biochemistry lect 7 2011 colour 2 slides per page.pdf

8/13/2019 Biochemistry Lect 7 2011 colour 2 slides per page.pdf

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LECTURE 7: Glucose: eat it or make it.

LECTURE 7: Glucose: eat it or make it.

KeyKey Concepts: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


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WHAT YOU NEED TO KNOW!! You should:WHAT YOU NEED TO KNOW!! You should:

understand glycogens structure

understand different roles of liverand muscle

glycogen stores

understand glycogen synthesis and degradation

understand roles of glycogen synthase and glycogen

phosphorylase

glycogen storage diseases

understand how the liver synthesizes glucose

Reading: (for onReading: (for on--line testing)line testing)

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

Chapter 5, The Structure and Function o f Macromolecules

Sugars, the smallest carbohydrates, serve as fuel and

carbon sources

Polysaccharides, the polymers of sugars, have storage

Relevant material in Chapter Reviews; including Self

Quizzes; Interactive Study Partner (CD)

----------------------------------


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GlycogenGlucose storage in the cytosol, in many tissues

Rapidly accessed & water soluble, efficiently accessedBut its heavy (associated H20)

Onl liver & some kidne l co en is accessible to other

tissues

Liver can store 8-10% of wet mass as glycogen

Muscles 1-2% (space limits in muscle)?

George Palade


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There are different pathways for

glycogen synthesis and degradation

diseases (more on this later)

(briefly) Mc Ardles disease (glycogen in

muscle but severe muscle cramps, due to a

,

phosphorylase in muscle)

Normal person

rest

Light exercise

McArdles

patients

Heavy exercise till exhaustion

Second wind effect

0 50 100 150 200

[ADP] uM


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Figure 7.1: Glycogen Structure


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Glycogen synthesis - Glycogenesis

Hepatic

portal vein

Hexokinase, or glucokinase (liver only)

Km 0.1 mM Km 10 mM

Glucose 6-phosphate

Hepatocyte

Hexokinase 1 mM Km

Glucokinase 10 mM Km

[Glucose] mM


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Phosphoglucomutase

G6P G1P

UTP + UDPG pyrophosphorylase

Endergonic (i.e. loss of energy)

Glycogen synthase

glycogenin

= UMP (a phosphate from UTP and the phosphate on the G1P makes the

bond)

GS is associated with glycogenin, controls size of granules

= reducing end

Glycogenesis

Glucose added to reducing ends, -1-4 glycosidic bonds

and -1-6 glycosidic bonds


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6-7 x UDP glucose& glycogen synthase

Branchin enz me

Permits denseconstruction of glycogen

Branching makes many

termini

97% efficient storage

Amylo(1,41,6)-transglycosylase

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


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ycogen rea own

= 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 phosphorylasephosphorylysis

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

To core-1,6 link

transferase that transfers 3 units

and then hydrolyses the -1,6 link


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Glycogen breakdown - Glycogenolysis

Glycolysis

Pentose

phosphate

pathway

Glucose 1-phosphate Glucose 6- phosphate

Glycogen breakdown - Glycogenolysis

Glucose 6-phosphatase

Blood

Glucose 6-phosphate

G6Pase only in the liver and kidneys!

Glucose


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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)

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

Active Inactive

Cascade


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Abnormal GlycogenMetabolism

, ,

Glycogen storage diseases


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Glycogen Storage Diseases

Incidence ~ 2.5 children / 100,000 births

7 result in muscle weakness or wastage

5 result in enlarged livers

-

I GSD) glucose 6-phosphatase mutation

von Gierkesdisease

H o l caemia

Excess G6P shunted to

triglycerides, hyperlipidaemia

Elevated lactate during

fasting

Gout (hyperuricaemia)

n arge ver an neys 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

Stores 20 g blood gluc, 190g glycogen

90% gluc used / day, 57% by brain

n y e a e en o ay

Make glucose! Gluconeogenesis


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Sources of building blocks for

gluconeogenesis

Amino acids (except leucine and lysine)

Glycerol (remainder of fats cannot be used inanimals to make glucose)

TCA intermediates conversion tooxaloacetate/malate)

Fig 7.6: Gluconeogenic precursors


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Gluconeogenesis

Overall luconeo enesis:

2Pyr + 4ATP +2GTP+2NADH + 6H2O Glucose +4ADP +2GDP +2NAD+ + 2H+ + 6Pi

G = -15.6 kJ/mol

Using glyconeogenesis

G = + 83.7 kJ/mol

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 ofl col sis

are

reversible

ome are

not!

Equilibrium versus non-equilibrium enzymes

Equilibrium


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Equilibrium versus Non-

Equilibrium enzymes

Non-Equilibrium

Three bypasses


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Fig. 7.7: The gluconeogenic pathway

Bypass 1 (PK)

Cytosol

Pyruvate Kinase

Mitochondrial


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

Gluco/Hexokinase

Phosphofructokinase

ER

Important gluconeogenicenzymes

Phosphoenolpyruvate carboxykinase

(PEPCK) (bypass I)

Fructose 1,6-bisphosphatase (bypass II)

-


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Control of gluconeogensis and

glycolysis -

Glycolysis makes + 2 ATP

mis-match of - 4 ATP

Fructose 6-PhosphateF 2,6P +

AMP +

ATP -

-

F 2,6P -

AMP -

Citrate +

Fructose 1, 6-Phosphate


H+ -

F 2,6P +

AMP +

ADP -

Pyruvate

xa oace a eATP -Citrate -

H+ -

Modified from Stryer 4th edition

Acetyl CoA+

ADP -

Green means go

Red means stop


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Futile cycles canbe useful

Bumblebees can

fly on cold days

Honey Bees

cannot

Fructose 6-Phosphate


Heat


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Fuel utilization by a PEPCK-Cmus and control

mouse during strenuous exercise.

biochemistry lect 7 2011 colour 2 slides per page.pdf

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