The adrenal gland, catecholamine synthesis


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The adrenal gland, catecholamine synthesis

  1. 1. The Adrenal Gland Atif Hassan Khirelsied, Ph.D , Department of Biochemistry Faculty of MedicineInternational University of Africa
  2. 2. The Adrenal Glands• The two adrenal glands are  g located on the anterior  surface above the kidneys. y• Each gland weighs about 6  grams, the left adrenal is  th l ft d li longer and thinner. 
  3. 3. The Adrenal Glands
  4. 4. The Adrenal Glands
  5. 5. The Adrenal GlandsThe adrenal gland is compound gland, comprises The adrenal gland is compound gland comprisestwo different endocrine tissues. Cross sectioning through the adrenal gland reveals a pale medulla in the centre  surrounded by a darker cortex.Each of these two regions produces a distinctly Each of these two regions produces a distinctlydifferent group of hormones.
  6. 6. The cortex• It is the outer part of the gland.• It consists of three concentric  zones of cells, rich in cholesterol.  zones of cells rich in cholesterol• Each zone has a characteristic arrangement of cells and  contains different set of enzymes, thus differ in their  major hormonal products.
  7. 7. The adrenal cortex• Zona glomerulosa glomerulosa,  predominantly secretes  mineralocorticoids (aldosterone). • Zona fasiculata, the main  source of glucocorticoids source of glucocorticoids (cortisol) and androgens.• Zona reticularis, produces  androgens
  8. 8. The Adrenal Gland• The adrenal medulla (AM) is actually an extension of The adrenal medulla (AM) is actually an extension of  the sympathetic NS “special ganglion”. 1. The splenic nerve terminates in the AM, innervates  the chromaffin cells. th h ffi ll 2. Chromaffin cells produce the catecholamines.
  9. 9. The hormones of the adrenal medulla• Chromaffin cells produce the catecholamines. 1. Epinephrine 2. Norepinepherine 3. Dopamine.• Th They are not essential for life. i l f lif• A Are required for adaptation to stress (acute ,  i df d i ( chronic).• Major element for severe stress.
  10. 10. The biosynthesis of catecholamines
  11. 11. The biosynthesis of catecholaminesTyrosine hydroxylase , y yp y ( ) 1. Produces L‐3,4‐dihydroxyphenylalanine (L‐DOPA).  2. Is the rate limitting enzyme. 3 Iron‐containing protein[ferric state(Fe2)] 3. Iron‐containing protein[ferric state(Fe )]. 4. Exists in soluble and particle forms. 5. Uses molecular oxygen. 5 U l l 6. Requires tetrahydrobiopterin (BH4).
  12. 12. The biosynthesis of catecholamines• Tyrosine hydroxylase inhibitors. 1. Feedback inhibited by its products. 1 Feedback inhibited by its products 2. Can be competitively inhibited by tyrosine derivatives  2 Can be competiti el inhibited b t rosine deri ati es ( e.g., α‐methyltyrosine), used for treatment of  pheochromocytoma. pheochromocytoma 3. Can also be inhibited by iron‐chelating agents (e.g.,  3 C l b i hibit d b i h l ti t ( αα‐‐bipyridine). 22‐‐bipyridyl
  13. 13. The biosynthesis of catecholamines• Aromatic L‐amino acid (Dopa)  decarboxylase Synonyms:  – tryptophan decarboxylase,  – 5‐hydroxytryptophan decarboxylase.  It catalyzes several different  decarboxylation reactions: • L‐DOPA to dopamine • 5‐HTP to serotonin • tryptophan to tryptamine
  14. 14. The biosynthesis of catecholamines• Aromatic L‐amino acid (Dopa) decarboxylase 1. Soluble form. 2. 2 Requires pyridoxal phosphate. Req ires pyridoxal phosphate 3. Is competitively inhibited by α‐methyl dopa. 4. Can also be inhibited by halogenated compounds. 5. Anti‐hypertension drugs (methyl dopa, 3‐ hydroxtyramine, α‐methyl tyrosine, metaraminol)  inhibits this enzyme .
