LECTURE 7: Glucose: eat it or make it.

LECTURE 7: Glucose: eat it or make it.

Key Concepts:
Certain tissues of the body, highly dependent on glucose (brain!) blood glucose constant ~ 80 mg/dl (~ 5 mM) excess glucose stored in liver and muscle as glycogen when blood glucose levels drop, liver glycogen is the glucose source during fasting the liver synthesizes glucose to maintain blood glucose levels

WHAT YOU NEED TO KNOW!! You should: understand glycogens structure understand different roles of liver and muscle glycogen stores understand glycogen synthesis and degradation understand roles of glycogen synthase and glycogen phosphorylase be familiar with enzyme defects associated with glycogen storage diseases understand how the liver synthesizes glucose

Reading: (for onon-line testing)

Campbell et al., Biology, 6th/7th ed Benjamin/Cummings

Chapter 5, The Structure and Function of Macromolecules Sugars, the smallest carbohydrates, serve as fuel and carbon sources Polysaccharides, the polymers of sugars, have storage and structural roles Relevant material in Chapter Reviews; including Self Quizzes; Interactive Study Partner (CD) ----------------------------------

Glycogen
Glucose storage in the cytosol, in many tissues Rapidly accessed & water soluble, efficiently accessed But its heavy (associated H20) Only y liver ( (& some kidney) y) g glycogen y g is accessible to other tissues Liver can store 8-10% of wet mass as glycogen Muscles 1-2% (space limits in muscle)?

George Palade

There are different pathways for glycogen synthesis and degradation

Glycogen processes discovered due to diseases (more on this later) (briefly) Mc Ardles disease (glycogen in muscle but severe muscle cramps, due to a lack of glucose release release, no glycogen phosphorylase in muscle)

rest Normal person Light exercise Heavy exercise till exhaustion

McArdles patients p Second wind effect 0 50 100 150 200

[ADP] uM

Figure 7.1: Glycogen Structure

Glycogenin

Victor et al. (2007). Exercise physiology: energy, nutrition, and human performance. Philadelphia: Lippincott Williams and Wilkins. pp. 12.

Glycogen synthesis Gl th i = glycogenesis

Glycogen synthesis - Glycogenesis

Hepatic portal vein

Glucose 6-phosphate

Hexokinase, or glucokinase (liver only) Km 0.1 mM Km 10 mM

Hepatocyte

Hexokinase 1 mM Km V Glucokinase 10 mM Km

[Glucose] mM

Glycogen synthesis - Glycogenesis

Phosphoglucomutase G6P G1P

Glycogen synthase glycogenin

UTP + UDPG pyrophosphorylase Endergonic (i.e. loss of energy)

GS is associated with glycogenin, controls size of granules = UMP (a phosphate from UTP and the phosphate on the G1P makes the bond)

= reducing end

Glucose added to reducing ends, -1-4 glycosidic bonds and -1-6 glycosidic bonds Glycogenesis

Glycogen synthesis - Glycogenesis

6-7 x UDP glucose & glycogen synthase

Branching g enzyme y Amylo(1,41,6)-transglycosylase

Permits dense construction of glycogen Branching makes many termini 97% efficient storage

Branches are created by the transfer of ~7 glycosyl residues Each branch must grow to 11 residues before transfer New branches are 4 residues away, & move into the core

Gl Glycogen b breakdown kd = glocogenolysis

3 enzymes 1) Glycogen Phosphorylase 2) Glycogen de-branching enzyme 3) Phosphoglucomutase

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= non reducing end

Glycogen breakdown = glycogenolysis From the non-reducing ends

Glycogen breakdown Glycogenolysis Glycogen phosphorylase

phosphorylysis

Glucose 1 phosphate Glycogen phosphorylase only works to 5 glycosyl residues Inhibited by ATP, glucose, and G6P

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Phosphorylyisis? Why not hydrolysis?

1) Ensures released glucose is charged and trapped in cells 2) Primed for use by glycolysis (e.g. by muscle) 3) It saves an ATP! (Pi is used)

-1,4 link - 1,6-glucosidase -1,6 link

To core

Debranching enzyme acts as a transferase that transfers 3 units and then hydrolyses the -1,6 link

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Glycogen breakdown - Glycogenolysis

Phosphoglucomutase Glycolysis Pentose phosphate pathway Glucose 1-phosphate Glucose 6- phosphate

Glycogen breakdown - Glycogenolysis

Glucose 6-phosphatase

Blood

Glucose 6-phosphate

Glucose

G6Pase only in the liver and kidneys!

