Glycolysis tough concepts

Net yield of glycolysis

Net yield: +2 ATP and +2 NADH per glucose

Committed step of glycolysis

PFK1

TPI deficiency

traps carbon as DHAP, producing toxic methylglyoxal

GAPDH step importance

GAPDH uses a thioester intermediate to couple oxidation to phosphorylation

GAPDH coupling

Without coupling, the reaction would be too slow and wasteful

Why is PEP high-energy?

Phosphate traps unstable enol form

The three irreversible control points have…

Large -delta G

Ethanol fermentation

Pyruvate —> pyruvate decarboxylase (TPP req) —> acetaldehyde —> alcohol dehydrogenase —> ethanol

Lactic acid fermentation

pyruvate —> lactate dehydrogenase —> lactate

PFK1 regulation (muscle)

inhibitors: ATP, citrate, low pH

activators: AMP, ADP

PFK1 regulation (liver)

inhibitors: ATP, citrate, glucagon (lower F-2,6-BP)

activators: F-2,6-BP (via insulin), AMP (less sensitive)

F-2,6-BP

master allosteric activator in the liver

PK (muscle) regulation

*M1 ISOFORM* —> only allosteric

inhibitors: ATP, alanine

activators: F-1,6-BP (feed forward)

PK (liver) regulation

*L ISOFORM*

inhibitors: alanine, ATP, glucagon

activators: insulin, F-1,6-BP

glucagon pathway for L PK

glucagon —> high cAMP —> PKA —> phosphorylates PK —> inactive —> PEP preserved for gluconeogenesis

glucagon pathway for PFK1

glucagon —> high cAMP —> PKA phosphorylates PFK2 —> switch to FBPase2 —> low F-2,6-BP —> PFK1 off

insulin pathway for L PK

insulin —> low cAMP —> PK active —> glycolysis

Warburg effect

cancer cells prefer glycolysis even with O2 available

HIF-1a

transcription actor that facilitates aerobic glycolysis; activated in both exercise and tumors

GLUT 1

tissue: all tissues

low kM

GLUT 2

tissue: liver, pancreatic B cells

high kM

Glucose sensor

GLUT 3

tissue: neurons

very low kM

GLUT 4

tissue: muscle and fat

medium kM

Insulin responsive (translocates to membrane)

pancreatic b cell mechanism

glucose —> GLUT2 —> glycolysis —> ATP increases —> K+ channel closes —> depolarization—> Ca2+ influx —> release of insulin