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Zinc

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  • In ancient India the production of zinc metal was very common. Many mine sites of Zawar Mines, near Udaipur, Rajasthan;- Zawarmaala were active even during 1300-1000 BC. There are references of medicinal uses of zinc in the Charaka Samhita (300 BC). The Rasaratna Samuccaya (800 AD) explains the existence of two types of ores for zinc metal, one of which is ideal for metal extraction while the other is used for medicinal purpose. [ citation needed ] Zinc alloys have been used for centuries, as brass goods dating to 1000 – 1400 BC have been found in Israel and zinc objects with 87% zinc have been found in prehistoric Transylvania . Because of the low boiling point and high chemical reactivity of this metal (isolated zinc would tend to go up the chimney rather than be captured), the true nature of this metal was not understood in ancient times. The manufacture of brass was known to the Ebi by about 30 BC , using a technique where calamine and copper were heated together in a crucible. The zinc oxides in calamine were reduced, and the free zinc metal was trapped by the copper, forming an alloy . The resulting calamine brass was either cast or hammered into shape. Smelting and extraction of impure forms of zinc was accomplished as early as 1000 AD in India and China . In the West, impure zinc as a remnant in melting ovens was known since Antiquity, but usually discarded as worthless. Strabo mentions it as pseudo-arguros — "mock silver". The Berne zinc tablet is a votive plaque dating to Roman Gaul , probably made from such zinc remnants. Metallic zinc in the West The English metallurgist Libavius received in 1597 a quantity of zinc metal in its pure form, which was unknown in the West before then. Libavius identified it as Indian/Malabar lead. Paracelsus ( 1516 ) was credited with the name "zinc". It was regularly imported to Europe from the orient in the 17th century , but was at times very expensive. The isolation of metallic zinc in the West may have been achieved independently by several people: Dr John Lane is said to have carried out experiments, probably at Landore , prior to his bankruptcy in 1726 . Postlewayt 's Universal Dictionary, the most authentic source of all technological information in Europe, did not mention zinc before 1751. In 1738 , William Champion patented in Great Britain a process to extract zinc from calamine in a smelter, using a technology somewhat similar to that used at Zawar zinc mines in Rajasthan . However, there is no evidence that he visited the orient. [2] The discovery of pure metallic zinc is also often credited to the German Andreas Marggraf , in the year 1746 , though the whole story is disputed. [ citation needed ] Before the discovery of the zinc sulfide flotation technique, calamine was the mineral source of zinc metal. Foods and spices that contain the essential mineral zinc
  • Oyster > 70 mg per serving Meats =2-3 mg per 100g Shellfish =2.7 mg per 100 g
  • The main mechanism for zinc uptake from the intestinal lumen is with ZIP4 (SLC39A4), a member of the ZIP family .This transporter is expressed at the luminal side of enterocytes through the small and large intestine.A related protein, provisionally designated hoRF1 , may contribute to zinc uptake from the colon. Genetic variants of this gen are associated with the rare familial condition acrodermatitis enteropathica. The proton coupled divalant cation transporter 1 ( DMT1 ,SLCA11A2)appears to provide a minor uptake route. DMT1 also transports iron, copper, cadmium and other divalent metal ions that may compete with zinc. Hydrogen ion/peptide cotransporter (PepT,SLC15A1) is a posible alternative route for zinc uptake when complex to small peptides.uptake as a complex with individual amino acids may explain why histidine and cysteine improve intestinal zinc absorption. Metallothinein regulates zinc transfer into portal blood through binding and retaining it within the enterocyte until shedding into the intestinal lumen. Zinc is exported from enterocytes into portal blood by transporters 1 (ZnT-1,SLC30A1) and 2 (ZnT-2,SLC30A2).ZnT-1 is upregulated when zinc intake is high. With increasing intra luminal concentrations, net zinc movement across the tight junctions of the epithelial lyer(paracellular pathway) becomes more significant.regulatory mechanisms involving DMT1 or metallotionein thus are bypassed when high-dose supplement are ingested.
  • Alcohol dehydrogenase uses two molecular tools to convert ethanol to acetaldehyde. The first is a zinc atom which is used to hold and position the alcohol group on ethanol. The second is a large NAD cofactor, which actually performs the reaction. The molecule on the left contains ethanol molecules bound to the two active sites. The ethanol, shown in green and magenta, binds to the zinc and is positioned next to the NAD cofactor. A hydrogen binds to the ethanol carbon and the zinc polarizes the oxygen of the alcohol group. The ethanol carbon loses a hydrogen to NAD and is now acetaldehyde.
