STEROID & THYROID
HORMONES
UNIQUE PROBLEMS IN DELIVERY &
PROCESSING
INTRODUCTION:
• TYPES AND ORIGINS
• SYNTHESIS: STEROIDS, T3/ T4
• CARRIER MOLECULES (BOUND VS. UNBOUND)
• LISTING OF SOME IMPORTANT TYPES
• RECEPTORS & MECHANISMS OF ACTION
STERIOD HORMONES
(DERIVED FROM CHOLESTEROL)
TYPES
EVEN THOUGH THERE ARE LITERALLY HUNDREDS
OF DIFFERENT STEROIDAL HORMONES SYNTHESIZED
IN THE BODY, THEY CAN ALL BE CLASSIFIED INTO THE
FOLLOWING GENERAL CATEGORIES:
GLUCOCORTICOIDS: SUPPORT INCREASED METABOLISM
OF CARBOHYDRATES, LIPIDS AND PROTEINS AS WELL
AS INFLAMMATORY REACTIONS AND STRESS COPING.
MINERALOCORTICOIDS: REGULATE SALT RECOVERY
AND WATER VOLUME (VIA THE KIDNEYS).
ANDROGENS & ESTROGENS: AFFECT SEXUAL DEVELOPMENT AND FUNCTION AS WELL AS SUPPORT
PREGNANCY.
ORIGINS OF STEROIDAL SYNTHESIS
STEROID SYNTHESIS
HAS BEEN LOCATED
AT THREE MAJOR
LOCATIONS.
SYNTHESIS IS
STIMULATED BY
ACTH.
ORIGINS
STEROIDS ARE MADE FROM CHOLESTEROL
ON THE OUTER MITOCHONDRIAL SURFACE IN THE
ADRENAL GLANDS AND GONADS. THIS IS DONE
UNDER THE INFLUENCE OF ADRENOCORTICOTROPIC HORMONE (ACTH) FROM THE ANTERIOR
PITUITARY GLAND. THE ADRENAL
GLANDS MAKE THREE
STEROIDS:
CORTICOSTERONE,
CORTISOL AND
ANDROGENS. ACTH
IS LARGELY INVOLVED
IN MAKING GLUCOCORTICOIDS (MORE
TO FOLLOW)
STEROID SYNTHETIC PATHWAYS
ESTRA.
TES.
SEE NOTES ON NEXT
TWO SLIDES
NOTES: (DHEA = 5-DEHYDROEPIANDROSTERONE)
1. SYNTHETIC PATHWAYS OCCUR IN THE ADRENAL
CORTEX - DO NOT MEMORIZE STRUCTURES!
2. MUCH OF THE SYNTHESES INVOLVE OXIDATION
AND REQUIRES NADPH (WHERE DOES THAT COME
FROM?)
3. MANY OF THE ENZYMES ARE MEMBERS OF THE
CYTOCHROME P450 FAMILY OF OXIDASES -NOTED INHABITANTS OF MITOCHONDRIA.
4. MAJOR STEROID PRODUCTS ARE UNDERLINED.
5. CORTCOSTERONE (BROWN ARROW) HAS WEAK
MINERALO-GLUCORTICO-LIKE ACTIVITY.
ALDOSTERONE HAS A SIMILAR STRUCTURE & IS
PRODUCED AFTERWARDS (2nd BLUE ARROW).
6. CORTISOL (RED ARROW) IS A GLUCOCORTICOID
CONCERNED WITH ENERGY PRODUCTION.
ALDOSTERONE IS A MINERALOCORTICOID.
P450 ENZYMES
OVER A DOZEN ENZYMES
ARE INVOLVED IN STEROID
SYNTHESIS. THEIR PRINCIPAL
oxidase
FUNCTION IS TO MODIFY THE
TAIL OF THE CHOLESTEROL
MOLECULE. P450 ENZYMES
(IN THE MITOCHONDRIA)
BEGIN BY BREAKING THE TAIL
(AT C20 AND C22) AS SHOWN
BY MIXED FUNCTION OXIDATION.
