glycolysis and gluconeogenesis - REGULATION

locations

gluconeogenesis: primarily liver, provides glucose for other tissues

glycolysis: many types of cells and tissues, produce energy molecules from glucose

futile cycle

• uneconomical process

• would occur if gluconeogenesis and glycolysis occurred simultaneously

• no net gain of energy

substrate cycle

regulated futile cycle; advantageous b/c substrates are regenerated in continuing process

hexokinase

isozymes: different proteins that catalyze the same enzymatic rxn (labelled with I, II, III, etc)

• different isozymes are found in different tissues, different kinetic properties

hexokinase IV + regulatory protein:

• when glucose is low (fasting)

• fructose-6-phosphate triggers regulatory protein

• regulatory protein anchors HKIV inside nucleus

• glucose competes w/ fructose-6-phosphate binding to regulatory protein → reverses inhibition

  • pulls hexokinase back out of the nucleus when needed

• form of sequestration

transcriptional regulation of HKIV and glucose-6-phosphatase

• regulation also occurs by changing [enzyme] through protein synthesis

• HKIV (glycolysis)

  • occurs when [ATP] is low, [AMP] is high or high blood glucose

  • causes an increase in transcription of HKIV

• glucose-6-phosphatase (gluconeogenesis)

  • occurs when blood glucose is low

  • bypass step for hexokinase

phosphofructokinase-1

• commits G6P to glycolysis

• allosteric modulation:

  • ATP → inhibitory

  • AMP/ADP → activating

  • citrate → inhibitory intracellular signal

fructose 1,6-bisphosphatase (gluconeogenesis)

• reciprocal of PFK-1

• step 9 of gluconeogenesis

• AMP → inhibitor

fructose 2,6-bisphosphate

• only an allosteric regulator (not intermediate)

• produced specifically to regulate glycolysis and gluconeogenesis

  • activates PFK

  • inhibits fructose 1,6-bisphosphatase

• concentration is maintained by:

  • PFK-2

  • fructose 1,6-bisphosphate-2

• two activities of the same protein

• ultimately regulated via phosphorylation, cAMP, insulin

  • insulin → increase F26BP → glycolysis

  • glucagon (cAMP) → lowers F26BP → gluconeogenesis

pyruvate kinase

• allosterically activated by fructose-1,6-bisphosphate

  • increase flow through glycolysis

• inhibited by signs of abundant energy supply

  • ATP

  • acetyl-coA and long-chain fatty acids

  • alanine

• inactivated by phosphorylation in response to signs of glucose depletion (glucagon) *liver only

  • glucose from liver is exported to brain and other vital organs

pyruvate → phosphoenolpyruvate

• steps 1 and 2 commit pyruvate to gluconeogenesis

• fate of pyruvate determined via regulation

• regulation of pyruvate carboxylase:

  • acetyl-coA (promotes GG over citric acid cycle)

  • positive allosteric modulator

  • negative allosteric modulator of pyruvate dehydrogenase

• regulation of PEP carboxykinase:

  • synthesis and breakdown of enzyme

metabolic enzymes are regulated at transcription level

• some genes are regulated by insulin

• expression can be increased

  • glycolysis, energy production

• expression can be decreased

  • gluconeogenesis

ChREBP

• transcription factor important for carb metabolism

  • found in liver, adipose tissue and kidney

• coordinates synthesis of enzymes needed for carb and fat synthesis

• regulated by phosphorylation

  • dephosphorylation lets it enter the nucleus

  • 2nd dephosphorylation activates transcription factor

• associates w/ Mlx → then response element ChoRE → transcription

insulin stimulated inactivation of TFs

• FOXO1

  • transcription factor that stimulates synthesis of gluconeogenic enzymes

  • suppresses synthesis of other pathways

• insulin binds to receptor → FOXO1 leaves nucleus → phosphorylated by PKB → tagged by ubiquitin → degraded by proteasome