  • Picture:Cartoon representation of the protein Zif268 (blue) containing three zinc fingers in complex with DNA (orange). The coordinating amino acid residues of the middle zinc ion (green) are highlighted.
  • Clinical information abstracted from the presentation by Anneli Bowen, M.D., Glen Bowen, M.D., and Payam Tristani, M.D. of the University of Utah Department of Dermatology They also provided the clinical photographs. April 2000 This 68 year male, with a history of arterial insufficiency of the lower extremities, was admitted for the evaluation of non-healing ulcers. There is a history of 'blisters' preceding the ulcers. There is a history of alcohol abuse in the past but not recently. His wife indicated that he eats well. There is no history of inflammatory bowel disease. There is an unexplained recent history of  thirty pound weight loss. Physical examination revealed erythema, blisters, pustules, ulcers, and weeping yellowish areas of both lower extremities. Following two biopsies and the demonstration of abnormally low zinc levels on two occasions, the patient was placed on zinc supplementation. Levels of niacin, glucagon, and folate were normal. All of his lesions, with the exception of the ulcers, disappeared over a two week period.  The persistence of the ulcers (one of which went into his Achilles tendon) and continued poor perfusion in spite of a right femoral artery bypass prompted the surgeons to amputate both legs. The histology of the skin from the amputation specimens (away from the ulcers) was normal. The cause for his zinc deficiency is not explained.  
  • DISCUSSION Acrodermatitis enteropathica is classically a disease of infancy or childhood related to the malabsorption of zinc. Zinc deficiency can be an acquired condition in adults as a result of inflammatory bowel disease or as a result of nutritional deprivation of zinc. Eczematous, psoriasiform, and vesicular lesions have been described, and most of these occur in acral locations and, sometimes, additionally on the face. The dermatosis ('nutritional dermatosis') associated with zinc deficiency is stated to have the same pathology as that associated with niacin deficiency and that which is associated with the glucagonoma syndrome (necrolytic migratory erythema). Pallor of the superficial keratinocytes is seen in each of these. Spongiosis, infiltrates of polymorphonuclear leukocytes, intracellular edema, and intraepidermal vesicle formation have been described. It is likely that a variety of pathologic patterns may be observed as counterparts to the variety of clinical lesions observed.
  • Transcript

    • 1. B io l o g ic a l F u n c t io n o f Z in cIs f a h a n U n iv e r s it y o f M e d ic a l S c ie n c e , S c h o o l o f P ha rma c y D e p a r t m e n t o f C lin ic a l B io c h e m is t r y
    • 2. B io l o g ic a l F u n c t io n o f Z in c Z in c B io lo g y (An o v e r v ie w )B y :e 2 6 ., N0 .1 2E m a m i R a z a v i Ju n A 2 T o t a l s l id e s : 7 8 2
    • 3. B io l o g ic a l F u n c t io n o f Z in c Outlines  Introduction  Sources, requirement and homeostasis  Zinc deficiency  Zinc toxicity  Biolochemical functions of zinc  Molecular biology of zinc  Immunological & Endocrinological Functions of zinc  Case report (acrodematitis enteropathica)Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 3
    • 4. B io l o g ic a l F u n c t io n o f Z in c Z in c In t r o d u c t io nJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 4
    • 5. B io l o g ic a l F u n c t io n o f Z in c  In ancient India the production of zinc metal was very common. Many mine sites of Zawar Mines, near Udaipur, Rajasthan;-Zawarmaala were active even during 1300-1000 BC. There are references of medicinal uses of zinc in the Charaka Samhita (300 BC). The Rasaratna Samuccaya (800 AD) explains the existence of two types of ores for zinc metal, one of which is ideal for metal extraction while the other is used for medicinal purpose.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 5
    • 6. B io l o g ic a l F u n c t io n o f Z in c Pure metallic zinc was discovered by Andreas Marggraf (Germany) in 1 746  Atomic number: 30  Atomic weight: 65.409  Valency: +2  Group #: 12  Periodic #: 4  State: solid metal at room temperature  Isotopes: 21 isotopes (5 stable and 16 unstable)Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 6
    • 7. B io l o g ic a l F u n c t io n o f Z in c Appearance Bluish pale grayJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 7
