Chapter 15 (abbreviated): Principles of Metabolic

RegulationCHEM 7784

Biochemistry

Professor Bensley

CHAPTER 15 (Abbreviated) Principles of Metabolic Regulation

– Principles of regulation in biological systems – Glycolysis vs. gluconeogenesis – which one is

turned “on” and which one is turned “off”?

Today’s Objectives: (To learn and understand the)

Homeostasis

• Organisms maintain homeostasis by keeping the concentrations of most metabolites at steady state

• In steady state, the rate of synthesis of a metabolite equals the rate of breakdown of this metabolite

Principles of Regulation

• The flow of metabolites through the pathways is regulated to maintain homeostasis

• Sometimes, the levels of required metabolites must be altered very rapidly– Need to increase the capacity of glycolysis during the

action

– Need to reduce the capacity of glycolysis after the action

– Need to increase the capacity of gluconeogenesis after successful action

Feedback Inhibition

• In many cases, ultimate products of metabolic pathways directly or indirectly inhibit their own biosynthetic pathways– ATP inhibits the commitment step of

glycolysis

Factors that Affect the Activity of Enzymes

Some Enzymes in the Pathway Limit the Flux of Metabolites

More than Others

• Hexokinase and

phosphofructokinase

are appropriate

targets for regulation

of glycolytic flux

Elasticity Coefficient Measures the Responsiveness to Substrate

Control of Glycogen Synthesis

• Insulin signaling pathway– increases glucose import into muscle

– stimulates the activity of muscle hexokinase

– activates glycogen synthase

• Increased hexokinase activity enables activation of glucose

• Glycogen synthase makes glycogen for energy storage

UDP-Glucose

Isozymes may Show Different Kinetic Properties

• Isozymes are different enzymes that catalyze the same reaction

• They typically share similar sequences

• Their regulation is often different

Glycolysis vs.

Gluconeo-genesis

Regulation of Phosphofructokinase-1

• The conversion of fructose-6-phosphate to fructose 1,6-bisphosphate is the commitment step in glycolysis

• ATP is a negative effector– Do not spend glucose in

glycolysis if there is plenty of ATP

Regulation of Phosphofructokinase 1 and

Fructose 1,6-Bisphosphatase• Go glycolysis if AMP is high and ATP is low• Go gluconeogenesis if AMP is low

Regulation by Fructose 2,6-Bisphosphate

• F26BP activates phosphofructokinase (glycolytic enzyme)

• F26BP inhibits fructose 1,6-bisphosphatase (gluconeogenetic enzyme)

Regulation by Fructose 2,6-Bisphosphate

• Go glycolysis if F26BP is high• Go gluconeogenesis if F26BP is low

Chapter 15: Summary

• living organisms regulate the flux of metabolites via metabolic pathways by– increasing or decreasing enzyme concentrations

– activating or inactivating key enzymes in the pathway

• the activity of key enzymes in glycolysis and gluconeogenesis is tightly regulated via various activating and inhibiting metabolites

In this chapter, we learned that: