1 / 57

Zinc

Zinc. 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

irisa
Download Presentation

Zinc

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related