    • 8. B io l o g ic a l F u n c t io n o f Z in c What is zinc?  Zinc is an essential mineral that is found in almost every cell. It stimulates the activity of approximately 300 enzymes, which are substances that promote biochemical reactions in the body. Zinc supports a healthy immune system , is needed for wound healing , helps maintain the sense of taste and smell , and is needed for DNA synthesis . Zinc also supports normal growth and development during pregnancy, childhood, and adolescence .Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 8
    • 9. B io l o g ic a l F u n c t io n o f Z in c Z in c S ourc e s , R e q u ie r m e n t & H e m o s t a s isJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 9
    • 10. B io l o g ic a l F u n c t io n o f Z in c Sources Foods contain element zinc, much of it bound to protein or DNA.  Oysters (> 70 mg per serving).  Meats (2-3 mg/100g).  Shellfish (2.7 mg/100g)  Other good food sources include:  beans, nuts, certain seafood, whole grains, fortified breakfast cereals, and dairy products .Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 1 0
    • 11. B io l o g ic a l F u n c t io n o f Z in c  Zinc absorption is greater from a diet high in animal protein than a diet rich in plant proteins . Phytates, which are found in whole grain breads, cereals, legumes and other products, can decrease zinc absorption .Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 1 1
    • 12. B io l o g ic a l F u n c t io n o f Z in c RDAJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 1 2
    • 13. B io l o g ic a l F u n c t io n o f Z in c Absorption  GIT modulates the quantity of exogenous dietary zinc absorbed and the quantity of endogenous zinc excreted  More than 70% of a small zinc dose (less than 3 mg) is absorbed from the small intestine.  Maximum absorption occurs in duodenum  There is sustained release from enterocytes into portal circulation for ~ 9hJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 1 3
    • 14. B io l o g ic a l F u n c t io n o f Z in c Fractional Absorption  Inversely proportional to the amount of zinc in the meal  Does not depend on the ‘zinc status’ of the body  Increased by breast milk; Decreased by phytates  Protein hydrolysates and some amino acids, particularly histidine and cysteine, increase fractional zinc absorption.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 1 4
    • 15. B io l o g ic a l F u n c t io n o f Z in c Transport and cellular uptake  ZIP4 (SLC39A4), a member of the ZIP family .  This transporter is expressed at the luminal side of enterocytes through the small and large intestine.  hoRF1, may contribute to zinc uptake from the colon.  Genetic variants of this gen are associated with the rare familial condition acrodermatitis enteropathica.  DMT1,(SLCA11A2)  The proton coupled divalant cation transporter 1 appears to provide a minor uptake route. DMT1 also transports iron, copper, cadmium and other divalent metal ions that may compete with zinc.  PepT,(SLC15A1)  Hydrogen ion/peptide cotransporter is a posible alternative route for zinc uptake when complex to small peptides.uptake as a complex with individual amino acids may explain why histidine and cysteine improve intestinal zinc absorption.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 1 5
    • 16. B io l o g ic a l F u n c t io n o f Z in c  Metallothinein  Regulates zinc transfer into portal blood through binding and retaining it within the enterocyte until shedding into the intestinal lumen.  Zinc transporters  Zinc is exported from enterocytes into portal blood by Zinc transporters 1 (ZnT-1,SLC30A1) and 2 (ZnT-2,SLC30A2).ZnT-1 is upregulated when zinc intake is high.  Paracellular pathway  With increasing intra luminal concentrations, net zinc movement across the tight junctions of the epithelial layer becomes more significant. Regulatory mechanisms involving DMT1 or metallotionein thus are bypassed when high-dose supplement are ingested.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 1 6
    • 17. B io l o g ic a l F u n c t io n o f Z in c Intestinal zinc absorptionJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 1 7
    • 18. B io l o g ic a l F u n c t io n o f Z in c Excretion  Routes: intestine, kidneys, integument, and semen  After a meal, maximum zinc secretion occurs through pancreatobiliary secretions  Maximum reabsorption occurs from mid-jejunum and ileum  Total amount excreted = Amount secreted – Amount reabsorbed  Excretion of endogenous zinc by the intestine depends on the ‘zinc status’ of the body.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 1 8
