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Biochemistry I Fall Term, 2004 December 10, 2004

Lecture 34: Integrated Metabolism

Assigned reading in Campbell: Chapter 21.1-21.4

Key Terms:

Homeostasis

Hormonal control:

Insulin

Glucagon

Epinephrine (Adrenaline)

Second messenger

Adenyl cyclase & cAMP

Protein kinase A

Phosphorylase kinase

Phosphoprotein phosphatase

Links:

(I) Review Quiz on Lecture 34 concepts

(I) Phosphorylation Cascade: Class Handout

(S) Signaling via G Proteins Flash tutorial: how receptor binding leads to cAMP synthesis.

Nutrition

Macronutrients: balanced intake is important, e.g. amino acid composition of diversefood sources.

Micronutrients: vitamins and minerals are required in small amounts as coenzymes andcofactors (Table 21.1).

Tables of DV's (RDA's) are only guidelines.The human population is genetically and metabolically diverse.

Update: Leptin (p. 696) was shown recently to be ineffective in controlling obesity.Hormones (acting in carbohydrate metabolism)

Hormones maintain homeostasis in an organism and effect communication betweendifferent and distant organs and tissues.

Hormones act by binding to specific receptors on (or within) target cells. Receptor binding causes the synthesis of an intracellular second messenger, e.g. cAMP. cAMP activates protein kinase(s).

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The following material is an overview of insulin, glucagon, and epinephrine action on glycogen

synthesis and breakdown. It is repeated from the Lecture 30 notes. (See also Campbell Figs. 21.9

and 21.10)

Hormonal Regulation of Protein Kinases and Protein Phosphatases.

Pancreas Adrenal Gland

cells cells

Insulin(high blood sugar)

Glucagon(low blood sugar) Epinephrine (Adrenalin)

Glycogen synthesis Glycogen catabolism

Steps in the activation of Glycogen Phosphorylase

Glucagon and/or epinephrine (adrenalin) bind to receptors on the surface of liver andmuscle cells.

The receptor-ligand (ligand = glucagon, epinephrine) complex activates adenyl cyclase. Adenyl cyclase converts ATP to cAMP (cAMP = 3',5'-cyclic AMP).

cAMP is called a "second messenger".

cAMP activates protein kinase A. Protein kinase A phosphorylates:

1. phosphorylase kinase (activating kinase activity).

2. glycogen synthase (inactivating it).

Phosphorylase kinase phosphorylates glycogen phosphorylase, activating it. Phosphoprotein phosphatase (which would remove phosphates) is also phosphorylated to

inactivate it.

P OO

O

O NO

N

N

OHOH

N

NH2

P

O

OO

O

NO

N

N

OH

N

NH2

AMP cAMP

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Steps in the activation of Glycogen Synthase

To reverse the above effects we need to dephosphorylate the proteins that were phosphorylated

in the above reactions. This occurs by activation of phosphoprotein phosphatase. This enzyme

removes phosphate groups from proteins.

During glycogen degradation, phosphoprotein phosphatase is inactive because:

a. It is not phosphorylated on the correct location.b. It is complexed with glycogen phosphorylase.

Phosphoprotein phosphatase becomes activated during glycogen synthesis because:

a. Phosphorylation by insulin-stimulated protein kinase activates it.b. Binding of glucose to glycogen phosphorylase releases phosphoprotein phosphatase.

Once activated phosphoprotein phosphatase does the following:

1. Removes the phosphate group from glycogen phosphorylase, inactivating it.2. Removes phosphate group from phosphorylase kinase, inactivating it.3. Removes phosphate group for glycogen synthase, activating it.

cAMP is hydrolyzed to AMP by a specific phosphodiesterase. The destruction of the

"messenger" is necessary to reset the system to its normal metabolic state and to make it

responsive to the next set of homonal signals. Two classic stimulants:

N

NN

N

O

O

CH3

CH3

CH3

N

NN

NH

O

O

CH3

CH3

Caffeine Theophylline

found in coffee (caffeine) and tea (theophylline) inhibit the phosphodiesterase. Other things

being equal, this keeps cAMP levels higher than normal and accounts for some of the effects of

these "uncontrolled drugs".

10.25.04