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Animation: Scheme of glycogen synthesis and degradation

UDPG pyrophosphorylase

Maximum recorded speed 117 km/hr, extremely active glycolysis in muscle

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Fig. 7.5 Coordinate control of glycogen metabolism

Stimulated/inhibited by glucagon or epinephrine (aka. adrenalin)

Active

Inactive

From: Biochemistry (5th edition) Berg, Tymoczico and Stryer

Cascade

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Abnormal Glycogen Metabolism

Diabetes, Diabetes Insulin (too little little, too little effect)
Glycogen storage diseases

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Glycogen Storage Diseases

11 known types of GSD Incidence ~ 2.5 children / 100,000 births 7 result in muscle weakness or wastage 5 result in enlarged livers Gierkes Gierke s Disease-most Disease most common (type I GSD) glucose 6-phosphatase mutation

von Gierkes disease

Hypoglycaemia yp g y Excess G6P shunted to triglycerides, hyperlipidaemia Elevated lactate during fasting Gout (hyperuricaemia) E Enlarged l d li liver and d kid kidneys Treatment fructose and other carbohydrates

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What happens when glycogen runs out?

Glycogen depletion, athletes Hitting the wall, caffeine and carbohydrates

In an average resting male

Brain uses 120 g/day gluc Entire body 160 g/day gluc Stores 20 g blood gluc, 190g glycogen 90% gluc used / day, 57% by brain Only O l 10% left l ft at t the th end d of f day d Make glucose! Gluconeogenesis

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Sources of building blocks for gluconeogenesis

Lactate pyruvate/alanine (Cori Cycle) Amino acids (except leucine and lysine) Glycerol (remainder of fats cannot be used in
animals to make glucose)

TCA intermediates ( (conversion to

oxaloacetate/malate)

Fig 7.6: Gluconeogenic precursors

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Gluconeogenesis
Overall gluconeogenesis: g g
2Pyr + 4ATP +2GTP+2NADH + 6H2O Glucose +4ADP +2GDP +2NAD+ + 2H+ + 6Pi

G = -15.6 kJ/mol Using glyconeogenesis G = + 83.7 kJ/mol if glycolysis simply reversed Enough to heat 250ml water to 100oC
Still expensive Investment of 6 ATP If NADH is included~12 ATP equivalents*
* Assumes 3 ATP / NADH

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Parts of gy y glycolysis are reversible Some are not!

Equilibrium versus nonequilibrium enzymes

ubstrate

P
Equilibrium

roduct

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Equilibrium versus NonEquilibrium enzymes

ubstrate

roduct

Non-Equilibrium

Three bypasses

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Fig. 7.7: The gluconeogenic pathway

Bypass 1 (PK)

Cytosol Mitochondrial Pyruvate Kinase

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Bypass 2 (PFK) & 3 (GK, HK)

Gluco/Hexokinase ER

Phosphofructokinase Cytosol

Important gluconeogenic enzymes

Pyruvate carboxylase (bypass I) Phosphoenolpyruvate carboxykinase (PEPCK) (bypass I) Fructose 1,6-bisphosphatase (bypass II) Glucose 6-phosphatase (bypass III)

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Control of gluconeogensis and glycolysis

Gluconeogenesis consumes - 6 ATP Glycolysis makes + 2 ATP mis-match of - 4 ATP Must not run at the same time!

Fructose 6-Phosphate
F 2,6P + AMP + ATP Citrate H+ F 2,6P AMP Citrate +

Fructose 1, 6-Phosphate

Fructose 1, 6-Phosphate
F 2,6P + AMP + ATP Citrate H+ ADP -

O l Oxaloacetate t t Pyruvate
Green means go Red means stop Acetyl CoA + ADP -

Modified from Stryer 4th edition

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Futile cycles can be useful Bumblebees can fly on cold days Honey Bees cannot
Fructose 6-Phosphate

Heat
Fructose 1, 6-Phosphate

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Fuel utilization by a PEPCK-Cmus and control mouse during strenuous exercise.

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