    • 19. B io l o g ic a l F u n c t io n o f Z in c Regulation  Metallothionein expression  The most important mechanism for maintaining zinc adequacy.  Increased expression in the small intestine decreases intestinal absorption  Increased expression in the liver expands stores.  Metallothionein expression is induced by the metal response element-binding transcription factor-1(MTF-1)  MTF-1 is bind to multiple metal response elements of the metallothionein promoters when the free zinc ion concentration is high.  MTF-1 also induces expression of ZnT-1Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 1 9
    • 20. B io l o g ic a l F u n c t io n o f Z in c Metallothioneins  Major Zn2+ binding protein in mammalian systems is metallothionein (MT)  MT contain Zn2+ coordinated to Cys by mercaptide bonds  Binding of Zn2+ by MT depends on the redox state of the cell – oxidization releases Zn2+ from MT and vice versa.  Zn2+ + Apothionein → MetallothioneinJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 20
    • 21. B io l o g ic a l F u n c t io n o f Z in c Cellular Zn2+ sensors  The cellular Zn2+ sensor is MTF-1 (Metal response element binding transcription factor-1)  Intracellular Zn2+ binds to MTF-1  Zn-MTF-1 binds to MRE and increases transcription of Metallothionein and ZnT1 mRNA.  MT binds intracellular Zn2+ and removes it from the free pool.  ZnT1 increases Zn2+ efflux from cellsJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 21
    • 22. B io l o g ic a l F u n c t io n o f Z in c Compartments: Endogenous Zinc Pools (EZP)  Plasma  75% of Zn2+ is bound to albumin and 20% to α2-macroglobulin.  Most of the remaining Zn2+ is complexed to His & Cys rich proteins.  The free Zn2+ concentration of serum is in nM range.  Rapidly Exchanging Pool/ Endogenous Zinc Pool (EZP)  Liver, spleen, kidneys, bone marrow, erythrocytes  exchanges with plasma zinc within 3 days  accounts for 10% of total body zinc  Slow Exchanging Pools  Nervous system, muscles, bones etcJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 22
    • 23. B io l o g ic a l F u n c t io n o f Z in c Intracellular Distribution of Zn2+  30-40% in nucleus  50% in cytosol and cytosolic organelles  10-20% in membranes.  The cytosolic free [Zn2+] is 1-2 nM  Zinquin fluorescence shows  Fluorescent cytosol  Non-fluorescent nucleus  Zincosomes (vesicles)Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 23
    • 24. B io l o g ic a l F u n c t io n o f Z in c Intracellular Distribution of Zn2+  Confocal microphotographs of mouse fibroblasts stained with probes for DNA (blue), microtubules (green). Next generation zinc probes reveal vesicular Zn(II) pools (purple). Note the change in vesicular distribution as the cell in the upper right hand corner undergoing mitosis.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 24
    • 25. B io l o g ic a l F u n c t io n o f Z in c Zinc TransportersJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 25
    • 26. B io l o g ic a l F u n c t io n o f Z in c Zinc deficiency Deficiency Manifestation Severe dermatitis, alopecia, diarrhea,  Causes: emotional disorder, weight loss, infections, hypogonadism in males  Malnutrition  Alcoholism Moderate growth retardation and delayed puberty  Malabsorption in adolescents, hypogonadism in males, rough skin, poor appetite, mental  Burns lethargy, delayed wound healing, taste  Chronic renal disease abnormalities and abnormal dark  Acrodermatitis adaptation enteropathica Mild oligospermia, slight weight loss and hyperammonaemiaJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 26
    • 27. B io l o g ic a l F u n c t io n o f Z in c(Left) This boy has a zinc deficiency, and his hair is very thin and sparse; (right) after treatment his hair is growing more stronglyJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 27
    • 28. B io l o g ic a l F u n c t io n o f Z in c Acrodermatitis Enteropathica  hZIP4 gene mutation  Erythematous, dry, scaly, eczematous skin.  Periorificial and acral pattern on the face, the scalp, the hands, the feet, and the anogenital areas.  Infants may also experience withdrawal, photophobia, and loss of appetite.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 28
    • 29. B io l o g ic a l F u n c t io n o f Z in cZinc deficiency as a cause of anorexia nervosa  Zinc deficiency causes a decrease in appetite -- which could degenerate in anorexia nervosa (AN). Appetite disorders, in turn, cause malnutrition and, notably, inadequate zinc nutriture. The use of zinc in the treatment of anorexia nervosa has been advocated since 1979 by Bakan. At least 5 trials showed that zinc improved weight gain in anorexia. A 1994 randomized, double-blind, placebo-controlled trial showed that zinc (14 mg per day) doubled the rate of body mass increase in the treatment of anorexia nervosa (AN). Deficiency of other nutrients such as tyrosine and tryptophan (precursors of the monoamine neurotransmitters norepinephrine and serotonin, respectively), as well as vitamin B1 (thiamine) could contribute to this phenomenon of malnutrition-induced malnutrition.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 29
