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Zinc
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Zinc

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  1. Zinc

  2. History • 1509, recognized as element • Essentiality demonstrated • Plants: 1869 • Animals: 1934 • Deficiency • Considered unlikely until 1955 • swine parakeratosis shown to be caused by Zn deficiency • conditioned human deficiency demonstrated in 1956 • 1961, hypogonadal dwarfism suggested to be zinc deficiency

  3. Facts • 30th element in the periodic table (IIB element) • MW = 65.37, completely filled d orbitals • In aqueous solutions • One oxidation state, namely Zn2+ • Prefers tetrahedral complex formation • Not a redox active metal • readily complexes with amino acids, peptides, proteins and nucleotides • affinity for thiols, hydroxy groups & ligands with electron-rich nitrogen donors

  4. Distribution • Whole body: 1.5g (female)-2.5g (male) • Skeletal Muscle 57% • Bone 29% • Skin 6% • Liver 5% • Brain 1.5% • Kidneys 0.7% • Heart 0.4% • Hair ~0.1% • Blood Plasma ~0.1%

  5. Sources • Relatively abundant mineral • Good sources: shellfish, beef and other red meats • Slightly less good: Whole-grains • most in bran and germ portions • 80% lost to milling • phytates, hexa & penta phosphates depress absorption • P/Zn ratios of 10 or more • Relatively good sources: nuts and legumes • Eggs, milk, poultry & fish diets lower than pork, beef, lamb diets • High meat diets enhance absorption • 280g or 10 oz fits right into food pyramid guide • cys & met form stable chelate complexes

  6. Zinc Methionine

  7. Effect of trace mineral source on animal performance

  8. Relative bioavailability of trace mineral sources

  9. Whole Body Fluxes Plasma/Serum2.4 mg a-2 macroglobulin (30%) albumin (60%) Target tissues Including Liver 1.2 g DietZn++ 4-15 mg/da (~0.15 mM) Intestine Zn++ (50-100mM) 1-2 mg/da Metallothionine Chelating Agents Phytates Milk:2-3 ug/mL Pancreatic & Biliary Excretion: 4-5 mg/da Other Losses: Sweat, Skin, Hairup to 1 mg/da Seminal Fluid:196 ug/mL Menstrual Loss:0.1-0.5 mg Feces:3-14 mg/da Urine:0.4-0.6 mg/da

  10. Feed/Food source Phytate (calcium-phytate-zinc complex) Mainly hexa- and pentaphosphate derivatives Highly dependent on calcium Amino Acids histidine, cysteine Presence/Absence of other divalent cations Fe, Ca Efficiency of absorption can vary from 15-60% Under normal conditions 1/3 of dietary Zn is absorbed Zn status alters efficiency of absorption Uptake and retention is > in growing animals Dietary Factors that Affect Zn Absorption

  11. Overview • Approximately 300 enzymes are associated with zinc • Biological functions of Zn are divided into three categories • Catalytic, Structural, Regulatory • Role in metabolism • Protein synthesis • Nucleic acid metabolism • Carbohydrate and energy metabolism • Lipid • Epithelial tissue integrity • Cell repair and division • Vitamin A and E transport and utilization • Immune function • Reproductive hormones

  12. Absorption • Absorption takes place throughout the intestine • Glycocalyx • Barrier? Storage site? • Primarily in the jejunum • Some absorption in the rumen • No measurable amounts absorbed from stomach cecum or colon

  13. Absorption • In small intestine • Nonmediated (nonsaturable) process • Not affected by dietary Zn intake • Mediated (saturable) process • Stimulated by Zn depletion

  14. Absorption Serosa Mucosa NSBP Zn++-Albumin CRIP Zn++ Zn++ Saturable = Bound to form transport ligand CRIP-Zn Albumin MTI-Zn Zn++-Albumin MTI Zn++ Zn++ Non-saturable = Passive Diffusion CRIP=cysteine-rich intestinal protein; MTI=metallothionine; NSBP, non-specfic binding protein

  15. Transport in blood • Plasma contains approx .1% of the total zinc of the body • Albumin is major portal carrier • Binds to albumin by tetrahedral ligation to sulfur atoms • 70% of Zn is bound to albumin in plasma • 20-30% bound to α-2 macroglobulin • Other plasma proteins • Transferrin, histidine-rich glycoprotein, metallothionine • Plasma Zn concn’s respond to external stimuli • Intake fluctuations • Fasting • Acute stresses • infection • Plasma Zn levels do not influence absorption from mucosa • Most reductions in plasma levels reflect increased hepatic uptake • Hormonal control

  16. Transport • Rapidly cleared from plasma by liver • Fast component of 2 pool model (T1/2 = 12.3 da) • Single dose of zinc is taken up with T1/2 = 20 s • Slow component, other tissues (T1/2 = 300 da) • Bone and CNS uptake slow • Pancreas, liver and kidney most rapid • RBC & muscle in between • Exchangeable pool & zinc status

