Metabolic regulation

Boththeamountandthecatalyticactivityofanenzymecanbe
regulated

1. Extracellularsignal:hormonal,neuronal,growthfactorsetc.
2. Transcription:activateorrepressthetranscription
3. ThestabilityofmRNA
4. Therateoftranslation
5. Therateofproteindegradation
6. Sequestertheenzymeanditssubstrateindifferent
compartments
7. Bytheconcentrationofsubstrate
8. Thepresenceofallostericeffector
9. Covalentmodification
10. Bindingofregulatoryprotein
 AdenineNucleotidesplayspecialRolesinMetabolicregulation

1. ItisimportanttomaintainaconstantsupplyandconcentrationofATP:
[ATP]dropreactionrateisdecreased.
2. AMPconcentrationismoresensitiveindicatorofcellsenergeticstatethanis
[ATP]
3. AMPactivatedproteinkinase
regulatedby[AMP]
Areducednutrientsupplyorbyincreaseexercisecausetherisein[AMP]
increaseglucoseuptake,activatesglycolysisandfattyacidoxidation
suppressenergyrequiringprocessessuchasfattyacid,cholesterol,and
proteinsynthesis
4. NADHandNADPH:changeintheirmassactionratioshaveglobaleffects
onmetabolism
5. Glucose
CoordinatedRegulationofGlycolysisandGluconeogensis
 Hexokinase

1. Humanhavefourisozyme,encodedbydifferentgenes
Isozyme:Differentproteinsthatcatalyzethesamereaction
2. Inmyocytes,hexokinaseII:highaffinityforglucose,inhibited
byG6P
3. Inliver,hexokinaseIV(glucokinase)
lowaffinityforglucose:directregulationbythelevelofblood
glucose
notinhibitedbyG6P
issubjectedtoinhibitionbyreversiblebindingofaregulatory
proteinspecifictoliver
aretranscriptionallyregulated:[ATP]lowor[glucose]high

Regulation of hexokinase IV (glucokinase) by sequestration in

the nucleus. The protein inhibitor of hexokinase IV is a nuclear
binding protein that draws hexokinase IV into the nucleus when the
fructose 6-phosphate concentration in liver is high and releases it
to the cytosol when the glucose concentration is high.
 Phosphofluctokinase1

1. Higherenzymeactivity:[ADP]or[AMP]high
Lowenzymeactivity:[ATP]high
2.Citrate:High[citrate]increasestheinhibitoryeffectofATP
3.F2,6BP:activatesPFK1

 Fructose1,6bisphosphatase

1. InhibitedbyAMP
2. InhibitedbyF2,6BP
3. PFK1andFBPase1aregulatedinacoordinatedandreciprocal
manner
energyhigh:gluconeogenesis
energylow:glycolysis

 F2,6BPispotentallostericregulatorofPFK1and
FBPase1
1. Thespecialroleofliverinmaintainingaconstantbloodglucose
levelrequiresadditionalregulatorymechanismtocoordinate
glucoseconsumptionandproduction
2. Glucagon:thelivertoproduceglucoseandtostopconsumingit
forownneed
3. Insulin:thelivertouseglucoseasfuelandasaprecursorforthe
synthesisandglycogenandtriacylglycerol.
4.HormonalregulationismediatedbyF2,6BP
5. F2,6BPincreasethePFK1saffinityforitssubstrate
inabsenceofF2,6BP,atphysiologicalconditionPFK1is
inactive
6.F2,6BPreducetheFBPase1saffinityforitssubstrate.

F2,6BPissetbytherelativeratesofitsformationand
breakdown
Pyruvatekinase
 Pyruvate kinase
The enzyme is allosterically inhibited by ATP, acetyl-CoA, and long-
chain fatty acids (all signs of an abundant energy supply), and the
accumulation of fructose 1,6-bisphosphate triggers its activation.
Accumulation of alanine, which can be synthesized from pyruvate in
one step, allosterically inhibits pyruvate kinase, slowing the production
of pyruvate by glycolysis.
The liver isozyme (L form) is also regulated hormonally. Glucagon
activates cAMP-dependent protein kinase (PKA), which
phosphorylates the pyruvate kinase L isozyme, inactivating it.
When the glucagon level drops, a protein phosphatase (PP)
dephosphorylates pyruvate kinase, activating it. This mechanism
prevents the liver from consuming glucose by glycolysis when blood
glucose is low; instead, the liver exports glucose. The muscle isozyme
(M form) is not affected by this phosphorylation mechanism.
 Two alternative fates for pyruvate. Pyruvate
can be converted to glucose and glycogen via
gluconeogenesis or oxidized to acetyl-CoA for
energy production.
The first enzyme in each path is regulated
allosterically; acetyl-CoA, produced either by
fatty acid oxidation or by the pyruvate
dehydrogenase complex, stimulates pyruvate
carboxylase and inhibits pyruvate
dehydrogenase.
1. Pyruvatecarboxylaseis
activatedbyacetylcoA
2. PEPcarboxykinaseis
regulationbyitssynthesis
andbreakdown
Glucagon
cAMP
increasetranscriptionof
PEPcarboxykinase
Insulin:oppositeeffect