    • 30. B io l o g ic a l F u n c t io n o f Z in c Zinc toxicity  Even though zinc is an essential requirement for a healthy body, too much zinc can be harmful. Excessive absorption of zinc can also suppress copper and iron absorption. The free zinc ion in solution is highly toxic to plants, invertebrates, and even vertebrate fish. The Free Ion Activity Model (FIAM) is well- established in the literature, and shows that just micromolar amounts of the free ion kills some organisms. A recent example showed 6 micromolar killing 93% of all daphnia in water. Swallowing an American one cent piece (98% zinc) can also cause damage to the stomach lining due to the high solubility of the zinc ion in the acidic stomach.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 30
    • 31. B io l o g ic a l F u n c t io n o f Z in c Zinc toxicity  Zinc toxicity, mostly in the form of the ingestion of US pennies minted after 1982, is commonly fatal in dogs where it causes a severe hemolytic anemia. In pet parrots zinc is highly toxic and poisoning can often be fatal.  There is evidence of induced copper deficiency at low intakes of 100-300 mg Zn/d. The USDA RDA is 15 mg Zn/d. Even lower levels, closer to the RDA, may interfere with the utilization of copper and iron or to adversely affect cholesterol.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 31
    • 32. B io l o g ic a l F u n c t io n o f Z in c Physiological functions of zinc  Biochemical functions :  Cofactor for enzymes  Activity of zinc finger proteins  Cellular functions :  Growth & cell development  Cell membrane integrity  Tissue growth & repair  Wound healing  Endocrinological functions:  Reproduction: spermatogenesis & oogenesis  Thyroid function  Pancreatic function  Prolactin secretion  Thymopoetin synthesis  Immunological functions : function of neutrophils, T cells, B cells and NK cells  Neurological function: Cognition, memory, taste acuity, vision  Hematological function : coagulation factors  Skeletal function : Bone mineralizationJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 32
    • 33. B io l o g ic a l F u n c t io n o f Z in c Z in c B io c h e m ic a l f u n c t io nJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 33
    • 34. B io l o g ic a l F u n c t io n o f Z in c Zn2+ containing enzymes  Zn2+ is an essential cofactor for ~ 300 enzymes from all 6 classes.  There are 3 primary types of Zn2+ sites: catalytic, structural & co- catalytic  His, Glu, Asp and Cys are the main amino acids that supply ligands to these sites.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 34
    • 35. B io l o g ic a l F u n c t io n o f Z in c Catalytic sites 3 protein ligands, bound water  Conformational change during catalysis activates Zn2+ bound water  Ionization or polarization of water → acid base catalysis Carbonic anhydrase Alcohol dehydrogenase Carboxypeptidase  Displacement of water Matrix metalloproteinase → Lewis acid catalysis Thermolysin β lactamaseJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 35
    • 36. B io l o g ic a l F u n c t io n o f Z in c Carbonic anhydraseJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 36
    • 37. B io l o g ic a l F u n c t io n o f Z in c Zn 2+Polarizes H2O, making it a better nucleophile His His O O .. His –Zn2+ O + C His –Zn2+ O C O H O H His His H2O His Displaces HCO3- O .. His –Zn 2+ O + H+ + H O C O H His BicarbonateJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 37
    • 38. B io l o g ic a l F u n c t io n o f Z in c Structural sites 4 protein ligands, no bound water  Responsible for chemical properties  Alcohol dehydrogenase  Protein kinase family  DNA, RNA polymerase  Matrix metalloproteinase  tRNA synthase familyJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 38
    • 39. B io l o g ic a l F u n c t io n o f Z in cR-alcohol Dehydrogenase from Lactobacillus brevis  Alcohol dehydrogenase uses two molecular tools to convert ethanol to acetaldehyde. The first is a zinc atom which is used to hold and position the alcohol group on ethanol. The second is a large NAD cofactor, which actually performs the reaction.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 39
    • 40. B io l o g ic a l F u n c t io n o f Z in c Co-catalytic sites bridging of two metal sites by an AA usually Asp  Responsible for the overall fold of the protein as well as catalysis  Superoxide dismutase  Phosphatase  Aminopeptidase  β-lactamaseJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 40
