Chapter 15
Principles of Metabolic Regulation:
Glucose and Glycogen
Part 1
Principles of Metabolic Regulation
Key topics: Learning Goals
– Principles of regulation in biological systems
– Glycolysis vs. gluconeogenesis? How are they
regulated?
Metabolic Pathways
• The biochemical reactions in the living
cell―metabolism―are organized into metabolic
pathways
• The pathways have dedicated purposes:
– Extraction of energy
– Storage of fuels
– Synthesis of important building blocks
– Elimination of waste materials
• The pathways can be represented as a map
–
–
–
–
Follow the fate of metabolites and building blocks
Identify enzymes that act on these metabolites
Identify points and agents of regulation
Identify sources of metabolic diseases
All Sorts of Things Affect Enzyme
Activity
Proteins Can be
Covalently Modified
Metabolome of Escherichia coli growing on Glucose
Take Me Back to Chapter 6
Km vs. [Metabolite]
Pathway’s Flux is Controlled at Select
Points
Which reaction is driving this sequence?
Which has the most negative ΔG ?
Elastisity Coefficient Depends on [S]
Energy Charge:
0.90
0.82
Role of AMP-activated Protein Kinase
Metabolic Regulation Functions To:
1. Maximize efficiency of energy source use, stops futile
cycles.
2. Partitions metabolites and enzymes (alternative pathways –
Glycolysis and PPP).
3. Use best suited energy source of the immediate need of the
organism (glucose, glycogen, fatty acids, amino acids).
4. Shuts down biosynthesis when products accumulate.
What is a Futile Cycle? Have we seen one already?
Which Enzyme Controls Glycolytic Flux ?
Experiment: purified enzymes added to liver cell extract
carrying out glycolysis with own enzymes.
Flux Coefficients Determine Flow Path
Insulin Regulation On Muscle Cells
EOC Problem 5 is all about cytoplasmic concentration of glucose
Hexokinase-1 Regulation in Muscles
Glucose-6-Phosphate is a negative allosteric regulator of
Hexokinase I and II
So how many binding sites on Hexokinase I and II for
Glucose-6-P are there?
Glucose + ATP  Glucose-6-P + ADP
Potential Futile Cycles
between Glycolysis and
Gluconeogenesis
Hexokinase Isozymes
Hexokinase IV Regulation in Liver
Glycogen
Glucokinase=Hexokinase IV
Signal Sequences: 300-310 ELVRLVLLKLV
says export me to the cytoplasm.
347-358 QIHNILSTGLR
says associate with GKRP:
Glucokinase Regulatory Protein = GKRP
Nuclear Localization Sequence: PKKKRKV (prototype)
+ Importins α and β
Fig 27-42
pgs 1104-1105
NLS = Nuclear Localization Sequence.
4-8 aa’s of which there are consequitive
K’s and R’s.
PFK-1 Is Energy Regulated
Three Major forms of Allosteric Regulation of
PFK-1
EOC Problem 4 is all about PFK-1 regulation
Adenylates and Citrate on PFK-1 and FBPase-1
This Sugar was not discovered until the ‘80s
At pH = 7…what is the Charge?
F2,6BP is a Major Regulator
F-2,6-BP is a Major Regulator
Reciprocal Effects
Making and Breaking F2,6BP
This is super easy to remember:
PFK-1 phosphorylates the number 1 carbon of F6P,
PFK-2 phosphorylates the number 2 carbon of F6P
WOW !!! PFK-2 and FBP-2 are the Same Protein
Phosphoprotein Phosphatase is Stimulated by
Xylulose-5-P stimulated Pyr Kinase
Xylulose-5-P also stimulates fatty acid synthesis
Phosophoprotein
Phosphatase can
Recognize Different
Proteins
EOC Problem 3 is about Oxygen supply and this Regulation
Things to Know and Do Before Class
1. Regulation of enzyme activity: allosteric, covalent
modification, “hiding” out in another cell compartment.
2. Concept of enzyme elasticity.
3. Role of the adenylates in control, and AMPKinase.
4. Fructose-2,6-bisphosphate: how it is made and broken
and how it helps prevent a futile cycle.
5. Isozymes (hexokinase). There are others.
6. Pyruvate kinase allosteric and covalent modification
(liver only).
7. EOC Problems: 3, 4, 5.