eric niederhoffer siu-som

Eric NiederhofferSIU-SOM

Regulation of Phosphofructokinase-1: Too Much of a Good Theme?

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?

PK

PFK-1

Glc

Acetyl-CoA

Pyr

F6P

F16BP

PEP

G6P

PDH

F26BPasePFK-2

Glycolysis: Regulatory Steps

HK

InsulinGlucagon

Ep

Adipose

HeartLiver

GK

Liver

Liver

Liver

Heart

NH4+

AMPPi

PFK-1

Glc

F6P

F16BP

G6P

PFK-2

F26BP

ATPCitrate

PEPH+

Regulation Focus

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

F26BPase-PFK-2

F26BPase-PFK-2P

Insulin

PrPase2A

GlucagonEp

PKALiver

F26BPase-PFK-2

F26BPase-PFK-2F6P↑F6P↓Skeletal

Muscle

F26BPaseP-PFK-2

F26BPase-PFK-2

???PKA

Ep

Insulin

AMPK/AKT/WISKHeart