    • 41. B io l o g ic a l F u n c t io n o f Z in c Zinc fingers  A zinc finger is a protein domain that can bind to DNA. A zinc finger consists of two antiparallel β sheets, and an α helix. The zinc ion is crucial for the stability of this domain type -in absence of the metal ion the domain unfolds as it is too small to have a hydrophobic core  Zinc fingers are important in regulation because when interacted with DNA and zinc ion, they provide a unique structural motif for DNA-binding proteins.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 41
    • 42. B io l o g ic a l F u n c t io n o f Z in c Classes of zinc finger  C2H2 motif  2 Cys and 2 His residues bind to one Zn2+ .  E.g. TFIIA, developmental/cell cycle regulators, metabolic regulatorsJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 42
    • 43. B io l o g ic a l F u n c t io n o f Z in c Classes of zinc finger  C4 motif  Nuclear hormone receptors  E.g. Estrogen Receptor (ER). ER forms a dimer. Each ER binds to 2 Zn2+ . All steroid receptors have the C4 motifJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 43
    • 44. B io l o g ic a l F u n c t io n o f Z in c Classes of zinc finger  C6 motif  Gal4. Forms a dimer. 6 Cys residues bind to 2 Zn2+  E.g. metabolic regulatorsJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 44
    • 45. B io l o g ic a l F u n c t io n o f Z in c Zinc Finger Motifs: Protein-Protein Interaction  RING-finger  specialized Zn-finger involved in mediating protein-protein interactions  a series of His and Cys residues with a characteristic spacing that allows the coordination of two zinc ions  Ubiquitin Ligase complexJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 45
    • 46. B io l o g ic a l F u n c t io n o f Z in c Zinc Finger Motifs: Protein-Protein Interaction  LIM domain  2 tandemly repeating Zn-fingers  Homeobox proteins  Transcription regulatory proteinsJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 46
    • 47. B io l o g ic a l F u n c t io n o f Z in c Z in c M o le c u la r b io lo g yJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 47
    • 48. B io l o g ic a l F u n c t io n o f Z in c Zn2+ and cell signaling  Interaction with signal transduction pathways  Protein phosphorylation and dephosphorylation  Second messenger metabolism  Enzyme regulatory activity  Activity of transcription factorsJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 48
    • 49. B io l o g ic a l F u n c t io n o f Z in c Interaction with signal transduction pathways & Protein phosphorylation / dephosphorylationJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 49
    • 50. B io l o g ic a l F u n c t io n o f Z in c Interaction with signal transduction pathways: Ca2+ signaling pathways  Electrical stimulation of cardiac cells can cause Zn2+ entry through voltage gated Ca2+ channels  Elevation of extracellular Zn2+ can act via HHS-R to mobilize Ca2+ from hormone sensitive Ca2+ stores → increases intracellular [Ca2+]  Ca2+ -Calmodulin dependent PK activity:  Low [Zn2+] increase calmodulin independent activity  High [Zn2+] inhibit the binding of Ca2+ -CalmodulinJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 50
    • 51. B io l o g ic a l F u n c t io n o f Z in c Second messenger metabolism: Cyclic Nucleotides  cGMP PDE is activated by Zn2+ upto 1µM; at > 1µM cGMP PDE is inhibited  Increase in intracellular Zn2+ > 1µM increases cGMP  Increase in cGMP in turn downregulates Zn2+ uptake  NO, an activator of guanylyl cyclase enhances the downregulation of Zn uptake 2+Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 51
    • 52. B io l o g ic a l F u n c t io n o f Z in c Enzyme regulatory activity : Protein Kinase C function  PKC contain 2 Zn2+ binding motifs in the regulatory region  Zn2+ in nM concentrations can activate PKC and increase its translocation to the cell membrane and cytoskeleton  The cellular redox state can affect PKC activity: Oxidation causes release of Zn2+ from Zn2+ binding motifs of PKC →  increases autonomous activity of PKC,  decreases sensitivity to regulating cofactors.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 52
    • 53. B io l o g ic a l F u n c t io n o f Z in c Activity of transcription factors  Regulation through zinc finger domains:  MTF-1 (metal transcription factor-1)  CREB (cAMP response element binding protein)  Steroid receptors  Gal-4  Direct regulation:  Activation of NF-κBJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 53
    • 54. B io l o g ic a l F u n c t io n o f Z in c Neuronal Zn2+ signals  There are three types of neuronal Zn2+ signals:  Zn2+ -SYN  Zn2+ -TRANS  Zn2+ -INTJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 54
