By

Dr Khaled S. Algariri

MOLECULAR ENDOCRINOLOG

Y -2-

BIOSYNTHESIS OF HORMONES

Most commonly, hormones are categorized into four structural groups:

Peptides and ProteinsSteroidsAmino Acid Derivatives Fatty Acid Derivatives

1. Peptide and Protein 1. Steroids 1. Amino acid derivatives

1. Fatty acid derivatives

Insulin Testosterone Epinephrine Eicosanoids-prostaglandins, prostacyclins, leukotrienes and thromboxanes.

Glucagon Estrogen Nor-epinephrine

ACTH Progesteron Thyroxine

TSH Cortisol

Thyrotropin releasing hormone

Aldosteron

1- Peptides and Proteins Hormones Biosynthesis

Protein and peptide hormones are encoded in genes, with each hormone usually represented only once in the genome. The genes are transcribed in the nucleus and undergo transcriptional processing to yield mature mRNA, which is then transported from nucleus to the cytoplasm. On export from the nucleus, the mRNA transcripts attach to ribosomes, where they are translated into protein.

Several important peptide hormones are secreted from the pituitary gland. The anterior pituitary secretes three: prolactin, which acts on the mammary gland; adrenocorticotropic hormone (ACTH), which acts on the adrenal cortex to regulate the secretion of glucocorticoids; and growth hormone, which acts on bone, muscle, and the liver. The posterior pituitary gland secretes antidiuretic hormone, also called vasopressin, and oxytocin

Protein/Peptide hormones are synthesized in endoplasmic reticulum, transferred to the Golgi and packaged into secretory vesicles for export. They can be secreted by one of two pathways:

Regulated secretion: The cell stores hormone in secretory granules and releases them in "bursts" when stimulated. This is the most commonly used pathway and allows cells to secrete a large amount of hormone over a short period of time.

Constitutive secretion: The cell does not store hormone, but secretes it from secretory vesicles as it is synthesized

2-Steroid hormones

Steroid hormones are not water soluble so have to be carried in the blood complexed to specific binding globulins.

Corticosteroid binding globulin carries cortisol

Sex steroid binding globulin carries testosterone and estradiol

In some cases a steroid is secreted by one cell and is converted to the active steroid by the target cell: an example is androgen which secreted by the gonad and converted into estrogen in the brain

Steroid HormonesSteroid hormones are nonpolar (no net

charge), and can thus diffuse across lipid membranes (such as the plasma membrane). They leave cells shortly after synthesis.

phospholipid

Polar substances are water soluble (dissolve in water), nonpolar substances are lipid soluble.

Functions of Steroid HormonesSteroid hormones play important roles

in:- carbohydrate regulation (glucocorticoids)- mineral balance (mineralocorticoids)- reproductive functions (gonadal steroids)

Steroids also play roles in inflammatory responses, stress responses, bone metabolism, cardiovascular fitness, behavior, cognition, and mood.

How does the synthesis of steroids differ from that of peptide hormones?

• While peptide hormones are encoded by specific genes, steroid hormones are synthesized from the enzymatic modification of cholesterol.

• Thus, there is no gene which encodes aldosterone, for example.

• As a result:- There are far fewer different types of steroid

hormones than peptide hormones.- Steroid structures are the same from species to

species- The regulation of steroidogenesis involves control of

the enzymes which modify cholesterol into the steroid hormone of interest.

The Role of Cholesterol in Steroid Synthesis

The first enzymatic step in the production of ANY steroid hormone begins with enzymatic modification of cholesterol

Sources of Cholesterol for Steroid SynthesisCholesterol can be made within the cell from

acetyl CoA (de novo synthesis).This is a multistep process, involving many

enzymatic reactions.A key rate-limiting enzyme is HMG-CoA

reductase.There is negative feedback regulation of

HMG-CoA reductase activity by cholesterol, so that high intracellular cholesterol inhibits de novo synthesis.

acetyl CoA HMG-CoA mevalonate cholesterolHMG-CoA reductase

Sources of Cholesterol for Steroid SynthesisCholesterol is also taken up by the cell in

the form of low density lipoprotein (LDL).- LDL is a complex composed of cholesterol, phospholipids, triglycerides, and proteins (proteins and phospholipids make LDL soluble in blood).- LDL is taken into cells via LDL receptors, and broken down into esterified cholesterol, and then free cholesterol:

LDLreceptor

LDL esterified cholesterol free cholesterol

The amount of free cholesterol in the cell is maintained relatively constant:

Source of Cholesterol for Steroid Synthesis

steroid synthesis

freecholesterol

level

esterified cholesterol level

cellular synthesisof cholesterol

LDL

Cellular Localization of Cholesterol Metabolism for Steroid Production

The first enzymatic step in steroid synthesis is the conversion of cholesterol into pregnenolone.

The enzyme that catalyzes this reaction is located in the inner mitochondrial membrane.

Steroid hormone synthesisAll steroid hormones are derived from cholesterol. A series of enzymatic steps in the mitochondria and ER of steroidogenic tissues convert cholesterol into all of the other steroid hormones and intermediates.

The rate-limiting step in this process is the transport of free cholesterol from the cytoplasm into mitochondria. This step is carried out by the Steroidogenic Acute Regulatory Protein (StAR)

Transport of CholesterolCholesterol is lipid soluble, and mostly located

associated with the external mitochondrial membrane.

The conversion of cholesterol to steroids occurs in the internal mitochondrial membrane.

Now, to see if you have been paying attention…How does cholesterol get from the external

membrane to the internal membrane?Answer: Steroidogenic acute regulatory protein

(StAR), which transports cholesterol into the mitochondria, moving it from the outer membrane to the inner membrane.