  15. 15. The biosynthesis of catecholamines• Dopamine‐β‐hydroxylase (DBH) 1. Converts dopamine to norepinephrine p p p 2. Requires ascorbic acid as e‐ donor. 3. Has Cu in active site.  Has Cu in active site. 4. Use fumarate as modulator
  16. 16. The biosynthesis of catecholamines• Phenylethanolamine‐N‐methyl transferase (PNMT) Phenylethanolamine‐N‐methyl transferase 1. Soluble in cytoplasm. 2. Induced by glucocorticoids. 2 I d db l ti id 3. Uses SAM, methyl donor.
  17. 17. The regulation of catecholamines synthesis 1. Stimulated by splanchnic nerve. 1 Stimulated by splanchnic nerve 2. Increases after acute stress by activation of enzymes. 3. Enzymes are induced by chronic stress (corticoids). 3 En mes are ind ced b chronic stress (corticoids)
  18. 18. The storage, release and uptake of catecholamines• Storage . 1. Stored in the chromaffin granules 2. Associated with ATP‐Mg2+ and Ca2+• Release . 1. By exocytosis (Ca2+‐dependent) 2. Stimulated by cholinergic and β‐adrenergic 3. Inhibited by α‐adrenergic• Uptake. Neuronal uptake of the hormone is necessary for: 1. Conservation of the hormone 2. Termination of signal
  19. 19. The catecholamines receptors• α1 . 1. Acts via calcium. 2. Increases glycogenolysis. 3. Smooth muscle contraction (blood vessels, urinogenital tract). tract)• α2. 1. Inhibits cAMP formation. 2. Smooth muscle relaxation (GIT) 3. Smooth muscle contraction (some vascular beds) 4. Inhibits: 1. 1 lipolysis li l i 2. Renine release 3. Platelets aggregation 4. Insulin secretion
  20. 20. The catecholamines receptors• β1 . 1. Stimulates cAMP formation 2. Stimulates lipolysis 3. Increases mycocardial contraction (rate and force)• β2. 1. Stimulates cAMP formation 2. Increases smooth muscle contraction (bronchi, blood  vessels, GIT and GUT) vessels GIT and GUT) 3. Increases: 1. Hepatic gluconeogenesis p g g 2. Hepatic glycogenolysis 3. Muscle  glycogenolysis 4. Release of insulin, glucagon and renin
  21. 21. Types of adrenergic receptorsReceptor Effectively Effect of Ligand Physiologic Binds Binding Effects α1 Norepinephrine, Norepinephrine Increased free ↑ vasoconstriction. vasoconstriction Epinephrine. calcium ↑ smooth muscle contraction. ↑ skin and visceral ki d i l α2 Norepinephrine, Decreased cyclic arterioles constriction. Epinephrine. AMP ↑ sphincters and pilomotor constriction. ↓ insulin secretion
  22. 22. Types of adrenergic receptorsReceptor Effectively Effect of Ligand Physiologic Binds Binding Effects β1 Epinephrine, E i hi Increased cyclic I d li ↑ h t rate heart t Norepinephrine AMP ↑ heart strength ↑ lipolysis. Β2 Epinephrine Increased cyclic ↑ vasodilatation. AMP ↑ bronchodilatation. ↑ glycogenolysis. l l i ↑ glycolysis ↑ calorigenesis. ↑ relaxation of intestine, uterus and bladder wall.
  23. 23. The catecholamines mechanism of signaling• Binding to β1 and β2 Binding to β1 and β2 . 1. Stimulates G‐proteins coupled to adenylate cyclase.• Binding to α2. 1. Inhibits adenylate cyclase.• Binding to α1. 1. Is coupled to phospholipase C, increases  1 Is coupled to phospholipase C increases phosphoinsitol, DAG and Ca2+.
  24. 24. The catabolism of catecholamines1. Have very short t½ (10‐30 sec)2. Less than 5% is excreted in urine3. Catabolized by: 1. Catechol‐o‐methyl transferase ( h l h l f (COMT)  ) 2. Monoamine oxidase
  25. 25. Catecholamine degradationCOMT = Catechol‐o‐methyl transferase, MAO = Monoamine oxidase, DOPAC = 3,4‐Dihydroxyphenylacetic acid,  MHPG = 3‐Methoxy‐4‐hydroxyphenylglycol , DOPAC = 3 4 Dihydroxyphenylacetic acid MHPG = 3 Methoxy 4 hydroxyphenylglycolDHPG = 3,4 dihydroxyphenylglycol, VMA = Vanillylmandelic acid,  HVA = homovanillic acid (HVA,