Principles%20of%20Metabolic%20Regulation:

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Chapter 15
Principles of Metabolic Regulation Glucose and
Glycogen Part 1
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Principles of Metabolic Regulation
Key topics Learning Goals

• Principles of regulation in biological systems
• Glycolysis vs. gluconeogenesis? How are they
  regulated?

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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

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All Sorts of Things Affect Enzyme Activity
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Proteins Can be Covalently Modified
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Metabolome of Escherichia coli growing on Glucose
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Take Me Back to Chapter 6
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Km vs. Metabolite
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Pathways Flux is Controlled at Select Points
Which reaction is driving this sequence? Which
has the most negative ?G ?
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Elastisity Coefficient Depends on S
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Energy Charge 0.90 0.82
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Role of AMP-activated Protein Kinase
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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?
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Which Enzyme Controls Glycolytic Flux ?
Experiment purified enzymes added to liver cell
extract carrying out glycolysis with own enzymes.
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Flux Coefficients Determine Flow Path
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Insulin Regulation On Muscle Cells
EOC Problem 5 is all about cytoplasmic
concentration of glucose
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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
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Potential Futile Cycles between Glycolysis and
Gluconeogenesis
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Hexokinase Isozymes
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Hexokinase IV Regulation in Liver
Glycogen
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GlucokinaseHexokinase 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 a and ß
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Fig 27-42 pgs 1104-1105
NLS Nuclear Localization Sequence. 4-8 aas of
which there are consequitive Ks and Rs.
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PFK-1 Is Energy Regulated
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Three Major forms of Allosteric Regulation of
PFK-1
EOC Problem 4 is all about PFK-1 regulation
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Adenylates and Citrate on PFK-1 and FBPase-1
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This Sugar was not discovered until the 80s
At pH 7what is the Charge?
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F2,6BP is a Major Regulator
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F-2,6-BP is a Major Regulator
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Reciprocal Effects
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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
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WOW !!! PFK-2 and FBP-2 are the Same Protein
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Phosphoprotein Phosphatase is Stimulated by
Xylulose-5-P stimulated Pyr Kinase
Xylulose-5-P also stimulates fatty acid synthesis
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Phosophoprotein Phosphatase can Recognize
Different Proteins
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EOC Problem 3 is about Oxygen supply and this
Regulation
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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.