Glycolysis Rate Limiters

GlycolysisGlycolysis Rate Rate LimitersLimiters

LDHLDHHexokinaseHexokinase

PFK-1PFK-1NADH/NADNADH/NAD++ ratio ratio

PHOSPHOSCaCa2+2+

EpinephrineEpinephrine

Lactate Dehydrogenase (LDH)Lactate Dehydrogenase (LDH)

Catalyzes the reaction of pyruvate to lactateCatalyzes the reaction of pyruvate to lactate

Has a low KHas a low Kmm resulting in a high affinity for pyruvate resulting in a high affinity for pyruvate

Has the highest VHas the highest Vmaxmax of any glycolytic enzyme of any glycolytic enzyme The system favors lactate production. The system favors lactate production. Any pyruvate not immediately entering the mitochondria is Any pyruvate not immediately entering the mitochondria is

reduced to lactate.reduced to lactate.

HexokinaseHexokinase

Catalyze the reaction that turns glucose into Catalyze the reaction that turns glucose into Glucose 6-PGlucose 6-P

Regulated by its product Glucose 6-PRegulated by its product Glucose 6-P If G6-P increases too much, it binds to the If G6-P increases too much, it binds to the

hexokinase enzyme and slows the reaction rate.hexokinase enzyme and slows the reaction rate. Results in a sharp decrease in glucose uptake into Results in a sharp decrease in glucose uptake into

the cellthe cell This process is called Feedback or Product This process is called Feedback or Product

InhibitionInhibition

Phosphofructokinase-1 (PFK-1)Phosphofructokinase-1 (PFK-1)

Major regulatory enzyme for the glycolytic Major regulatory enzyme for the glycolytic pathway flux from G6-P to pyruvatepathway flux from G6-P to pyruvate

Control is primarily based on changes in Control is primarily based on changes in concentrations of several allosteric effectorsconcentrations of several allosteric effectors

Cytoplasmic NADH/NADCytoplasmic NADH/NAD+ Ratio

Affects activity of Glyceraldehyde 3-phosphate Affects activity of Glyceraldehyde 3-phosphate DehydrogenaseDehydrogenase Catalyzes reaction:Catalyzes reaction:

NADNAD++ is oxidized to NADH and H is oxidized to NADH and H++

Generated NADH can be re-oxidized to NADGenerated NADH can be re-oxidized to NAD++

Lack of NADLack of NAD++ will halt glycolysis will halt glycolysis Important for converting pyruvate into lactateImportant for converting pyruvate into lactate

Increase in ratio, through reduction, slows Increase in ratio, through reduction, slows glycolysisglycolysis

Decrease in ratio, through oxidation, speeds Decrease in ratio, through oxidation, speeds glycolysisglycolysis

Glycogen Phosphorylase (PHOS)Glycogen Phosphorylase (PHOS)

Glycogen is the primary source of G6-P to fuel Glycogen is the primary source of G6-P to fuel glycolysisglycolysis

Breakdown of glycogen is dependent on the Breakdown of glycogen is dependent on the PHOS enzymePHOS enzyme

Controlled through proportion of enzyme in the Controlled through proportion of enzyme in the active GPa form vs. inactive GPb formactive GPa form vs. inactive GPb form

Calcium Ion (CaCalcium Ion (Ca2+2+))

Regulates glycogen catabolismRegulates glycogen catabolism

Conversion of PHOS b (inactive) to PHOS a Conversion of PHOS b (inactive) to PHOS a (active) depends on stimulation of glycogen (active) depends on stimulation of glycogen phosphorylase kinase (GPK) by Caphosphorylase kinase (GPK) by Ca2+2+

Fast PHOS activationFast PHOS activation CaCa2+2+ released from sarcoplasmic reticulum immediately released from sarcoplasmic reticulum immediately

when muscles contractwhen muscles contract 4 Ca4 Ca2+2+ bind to calmodulin (subunit of GPK) to activate it bind to calmodulin (subunit of GPK) to activate it Active calmodulin can phosphorylate phosphorylase b Active calmodulin can phosphorylate phosphorylase b

to make it phosphorylase ato make it phosphorylase a

EpinephrineEpinephrine

Released when you are aroused or anxious Released when you are aroused or anxious before competitionbefore competition

Mediates stimulation of glucose production by Mediates stimulation of glucose production by the liver in advance of muscular uptakethe liver in advance of muscular uptake

Slow PHOS activationSlow PHOS activation Epinephrine binds to its Epinephrine binds to its ββ adrenergic receptor on adrenergic receptor on

skeletal muscleskeletal muscle Starts cascade of activation eventsStarts cascade of activation events Results in conversion of PHOS b to PHOS aResults in conversion of PHOS b to PHOS a