; pathway use still depends on tissue and demand.

• Depends on contextEnergy demand and carnitine transport

  Mitochondrial uptake and downstream respiratory capacity also shape oxidation rate.

Acetyl-CoA carboxylase links fuel abundance to fatty-acid building.

• Can speed upCitrate

  Citrate can allosterically activate acetyl-CoA carboxylase.

• Can slow downAMPK phosphorylation and long-chain acyl-CoA

  Energy stress and fatty-acid products restrain acetyl-CoA carboxylase.

• Depends on contextInsulin in fed tissues

  Insulin favors lipogenic enzyme activity and expression, especially in liver and adipose tissue.

HMG-CoA reductase is controlled by sterol supply and energy state.

• Can slow downCellular sterols

  Sterol feedback decreases the production and stability of HMG-CoA reductase.

• Can slow downAMPK phosphorylation

  Energy-stress signaling phosphorylates and inhibits HMG-CoA reductase.

• Depends on contextInsulin and sterol demand

  Hormones and cellular sterol demand regulate synthesis at multiple levels.

The liver increases nitrogen disposal when amino-acid breakdown rises.

• Can speed upN-acetylglutamate

  N-acetylglutamate activates carbamoyl-phosphate synthetase I, the first committed mitochondrial step.

• Depends on contextArginine availability

  Arginine supports N-acetylglutamate synthesis and helps signal amino-acid supply.

• Depends on contextProtein intake and catabolism

  Longer-term enzyme expression adjusts to nitrogen load; the response is not a single on/off switch.

Branched-chain amino-acid breakdown is controlled at the shared BCKDH complex.

• Can slow downBCKDK phosphorylation

  BCKD kinase phosphorylates and inhibits the branched-chain keto-acid dehydrogenase complex.

• Can speed upPPM1K dephosphorylation

  The mitochondrial phosphatase PPM1K activates the complex by dephosphorylation.

• Depends on contextAmino-acid supply and tissue

  The three amino acids share an initial route but their carbon products diverge; tissue use varies.

Purine end products provide feedback on new nucleotide synthesis.

• Can slow downAMP, GMP, and IMP

  Purine nucleotides feed back on early committed steps and help balance the nucleotide pool.

• Can speed upPRPP availability

  Phosphoribosyl pyrophosphate availability supports de novo purine synthesis.

• Depends on contextAMP/GMP branch demand

  Separate branch-point feedback helps balance adenine and guanine nucleotide production.

Pyrimidine synthesis responds to nucleotide-pool balance.

• Can slow downUTP

  UTP feedback inhibits the multifunctional CAD enzyme in mammalian cells.

• Can speed upPRPP and ATP

  Substrate and energy availability can favor de novo synthesis.

• Can slow downCTP

  CTP feedback restrains CTP synthetase at the later branch step.