THE POINT IS THAT NADPH (the desmolase
pentose shunt) & OXYGEN SERVE
TO REMOVE ELECTRONS FROM
CHOLESTEROL TO MAKE THE
FIRST STEROID IN THE PATHWAY.
CHOLESTEROL
Cytochrome
p450
20,22-DIHYROXY
CHOLESTEROL
residue
PREGNENOLONE
GLUCOCORTICOID VS.
MINERALOCORTICOID ACTIVITY
STEROID HORMONES HAVE NUMEROUS EFFECTS ON
CELLULAR FUNCTIONS THAT INCLUDE: METABOLISM,
ION TRANSPORT (WATER RETENTION), IMMUNE
FUNCTIONS AND SEXUAL CHARACTERISTICS. TWO
VERY DOMINANT CHARACTERISTICS ARE GLUCOCORTICO- AND MINERALOCORTICO- FUNCTIONS.
GLUCOCORTICO- FUNCTIONS PRIMARILY INVOLVE
INCREASING THE ENERGY LEVELS OF CELLS (1ST SEEN
AS INCREASING AVAILABLE GLUCOSE). [CORTISOL]
MINERALOCORTICO- FUNCTIONS PRIMARILY INVOLVE
THE RETENTION OF IONS IN THE BLOOD THROUGH
KIDNEY REABSORPTION OF Na+. [ALDOSTERONE]
ANTI-INFLAMMATORY ACTIVITY
IN ADDITION TO THE ACTIVITY MENTIONED, SOME STEROIDS ALSO ARE
ABLE TO REDUCE INFLAMMATION (A PROCESS THAT NORMALLY
PROTECTS AN ORGANISM BY TAKING AWAY CAUSES OF CELL INJURY
AND REMOVING DESTROYED TISSUES AND CELLS). INFLAMMATION,
ALTHOUGH IT HAS SOME PURPOSE, CAN CAUSE INJURY.
CORTISOL, LIKE MOST STEROIDS, HAS COMPLEX EFFECTS ON
METABOLISM, BUT ITS ANTI-INFLAMMATORY EFFECTS ARE WELL
KNOWN. CORTISOL IS A MOLECULE THAT
RESPONDS TO STRESS BY A COMPLEX
SET OF REACTIONS THAT INCLUDE
GLUCOSE MOBILIZATION (INCREASE
IN CIRCULATING GLUCOSE) AND
AN INCREASE IN BLOOD PRESSURE.
IMMUNOLOGICALLY, CORTISOL CAUSES
AN INCREASE IN THE PROLIFERATION
OF T-CELLS THAT DAMPEN IMMUNE
RESPONSES INCLUDING INFLAMMATION.
TRANSPORT
STEROID HORMONES ARE NOTORIOUSLY INSOLUBLE IN
BLOOD. THEY REQUIRE A CARRIER PROTEIN TO MAKE
THEM ENERGETICALLY COMPATIBLE WITH THE AQUEOUS
ENVIRONMENT OF PLASMA. TWO PROTEINS ARE KNOWN
TO TAKE ON THAT ROLE: TRANSCORTIN AND ALBUMIN.
TRANSCORTIN, ON
THE RIGHT, HAS A
MOLECULAR WT.
OF ~45.7 kD. ABOUT
75% OF ALL
CORTISOL BINDS TO
THIS PROTEIN. THE
REMAINDER BINDS
TO ALBUMIN.
HORMONES OF THE THYROID GLAND:
THYROXINE (T4)
AND TRIIODOTHYRONINE (T3)
SYNTHESIS OF T3 & T4
THE THYROID GLAND IS
A BUTTERFLY SHAPED
ORGAN THAT WRAPS
ITSELF AROUND THE
TRACHEA AS SHOWN ON
THE RIGHT (ARROW).
THE SOLE PURPOSE OF THE ORGAN IS TO PRODUCE
THYROID HORMONES THAT ARE INVOLVED IN
ESTABLISHING AND MAINTAINING AN OPTIMAL
METABOLIC RATE FOR THE CELLS IN THE BODY.
CUBOIDAL
EPITHELIAL
CELLS IN THE
GLAND MAKE
AND IODINATE
THYROGLOBULIN, A
LARGE PROTEIN
THAT CONTAINS
TYROSINE
PRECURSORS
FOR T3/ T4.
