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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.
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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
Pathway’s Flux is Controlled at Select Points Which reaction is driving this sequence? Which has the most negative ΔG ?
Metabolic Regulation Functions To: • Maximize efficiency of energy source use, stops futile cycles. • Partitions metabolites and enzymes (alternative pathways – Glycolysis and PPP). • Use best suited energy source of the immediate need of the organism (glucose, glycogen, fatty acids, amino acids). • 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.
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 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.
Three Major forms of Allosteric Regulation of PFK-1 EOC Problem 4 is all about PFK-1 regulation
This Sugar was not discovered until the ‘80s At pH = 7…what is the Charge?
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
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
Things to Know and Do Before Class • Regulation of enzyme activity: allosteric, covalent modification, “hiding” out in another cell compartment. • Concept of enzyme elasticity. • Role of the adenylates in control, and AMPKinase. • Fructose-2,6-bisphosphate: how it is made and broken and how it helps prevent a futile cycle. • Isozymes (hexokinase). There are others. • Pyruvate kinase allosteric and covalent modification (liver only). • EOC Problems: 3, 4, 5.