3. Amino Acid DerivativesThere are two groups of hormones derived from

the amino acid tyrosine:Thyroid hormones are basically a "double"

tyrosine with the critical incorporation of 3 or 4 iodine atoms.

Catecholamines include epinephrine and norepinephrine, which are used as both hormones and neurotransmitters.

The pathways to synthesis of these hormones is provided in the sections on the thyroid gland and the adrenal medulla.

The circulating halflife of thyroid hormones is on the order of a few days. They are inactivated primarily by intracellular deiodinases. Catecholamines, on the other hand, are rapidly degraded, with circulating halflives of only a few minutes.

Two other amino acids are used for synthesis of hormones:

Tryptophan is the precursor to serotonin and the pineal hormone melatonin

Glutamic acid is converted to histamine

4. Fatty Acid Derivatives - Eicosanoids

Eicosanoids are a large group of molecules derived from polyunsaturated fatty acids. The principal groups of hormones of this class are prostaglandins, rostacyclins, leukotrienes and thromboxanes.

Arachadonic acid is the most abundant precursor for these hormones. Stores of arachadonic acid are present in membrane lipids and released through the action of various lipases. The specific eicosanoids synthesized by a cell are dictated by the battery of processing enzymes expressed in that cell.

These hormones are rapidly inactivated by being metabolized, and are typically active for only a few seconds

Mechanism of Hormone actionThe hormones fall into two general classes based on

their solubility in water. 1. Hydrophilic Hormone: The water soluble

hormone. They are transported simply dissolved in blood

Examples: the catecholamines (epinephrine and norepinephrine) and peptide/protein hormones.

2. Lipophilic Hormone: They are poorly soluble in water. So they cannot be dissolved in watery blood. They bind to plasma protein and present in the blood in protein bound form. They are lipid soluble.

Examples: The lipid soluble hormones include thyroid hormone, steroid hormones and Vitamin D3

Types of ReceptorsTo initiate their effect, hormones must bind with the target cell

receptor. Interaction between hormone and target receptor produce transduction and amplification of signal leading to cellular response. The mechanism of hormone action depends on type of receptor and also on the solubility of hormone.

1. Cell Surface Receptors: Receptors for the water soluble hormones are found on the surface of the target cell, on the plasma membrane. These types of receptors are coupled to various second messenger systems which mediate the action of the hormone in the target cell.

2. Cytosolic or Intracellular receptors: Receptors for the lipid soluble hormones reside in the nucleus (and sometimes the cytoplasm) of the target cell. Because these hormones can diffuse through the lipid bilayer of the plasma membrane, their receptors are located on the interior of the target cell

General means of hydrophilic and lipophilic Hormone action1. Surface binding hydrophilic hormone acts

largely via activating 2nd messenger pathways. This leads to a series of events involving protein kinases/or phosphatases and finally acting on target enzyme so as evoke cellular response.

2. Lipophilic hormone function mainly by activating through the nuclear gene affecting transcription. It leads to formation of proteins for desired cellular response.

I. Types of cell surface receptor1. Ion-channel coupled receptor2. The G-Protein coupled receptor(GPCR

mediated hormone response)2.1. C-AMP System- elaborate with

example of Epinephrine2.2. The calcium ion: calmodulin system3. Enzyme coupled receptor mediated

hormone response3.1. Tyrosine kinase receptor-elaborate

with example of insulin

Signal amplification vi 2nd messenger pathways

Initial signal is in the form of hormone which acts as ligand whose concentration is just one/per receptor. The hormonal response has got multiple steps, and each step multiplies the signal (cascading effect) that finally leading to million fold amplification, i.e. one hormone molecule mediating its effect through million of molecules. This process is known as signal amplification.

STEPS OF ACTION OF HORMONES

Step1: Free lipophilic hormone (hormone not bound with its plasma protein carrier) diffuses through the plasma membrane of the target cell and binds with the receptor which is intracellularly located inside the cytosol/or in the nucleus.

Step2. Each receptor has specific binding region with hormone and another region with binding with DNA. Receptor alone cannot bind to DNA unless it binds to hormone. Once the hormone is bound to receptor, the hormone receptor complex binds to specific region of DNA known as Hormone response element(HRE).

Step3: Transcription of geneStep4: m RNA transported out of nucleus into the cytoplasmStep5: Translation at RibosomeStep6: Protein/enzyme released from ribosomeStep7: protein/enzyme mediate ultimate response

Steroid Hormones: Molecular Action

Lipophilic hormone response mediated through Cytosolic receptor/nuclear receptor

Mechanism of thyroid hormone actionReceptors for thyroid hormones are nuclear

and its affinity is tentimes higher for T3 than T4 The amount of nuclear receptors is very lowFour variants of nuclear receptor were

observed and mitochondrial receptor for T3 was also described

Free thyroid hormone receptor (TR) without bound hormone is bound to hormone response element of DNA (HRE) and corepressor (CoR)

After binding T3 to receptor - CoR is liberated and coactivators (CoA) is bound and the transcription to mRNA begins

Mechanism of thyroid hormone receptor action. The thyroid hormone receptor (TR) and retinoid X receptor (RXR) form heterodimers that bind specifically to thyroid hormone response elements (TRE) in the promoter regions of target genes. In the absence of hormone, TR binds co-repressor (CoR) proteins that silence gene expression. The numbers refer to a series of ordered reactions that occur in response to thyroid hormone: (1) T4 or T3 enters the nucleus; (2) T3 binding dissociates CoR from TR; (3) Coactivators (CoA) are recruited to the T3-bound receptor; (4) gene expression is altered.

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