(SEE ARROW)
IODINATION
OCCURS IN THE
COLLOID SPACE
OUTSIDE THE
CELLS.
THIS SCHEME SHOWS
HOW IODINE IS ADDED
TO TYROSINE ON TG;
THE TYROSINE IS
PIGGYBACKED ONTO
ANOTHER TYROSINE;
AND THE TG IS
HYDROLYSED. NOTE
THE KEY ENZYMES:
IODOPEROXIDASE,
COUPLING
ENZYME, AND TG
PROTEASE.
IODINATED THYROGLOBULIN (TG) IS TAKEN
BACK INTO THE CELL
INTO LYSOSOMES
WHERE THE TG IS
DIGESTED (ARROW).
T3/ T4 IS RELEASED
FROM ITS LYSOSOMES
(ARROW) UNDER THE
“INFLUENCE” OF TSH.
THYROID HORMONES RELEASED INTO THE BLOOD
THE HORMONES ARE CARRIED BY THYROXINE BINDING
GLOBULIN (TBG), THRYROXINE BINDING PREALBUMIN,
AND ALBUMIN.
WHAT HAPPENS WHEN THESE HORMONES
ARRIVE AT THEIR TARGET CELLS?
SINCE THE HORMONES (BOTH STEROIDS AND
THYROID HORMONES ARE LIPID SOLUBLE) THEY
IMMEDIATELY CROSS THE PLASMA MEMBRANE OF
THE CELLS. AT THAT POINT THEY ENCOUNTER AND
ARE BOUND BY A CYTOPLASMIC* RECEPTOR PROTEIN.
*IN SOME CASES, A
NUCLEAR PROTEIN.
DBD
LBD
STEROID
GENERAL SCHEME OF A STEROID/THYROID RECEPTOR
PROTEIN. THE LIGAND TRANSACTIVATION DOMAIN
(LEFT) HAS A VARIABLE LENGTH (RED ARROW).
GENERAL DIAGRAMS OF STEROID RECEPTOR PROTEINS
SHOWING VARIATIONS IN THE TRANSACTIVATION REGIONS
(N-TERMINAL END OF THE PROTEIN)
MECHANISM FOR TRANSCRIPTION
ACTIVATION
IN THIS DIAGRAM, THE LIGAND INDEPENDENT DOMAIN
MUST BE ABLE TO REACH FROM THE ENHANCER
REGION TO THE PROMOTER REGION TO INFLUENCE
TRANSCRIPTION (RED ARROW)
NOTES ON TRANSCRIPTION EFFECTS OF STEROID AND THYROID GLAND
HORMONE, BINDING PROTEINS:
1) THE EFFECTS OF BINDING TO DNA MAY BE EITHER PROMOTIONAL
(ACTIVATING) OR INHIBITORY (SILENCING) TO RNA SYNTHESIS.
2) BINDING MAY TAKE PLACE DOWNSTREAM AS WELL AS UPSTREAM (AT
THE PROMOTER) OF THE CODING (GENE) REGION.
3) THE LENGTH OF THE DOMAIN FROM THE ENHANCER REGION TO THE
ACTIVATING (INHIBITORY) PROMOTER VARIES FROM HORMONE TO
HORMONE.
SUMMARY:
1. STEROID HORMONES FALL INTO THREE GENERAL
CLASSIFICATIONS. THEY ARE MADE IN THE ADRENAL
GLANDS AND SEX ORGANS.
2. CHOLESTEROL IS THE PARENT COMPOUND FOR
STEROIDS THAT ARE PRODUCED BY OXIDATION
IN THE MITOCHONDRIA.
3. CARRIER PROTEINS ARE NEEDED FOR STEROIDS
AND THYROID HORMONES.
4. THYROID HORMONES SUPPORT GENERAL
METABOLISM – SEVERAL FORMS EXIST.
5. STEROID & THYROID HORMONES USE RECEPTOR
PROTEINS THAT ARE TRANSACTIVATORS FOR
RNA POLYMERASE.