    • 55. B io l o g ic a l F u n c t io n o f Z in c Zn2+ -SYN  Synaptic vesicular Zn2+ in the presynaptic boutons is released on axonal depolarization.  Zn2+ can reach 10-30μM in the extracellular fluid  Zn2+ -SYN reaches multiple Zn2+ modulated postsynaptic sites  Amino acid receptors: glutamate- and GABA- R  Tonic defacilitation of glutamate receptors: absence of synaptic Zn2+ increases seizuresJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 55
    • 56. B io l o g ic a l F u n c t io n o f Z in c Zn2+ -TRANS  Transmembrane flux of Zn2+. Zn2+-TRANS is analogous to transmembrane Ca2+ flux.  The Zn2+ channels are Ca-AK channels and NMDA channelsJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 56
    • 57. B io l o g ic a l F u n c t io n o f Z in c Zn2+ -INT  Analogous to intracellular Ca2+ signal, but no organelle analogous to SR/ER has been identified for Zn2+  Likely source of Zn2+ -INT is MT  NO is one of the main inducers of Zn2+ -INT signalJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 57
    • 58. B io l o g ic a l F u n c t io n o f Z in c Role of Zn2+ in cell proliferation  Zn2+ increases IGF-1. IGF-1 causes G1→S transition.  Zn2+ stimulates GF-R which act via MAPK pathway  Zn2+ increases phosphorylation of Jun & ATF-2Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 58
    • 59. B io l o g ic a l F u n c t io n o f Z in cRole of metallothioneins in Zn2+ mediated cell proliferation & differentiation  Cellular MT levels oscillate during the cell cycle reaching a maximum at G1→S transition.  MT translocates to nucleus during S phase in rapidly proliferating cells.  The nuclear translocation of MT is a vehicle for achieving high nuclear zinc level in the S-phase of the cell cycle.  Similarly MT translocates into the nucleus of differentiating cells. E.g. preadipocytes, myoblasts. After differentiation, MT translocates back to the cytoplasm.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 59
    • 60. B io l o g ic a l F u n c t io n o f Z in c Zn2+ inhibits apoptosis  Mitochondria releases ROS which causes lipid peroxidation, DNA damage, Protein SH oxidation  Mitochondria channel input signal pathways to the central pathway of Bcl-2(anti-apoptotic) or Bax (pro- apoptotic) genes.  Bcl2/Bax ratio determines whether cells are apoptosed or not.  When cells pass the Bcl2/Bax checkpoint, Cytochrome C is released  Cyt C activates the caspase cascade.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 60
    • 61. B io l o g ic a l F u n c t io n o f Z in c  Zn2+ inactivates the caspase cascade  Zn2+ binds to Cys163 and prevents disulfide bond formation  This prevents dimerization of Caspase-3 and inhibits its activity.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 61
    • 62. B io l o g ic a l F u n c t io n o f Z in c Z in c Im m u n o lo g y E n d o c r in o lo g y f u n c t io nJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 62
    • 63. B io l o g ic a l F u n c t io n o f Z in c Immunological function of Zn2+  Effect of Zn2+ deficiency on neutrophils:  Decreases bone marrow production  Decreases chemotaxis and adhesion  Impairs phagocytosis and oxidative burstJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 63
    • 64. B io l o g ic a l F u n c t io n o f Z in c  Decreases NK cell lytic activity and IFNα production Decreases monocyte/macrophage activation, phagocytosisJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 64
    • 65. B io l o g ic a l F u n c t io n o f Z in c  In B cells Zn2+ deficiency produces apoptosis  In T cells Zn2+ deficiency produces thymic atrophy → impaired T cell development and decreased counts.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 65
    • 66. B io l o g ic a l F u n c t io n o f Z in c Endocrinological function of Zn2+  Insulin is stored in pancreatic islets as osmotically stable zinc- insulin complex (2 Zn2+ : 6 insulin)  The hexamers are formed in the trans-Golgi complex.  Stimulating the islets by glucose and other stimulators result in the release of the hexamer which immediately dissociates into insulin and Zn2+.  Zn2+ ions released from β cells stimulate the secretion of glucagon from α cells by a paracrine mechanism.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 66
    • 67. B io l o g ic a l F u n c t io n o f Z in c Zn2+ and Diabetes Mellitus  Plasma Zn2+ concentration is decreased  Glucose-mediated hyperzincuria and decreased gastrointestinal absorption of zinc are responsible. Hyperzincuria responds partly to insulin treatment.  Hyperglycemia interferes with the active transport of Zn back into the renal tubular cells.  Zinc supplementation reduces blood glucose level in type 1 diabetics.  At the molecular level:  Zn2+ inhibits post insulin receptor intracellular events which results in a decreased glucose tolerance, and a relative decrease in insulin secretion.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 67
