Biochemical Endocrinology

8/7/2019 Biochemical Endocrinology

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Overview of Biochemical Endocrinology

Endocrinology is concerned with the study of thebiosynthesis, storage, chemistry, and

physiological function of hormones and with the

cells of the endocrine glands and tissues thatsecrete them.

Definition of Biochemical Endocrinology

The study of the chemistry of endocrine hormonesin living organisms.


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Hormone- "chemical substance secreted by aductless gland into blood that is transported to adistant target organ whose activity it specifically

affects".

Target Tissues- have receptors or specific binding

proteins for each hormone


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Properties of Hormones:

1. They are biosynthesized.2. They operate at vanishingly small

concentrations in blood (10-12 to 10-8 M,

nano-pico).3. They have short half lives.

4. They often exert multipoint control and

operate at a number of target organs;hormones awaken existing potential in targetcells that are preprogrammed to respond.


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5. They are feedback regulated by: (a)themselves, (b) the product(s) of their

action, (c) the central nervous system.


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Chemistrys

There are several chemically distinct classes of hormones:amine(epinephrine), peptide (insulin, glucagon) and steroid

(cortisol).


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Insulin, Glucagon, Epinephrine and Cortisol are theHormones that Control Glucose Homeostasis:


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Hormone Receptors:

Interaction between hormone and receptor forms the "hormonereceptor complex".

Strength of binding is expressed as the dissociation constant Kd,the concentration at which the binding sites are half-saturated.


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Classification of Hormones by Receptor Properties:

Group I: Hormones that bind to intracellular receptors:Glucocorticoids, mineralocorticoids, estrogens, progestins,

androgens, vitamin D, thyroid, retinoic acid

Group II: Hormones that bind to cell surface receptors:

Group IIA: The second messenger is cAMP: vasopressin, glucagon,F-adrenergic catecholamines, somatostatin, opioids.


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Group IIB: The second messengers are IP3 (inositol trisphosphate) / Ca2+

and diacylglycerol (DAG): oxytocin, angiotensin II, E-adrenergic

catecholamines.

Group IIC: The cell surface receptor posses tyrosine protein kinaseactivity (intracellular messenger unknown): insulin, growth factors.

Group IIC': The cell surface receptor recruits soluble tyrosine kinases:growth hormone.

Group IID: The second messenger is cGMP: atrial natiuretic peptide(ANP).


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General Features of Hormone Classes, Group I and Group II:

Feature Group I Group II

Solubility Lipophilic Hydrophilic

Plasma T1/2 Long (Hours to Days) Short (Minutes)

Receptor Location Intracellular Plasma Membrane

Signal Mediator Receptor-Hormone Comp. cAMP,cGMP,Ca2+,IP3,DAG


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Steroid / Thyroid / Retinoic Acid Hormone Actions:

Group I- lipophilic, derived from cholesterol (except thyroid andretinoic acid)

Passively diffuse through the plasma membrane of the target cell toassociate with their receptors.

The hormone-receptor complex is assumed to be the intracellularmessenger

Effects of these hormones are quite specific.

Cell Surface Acting Hormone Action:

Group II: peptide and amine hormones bind to membrane spanningreceptors (7 transmembrane); communicate through secondmessengers, cAMP (Group IIA) or Ca2+ / IP3 / DAG (Group IIB).


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G-Proteins

Review

E = The Effector Protein, Adenylate CyclaseR = Receptor, 7-transmembrane cell surface receptor

Note: once the Effector protein is active the second messenger c-AMP is

produced activating Protein Kinase A and starting a "cascade" of events leadingto transmission of message and physiological / biochemical responses.


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Hormones Functioning via IP3 / Ca2+ and DAG:

PIP2 = Phosphatidylinositol-4,5-bisphosphate

IP3 = Inositol-1,4,5-triphosphate

DAG = Diacylglycerol

PLC = Phospholipase C

PKC = Protein Kinase C

CaM Kinase = Calmodulin Kinase


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[1] hormones bind to receptor

[2] receptor is coupled to phospholipase C by Gp

[3] Phospholipase C splits PIP2 into IP3 and DAG

[4] and [5] IP3 mobilizes intracellular (stored) Ca2+ from the ER foractivation of CAM

[6] and [7] DAG activates protein kinase C which is further activatedby Ca2+

[8]the concerted action of these two kinases elicit cellular responses


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FIGURE 16-6 Diagrammatic overview of biochemical events in mast-cell activation and

degranulation. Allergen crosslinkage of bound IgE results in FcRI aggregation and

activation of protein tyrosine kinase (PTK).

(1) PTK then phosphorylates phospholipase C, which converts phosphatidylinositol-4,5bisphosphate (PIP2) into diacylglycerol (DAG) and inositol triphosphate (IP3).

(2) DAG activates protein kinase C (PKC), which with Ca2+is necessary for microtubular

assembly and the fusion of the granules with the plasma membrane. IP3is a potent

mobilizer of intracellular Ca2+stores.

(3) Crosslinkage ofFcRI also activates an enzyme that converts phosphatidylserine (PS)

into phosphatidylethanolamine (PE). Eventually, PE is methylated to form

phosphatidylcholine (PC) by the phospholipid methyl transferase enzymes I and II (PMT I

and II).

(4) The accumulation of PC on the exterior surface of the plasma membrane causes anincrease in membrane fluidity and facilitates the formation of Ca2+channels. The resulting

influx of Ca2+ activates phospholipase A2, which promotes the breakdown of PC into

lysophosphatidylcholine (lyso PC) and arachidonic acid.


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Clinical Correlate

Bacterial Toxins:

Cholera Toxin

Symptoms: watery stools, vomiting, cyanotic, low blood pressure, rapid / weak

pulseTreatment: IV solution of elctrolytes, tetracycline

Cause: cholera toxin inhibits GTPase preventing breakdown of GTP to GDPand locking the E subunit in the activated state producing a continuousoversupply of cAMP


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Biochemical Endocrinology