  17. Hepatic uptake via a biphasic process Contribution to overall Zn flux Sequesters newly absorbed Zn Removes Zn from the circulation Saturable process – initial step Temperature dependent rapid Stimulated by glucocorticoids Linear accumulation – subsequent step slow Not affected by dietary Zn intake Does not require energy Cellular Uptake

  18. Cellular Uptake • Erythrocytes • Depends upon bicarbonate ions • Fibroblasts, proximal tubule, lymphocyte • Biphasic uptake (same as liver)

  19. Intracellular Transport • Zinc transporters regulate Zn ion concentrations through import, export or sequestering Zn into vesicles • Storage, toxicity • 2 families exist: • ZnT- mainly exports Zn ions from cells • ZIP – important for Zn influx

  20. Intracellular Transport • Number of transporters • ZnT-1: all organs, small intestine (basolateral membrane), kidney (tubular cells), placenta • Efflux • ZnT-2: intestine, kidney, testis • Efflux & (?) intracellular vesicles • ZnT-3: brain (synaptic vesicles) & testis • Influx, intracellular retention • ZnT-4: mammary gland & brain • Efflux (into milk) • Lethal mouse transgenic

  21. Intracellular Transport • ZIP family transporters: • Consist of: • hZIP1 • hZIP2 • hZIP3 • Responsible for influx of Zn as well as Mn2+, Cd2+, and other divalent cations into cells

  22. Intracellular Transport • Number of transporters • DCT1: duodenum, jejunum, kidney, bone marrow, others • Non-specific: Zn, Cd, Mn & Cu actually have slightly higher affinity than Fe, the mineral for which the transport actions of this protein was first identified. • Competition between Fe & Zn & Cu

  23. Storage • Storage sites • No specfic storage sites are recognized • Within cells, amounts sequestered within metallothionine could be considered as stores • Anorexia, muscle catabolism, tissue zinc release • Metalloenzymes cling tenaciously to zinc • Serum/plasma zinc drops rapidly (~1 week) with zinc deficient diet • Zinc turnover is extensive and rapid • Two-components of turnover, fast ~12.3 days, and slow, ~300 days • Fast pool is also called the “exchangeable” pool • Usually amounts to 157-183 mg Zn

  24. Excretion • Lost via hair, sweat, desquamation, bile pancreatic secretions, seminal fluid, urine, feces • Main endogenous loss • Secretions into gut • Bile and pancreas • Mucosal cells • Urinary and integumental losses • < 20% under normal conditions • Losses increase with trauma, muscle catabolism, and administration of chelating agents (EDTA) • Primarily in fecal material • Unabsorbed Zn • Secreted Zn (endogenous sources) • From pancreatic and intestinal sources

  25. Regulation • Metallothionein • Concentrated in liver, kidney, pancreas, intestine • Acts as a Zn2+ buffer • Controls free Zn2+ level • Control intracellular Zn pool responsive to both hormones and diet • Zn-binding protein, metallothionein (MT), is involved in the regulation of Zn metabolism • MT is inducible by dietary Zn via the metal response element (MRE) and MTF-1 mechanism of transcriptional regulation • ↑ in cellular MT ↑ Zn binding within cells • Acute infections associated with proinflammatory cytokines increses Zn uptake into liver, bone marrow and thymus and reduces the amount going to bone, skin and intestine

  26. Metabolic Interactions • Interactions of other divalent cations in the intestinal lumen •  Fe,  Sn,  Cd → ↓ Zn • ↑ Zn → ↓ Cu

  27. Interactions • Copper • High Zn diets reduce Cu absorption • electronic configuration competition • Metallothionine synthesis induced • sequesters Cu in mucosal cell preventing serosal transfer • Happens with 150mg Zn for two years • Can be used with Wilson’s disease patients • High copper diets do not interfere with Zinc absorption • Iron • Supplements inhibit zinc absorption • Ferrous > Ferric, heme no effect • Pregnant and taking >60mg Fe/day should also take Zn

  28. Interactions • Calcium • High Ca diets reduce Zn absorption • effect enhanced in phytate rich diets • not sure how much of a problem in humans • post menopausal women yes, adolescent girls, no • Other • Tin (Sb), not usually high in diet, but diets high in Tin can increase fecal Zn excretion • Cadmium (Cd), alter Zn distribution in body rather than altering absorption • Folic acid, conjugase requires Zn • High doses sometimes impair Zn status further in low Zn situation - mechanism currently unclear

  29. Function • Zinc-containing enzymes • More than 70 enzymes • Secondary & tertiary protein structures • Metal stabilized active sites • Examples of general types • dehydrogenases • phosphatases • peptidases • kinases • deaminases • Insulin

  30. Function • Cu/Zn Superoxide Dismutase • General class of enzymes that protect against oxidative damage in the body. • Insulin • Zn important structurally • Zn needed for insulin “stored” in pancreas • Functionality drops rapidly so more of a “working store” than a static store

