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Lecture 15: Regulation of Carbohydrate Metabolism Chapter 8 regulation of metabolic pathways regulation of glycolysis and gluconeogenesis regulation of glycogen synthesis & breakdown

Practice Questions See blackboard

Regulation of metabolic pathways living cells maintain a dynamic steady state homeostasis Regulatory Strategies 1) Enzymes responds to changes in metabolite concentration Allosteric modulation 2) Covalent modification of enzymes: Hormone regulation

protein phosphorylation enzyme activity regulation

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How are these opposing pathways regulated?

1 Allosteric regulation! 2 PFK-1 FBPase-1 4

Reciprocal Regulation

Glycolysis and gluconeogenesis do not function at the same time. Both pathways are exergonic, so there is no energy barrier. Pathways are regulated by concentrations of precursors (substrates), intermediates, and products.

PFK

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Regulation of PFK-1 (phosphofructokinase-1)

allosteric inhibition by ATP and citrate allosteric activation by fructose 2,6-bisphosphate

Km altered by [ATP]

substrate yellow and blue; inhibitor - blue

glucagon leads to reduced glycolysis how?

Regulation of pyruvate kinase allosteric inhibition by ATP

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Reciprocal Regulation

Glycolysis and gluconeogenesis do not function at the same time. Both pathways are exergonic, so there is no energy barrier. Pathways are regulated by concentrations of precursors (substrates), intermediates, and products.

PFK

Regulation of Gluconeogenesis: Pyruvate Carboxylase gluconeogenesis is regulated at the level of pyruvate carboxylase (activated by acetyl-CoA) and FBPase-1 (which is inhibited by fructose 2,6bisphosphate and AMP) acetyl-Co-A turns off its own production (slows down glycolysis and enhances synthesis of more glucose)

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Regulation of fructose 1,6-bisphosphatase-1 (FBPase-1) and phosphofructokinase-1 (PFK-1) reciprocal allosteric regulation - opposite effects of fructose 6phosphate on PFK-1 and FBPase-1

F-2,6-BP

Regulation of Glycolysis in the Liver

Glucose F-6-P
FBPase2 PFK2 glycolysis PFK1

FBPase1 gluconeogensis

F-1,6 BP

F-2,6 BP Activator of PFK1 Feedforward stimulation

FBP: fructose bisphosphatase

The liver helps maintain bloodglucose levels - stores glucose as glycogen and releases glucose from glycogen. In the liver PFK is inhibited by citrate, a product of the citric acid cycle (a pathway following glycolysis). Citrate acts by enhancing the inhibitory effects of ATP.

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Domain structure of bifunctional enzyme, phosphofructokinase 2

Recall F-6P -> F-2,6-BP catalyzed by PFK-2 F-2,6-BP stimulates PFK F-2,6-BP inhibits fructose1,6-bisphosphatase (FBPase 2) in gluconeogenesis

Bifunctional enzyme

PFK-2

FBPase 2

This enzyme is regulated by phosphorylation of a serine residue.

Control of the Synthesis and Degradation of F-2,6-BP

Glucagon is a hormone that signals for gluconeogenesis to occur.

PKA

Insulin is a hormone that signals for glycolysis to occur.

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increased glycogenolysis increases [glucose]

insulin leads to decreased [glucose]

Figure 8.21 Major Factors Affecting Glycogen Metabolism

Glycogen Metabolism During Exercise or Fasting Red: inactive Blue: active

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Low Glucose in Blood! Epinephrine and Glucagon

The path of insulin to glycogen synthase

insulin turns on glycogenesis, reduces [glucose]

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Overview

Overview

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Low Glucose in Blood! Epinephrine and Glucagon

Liver hydrolyze glycogen to provide glucose in blood. Muscle breakdown glycogen to use it

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