Regulation of Phosphofructokinase-1:
Too Much of a Good Theme?
Eric Niederhoffer
SIU-SOM
Curriculum Context
•
Problem-based learning using electronic patient
cases
•
Organ-system, integrated disciplines
•
Specific example - diabetes mellitus/alcoholic
ketoacidosis
•
Learning Issues
Which steps in metabolic pathways are
regulated by insulin, glucagon, or other
important hormones or metabolites?
How do insulin and glucagon balance the
degradation, synthesis, and storage of glucose?
How does the regulation of glycolysis compare
between liver, cardiac muscle and skeletal
muscle?
Glycolysis: Regulatory Steps
Glucagon
Liver
Glc
GK
H
G6P K
F6P
PFK-1
Insulin
Liver
Ep
Heart
Liver
F26BPase
PFK-2
Heart
F16BP
PEP
PK
Pyr
Liver
Adipose
PDH
Acetyl-CoA
Regulation Focus
Glc
G6P
F6P
ATP
Citrate
PEP
H+
PFK-2
PFK-1
F26BP
F16BP
NH4+
AMP
Pi
PFK-1 - Facts
• Two genes - PFKL (21q), PFKM (12q)
• Tetramer - muscle (M4), liver/kidney
(L4), platelet (M4, M3L, M2L2, ML3, L4)
• T and R states
• Activators - AMP, ADP, cAMP, Pi, F6P,
F16BP, F26BP, NH4+
• Inhibitors - ATP, citrate, PEP, H+
• Interaction with renal H+ ATPase
• Glycogen storage disease VII (Tauri) autosomal recessive, gout, increased
O2 affinity (decreased 23BPG)
PFK-2 - Facts
• Four genes - PFKFB1 (X), PFKFB2 (1),
PFKFB3 (10), PFKFB4 (3)
• PFK-2 dimer
• Bifunctional protein (PFK/F26BPase)
• Activators/inhibitors - similar to PFK-1
except no ATP inhibition
• Brain no (or low) mRNA detected
• Skeletal muscle - F6P regulates
• Phosphorylation - liver (Ser32, N term),
cardiac (Ser406[466,483],Thr475,
F26BPase)
F26BPase-PFK-2
Regulation Comparison
Glucagon
Ep
Insulin
F26BPase-PFK-2P
Liver
PKA
PrPase2A
F26BPase-PFK-2
F26BPase-PFK-2
Skeletal
Muscle
F6P↓
F6P↑
F26BPase-PFK-2
Ep
F26BPase-PFK-2
Heart
PKA
??? AMPK/AKT/WISK
F26BPaseP-PFK-2
Insulin