  31. Function • Nuclear transcription factors (>130) • Same protein structural role forms “zinc-fingers” • “Zn-fingers” bind DNA • allow different nuclear hormones to interact with DNA via different DNA binding proteins • up to 37 “fingers” have been found on a single transcription factor • Vit. A, Vit. D, steroid hormones, insulin-like growth factor-1, growth hormone, and others bind to zinc-finger proteins to modulate gene expression • Zn is responsible for thymidine incorporation

  32. Function • Cell Differentiation • Thymidine kinase activity • Creatine kinase activity

  33. Transcription Factors • Transcription factors • Regulate gene expression • Involved in virtually all biological processes: • Development, differentiation, cell proliferation, response to external stimuli • Consists of 2 domains • DNA Binding Domain (DBD) – recognizes and binds to specific DNA sequence elements in the promoter of target genes • Protein-interacting Transactivation Domain (TAD) – influences the rate of transcription

  34. Zinc Finger Proteins • Zinc finger proteins are characterized by their utilization of zinc ions as structural components • C2H2 zinc finger binding motif • Predominant motif in eukaryotic transcription • Involved in skeletal differentiation • Zinc binding motif is determined by the presence of 2 cysteine and 2 histidine residues that engage in a four coordinate bond with a singe Zn ion • Bind to response elements in the upstream promoters of genes transcribed by RNA poly 2 • Binds to 5S ribosomal RNA gene, and 5S RNA, and activates transcription by RNA polymerase 3.

  35. Mech of Transcription

  36. Function Zinc-Finger

  37. Function Zinc-finger Interacting with DNA

  38. Function • Zinc Fingers • Mutation c/ablation of binding • in case of Zif268, loss in sequence-specific DNA binding that allowed viral infection • Iron can replace Zn in “fingers” • Low Zn and high Fe • Fe gives rise to ROS more readily • DNA damage & carcinogenesis? • Cadmium can replace Zn in “fingers” • Non-functional, cytotoxic

  39. Transcription Factors • Revelation • Gene expression is controlled by specific proteins call transcription factors • Zinc containing transcription factors account for 1% of genome • Zinc plays key structural role in transcription factor proteins • Ligands for transcription factors include: • Vitamin A • Vitamin D • Bile acids • Thyroid hormones

  40. Membrane Stability • Membrane fractions contain high concentrations of Zn • Increases rigidity of cell • Protection from oxidative damage • Competition for binding sites with redox metals

  41. Membrane Function • In deficient animals: • Failure of platelet aggregation • Due to impaired Calcium uptake • Peripheral neuropathy • Brain synaptic vesicles exhibit impaired calcium uptake • Increased osmotic fragility in RBCs • Decreased plasma membrane sulfhydryl concentration

  42. Immune Function • After Zinc depletion • All functions within monocytes were impaired • Cytotoxicity decreased in Natural Killer Cells • Phagocytosis is reduced in neutrophils • Normal function of T-cells are impaired • B cells undergo apoptosis • High Zn supplementation shows alterations in cells similar to Zn depletion

  43. Vitamin A & Zinc Zn influences Vitamin A metabolism Absorption, transport, and utilization Vitamin A transport is mediated through protein synthesis Zn deficiency can depress synthesis of retinol-binding protein in liver Oxidative conversion of retinol to retinal requires Zn-dependent retinol dehydrogenase enzyme Retinol to retinaldehyde (retinal), for visual processes Night Blindness Hallmark deficiency sign for Vitamin A Seen with Zn deficiency as well, why? Stojanovic, Stitham and Hwa: Critical Rose of Transmembrane segment Zn binding I the structure and function of rhodopsin JBC 279(34):35932-35941, 2004 Rhodopsin proteins

  44. Vitamin A Zn-dependent Protein folding Rhodopsin [11-cis-Retinal] “bleaching” Spontaneousindark + opsin Light Retinol isomerase works on vitamin A bound to CRBP 11-cis-Retinal trans-Retinal + opsin NAD+ (NADP+) Alcoholdehydrogenase NADH (NADPH) 11-cis-Retinol trans-Retinol Retinolisomerase Blood + Epithelium

  45. Zn and Vitamin A Interaction

  46. Mechanisms of Toxicity • Excess accumulation within cells may disrupt functions of biological molecules • Protein, enzymes, DNA • Leads to toxic consequences • Anemia • Impaired copper availability • Acute excessive intakes • Local irritant to tissues and membranes • GI distress, nausea, vomiting, abdominal cramps, diarrhea • Relatively non-toxic • Sources of exposure – drinking water, feed, polluted air

  47. Signs Growth retardation Delayed sexual maturation & impotence Impaired testicular development Hypogonadism & hypospermia Alopecia Acroorifical skin lesions Other, glossitis, alopecia & nail dystrophy Immune deficiencies Behavioral changes More signs Night blindness Impaired taste (hypoguesia) Delayed healing of wounds, burns, decubitus ulcers Impaired appetite & food intake Eye lesions including photophobia & lack of dark adaptation Deficiency