    • 68. B io l o g ic a l F u n c t io n o f Z in c Zn2+ and Type 1 Diabetes Mellitus  Type I DM is an autoimmune destruction of islets of pancreas mediated by free radicals.  Zn2+ is required for the function of Superoxide dismutase, catalase and peroxidase.  Zn-metallothionein complex in the islet cell provides protection against free radicals.  Zn2+ deficiency impairs the function of these enzymes and increases autoimmune destruction.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 68
    • 69. B io l o g ic a l F u n c t io n o f Z in c Zn2+ and Type 2 Diabetes Mellitus  In Type 2 DM there is insulin resistance at the receptor level.  In the initial stages this leads to increased insulin secretion  Excessive Zn2+ ions are co-secreted with insulin during hyperglycemia  Zn2+ induces islet cell death  Endogenous Zn2+ translocates to other islet cells, probably leading to their death  Chelation of released Zn2+ inhibits islet cell death in vitro and diabetes in vivoJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 69
    • 70. B io l o g ic a l F u n c t io n o f Z in c Summary  Zn2+ is an essential micronutrient that is maintained in the physiological range by various homeostatic mechanisms  Zn2+ is essential for the function of enzymes and zinc finger proteins  Metallothioneins, MTF-1 & ZnT1 regulate the intracellular level of Zn2+  Zn2+ plays an important role in various signaling pathways  Zn2+ is essential for cell proliferation, differentiation and apoptosis  Zn2+ deficiency can decrease the function of the immune system  Zn2+ is essential for the normal function of the pancreasJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 70
    • 71. B io l o g ic a l F u n c t io n o f Z in c Z in c C a s e R e portJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 71
    • 72. B io l o g ic a l F u n c t io n o f Z in c ACRODERMATITIS ENTEROPATHICA TYPE OF DERMATOSIS ZINC DEFICIENCY PRESENT  Bilateral, erythematous areas, some of which are weeping, plus vesicles, pustules and ulcers of the lower extremitiesJu n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 72
    • 73. B io l o g ic a l F u n c t io n o f Z in c  Note the weeping nature of some of the lesions on the dorsum of the foot. Yellowish foci probably correspond to pustules histologically. One of the small blisters it at the tip of the arrow. Erosions are present.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 73
    • 74. B io l o g ic a l F u n c t io n o f Z in c  Low power view, biopsy #1. The keratinocytes in the upper 1/3 of the epidermis are slightly pale when compared to those in the lower epidermis. All of the keratinocytes are much larger than normal.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 74
    • 75. B io l o g ic a l F u n c t io n o f Z in c  High power view of above (biopsy #1). Dyskeratosis of the type that has been described as being the result of condensation of tonofilaments in other diseases is apparently present here (arrows). Spongiosis and edema of the papillary dermis are also present.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 75
    • 76. B io l o g ic a l F u n c t io n o f Z in c  High power view of the superficial part of biopsy #1 showing polymorphonuclear leukocytes within the upper levels of the epidermis. More of these would have resulted in a pustule. The pallor of the keratinocytes in this area may be the result of increased cytoplasmic volume. The parakeratotic cap would account for a scaly lesion.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 76
    • 77. B io l o g ic a l F u n c t io n o f Z in c  Low power view of biopsy #2. The pallor of the superficial part of the epidermis is striking. Intraepidermal vesicles may result from severe ballooning of keratinocytes (intracellular edema in this case) or the coalescence of ballooned keratinocytes. Spongiotic vesicles also are forming.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 77
    • 78. B io l o g ic a l F u n c t io n o f Z in c  High power view of biopsy #2. The keratinocytes, even those in the basal layer, are huge, and some seem about to explode. There are small defects at the dermoepidermal junction in this area.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 78
    • 79. B io l o g ic a l F u n c t io n o f Z in c  Very high power view of the dermoepidermal junction in biopsy #2.Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 79
    • 80. B io l o g ic a l F u n c t io n o f Z in c Q u e s t io n s ?Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 80