Glycogen Metabolism

We have dealt with glucose catabolism and resynthesis and also the use of other sugars. So far we have not discussed the use of glycogen, the storage form of glucose, nor its synthesis. Glycogen is stored primarily in the muscles, and the liver. Muscles need vast amounts of ATP for contraction, and glycolysis can generate ATP as much as 100 times faster than TCA – sperm also depend on glycolysis for motility. The liver’s glycogen depot is largely used to maintain blood glucose levels.

G-1-P

Glycogen(n)

UDP-GlucoseGlycogen(n-1)

GlycogenolysisGlycogen

SynthesisGlycogen(n-1)

UTPPP 2P

Figure 18-1aStructure of glycogen. (a) Molecular formula.

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Figure 18-3:

The reaction mechanism

of glycogen posphorylase.

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Figure 18-5/8 Reactions catalyzed by debranching / branchingenzymes.

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debranching

branching

Figure 18-4 The mechanism of action of phosphoglucomutase.

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Figure 18-6 Reaction catalyzed by UDP–glucose pyrophosphorylase.

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Synthesis – Step 1

Figure 18-7 Reaction catalyzed by glycogen synthase.

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O

Synthesis – Step 2

Non-reducing end

New non-reducing end

G-1-P

Glycogen(n)

UDP-GlucoseGlycogen(n-1)

GlycogenolysisGlycogen

SynthesisGlycogen(n-1)

UTPPP 2P

Figure 18-9 The control of glycogen phosphorylase activity.

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Figure 18-2a X-Ray structure of rabbit muscle glycogen phosphorylase. (a) Ribbon diagram of a phosphorylase b subunit.

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Carbohydrate metabolism is regulated by hormone signals

• The vital and ancient pathways are under hormone control to coordinate needs of the entire organism

• Glucagon/epinephrine are key regulators as is insulin. We will confine our discussions here to the former scenario, which is relatively clear, at least in liver.

1. Glucagon (liver) or epinephrine (muscle) binds to its receptor.

Signal Transduction –activation of Adenylyl Cyclase

The extracellular hormone signal triggers an internal cascade with large chemical amplification. More about

this later

Figure 18-14: X-ray structures of the catalytic (C) and regulatory (R) subunits of mouse protein kinase A

(PKA).

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C2R2 + 4 c-AMP 2 C + R2(c-AMP)4C R

c-AMP

R-R-x-S/T-y

ATP

Tyr197-P

Figure 18-16X-Ray structure of rat testis calmodulin.Pa

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PhK (αβγδ)4 has MW ~1.3 million

Phosphorylase kinase contains a calmodulin subunit; it is one unit of a heterotetramer complex.

Calmodulin binds calcium (Kd~ 10-7 M) and resulting conformational change activates the enzyme.

Calmodulin has 4 Ca+2 binding sites, each on an “EF hand”.

Calmodulin is used as a Ca2+ sensor in many systems; it is prominent in muscle contraction.

PhK can be activated WITHOUT hormone signal, by the Ca+2 released during muscle contraction.

Glycogen synthase is also

regulated, but INHIBITED, by

phosphorylation

The picture is more complex than for glycogen phosphorylase. At least 11 kinases can phosphorylate GS, and some do it only in a hierarchical order.

Insulin activates GS by slowing or removing phosphate. Glucagon and epinephrine favor phosphorylation and inactivation of GS.

In liver, pyruvate kinase is regulated by phosphorylation

Phosphorylation regulates PFK2/FBP2.

2. Allosteric effectors

1.

3.

(+F6P) (-F6P)

Figure 23-8 Hormonal regulation of [F2,6P].Pa

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Hexokinase and G6-Phosphtase are spatially regulated

Catabolic and anabolic metabolism are co-coordinately regulated in several ways. As G6P accumulates with increased glycogenolysis and gluconeogenesis, and decreased glycolysis, it enters the ER, where it encounters the phosphatase and appropriate transporters.

Other tissues, like the heart, may alter this pattern.

The liver’s response to stress. (b) The participation of two second messenger systems.

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1) cAMP+ glycogenolysis- glycogen synth.

2) IP3, DAG, Ca2+

+ glycogenolysis- glycogen synth.

An activated metabolic system must be able to be inactivated, and vice-versa

The glucagon/epinephrine activated system we have described cannot persist indefinitely. By nature, a hormone SIGNAL is transient. We gave one simple example of how PP1 is partially controlled by the quaternary state of GP. Not surprisingly, thecomplete picture is more complex, but we will not describe it in detail here.

Schematic of enzymatic modification / demodification systems involved in the control of glycogen metabolism in muscle.

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PP1 is regulated in muscle

PKA phosphorylatesglycogen targeting protein GM, and this releases PPIcand renders it inactive.

The Pentose Pathway

• Glucose is anaerobically catabolized to lactate in glycolysis, as we have seen

• The 3-carbon sugars, pyruvate/lactate, can be oxidatively catabolized in the TCA cycle, as we WILL see.

• There is a separate pathway for the oxidation of glucose to CO2. It is quite significant; about 1/3 of glucose in liver is dealt with by the pentose pathway

• The pathway yields NADPH for reductive synthesis and ribose sugars for nucleic acid biosynthesis

Figure 23-25: The pentose phosphate pathway.

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Figure 23-26 The glucose-6-phosphate dehydrogenase reaction.

Stage 1 - Pentose phosphate pathway.

1

Figure 23-27 The phosphogluconate dehydrogenase reaction.

Stage 1 - Pentose phosphate pathway.

1

Enolate stabilization-fancy that!

The isomerase and epimerase work through enediolateswhere protons are removed from carbons α to a carbonyl.

Ribulose-5-phosphate isomerase and ribulose-5-phosphate epimerase

Stage 3 - The pentose phosphate pathway.

3

Figure 23-29 Mechanism of transketolase.

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C5 + E-TPP C3 + E-TPP-2C

C5 + E-TPP-2C C7 + E-TPP

C-C bond cleavage requires carbanionstabilization by thiazole

Carbanion (2 carbons) carries out nucleophilic attack on 5 carbon aldehyde.

Figure 23-30 Mechanism of transaldolase.

C7 + E-Lys C4 + E-Lys-C3

C3 + E-Lys-C3 C6 + E-Lys

Here, imine serves as sink for carbanionduring C-C bond cleavage

Unlike glycolysis, or TCA, the Pentose Pathway is more like a network than a path. Depending on cellular needs it may operate in different fashions, where NADPH production, or ribose synthesis, or even energy production is temporarily paramount.