Zinc

Zinc (Zn, atomic weight 65.38) is a metallic, divalent transition element.

Abbreviations

DMTI divalent cation transporter 1 (SLC11A2)

MTF-1 metal response element-binding transcription factor-1

ZnT-1 zinc transporter 1 {SIC30A1 )

ZnT-2 zinc transporter 2 (SLC30A2)

ZnT-3 zinc transporter 3 (SLC30A3)

ZnT-4 zinc transporter 4 (SLC30A4)

ZIP zinc- and iron-régula red protein

Nutritional summary

Function Zinc is essential for the activation of numerous genes and as cofaetor for many enzyme reactions.

Requirements. At least H mgd zinc are necessary to maintain adequate stores lor women consuming a mixed diet, and 11 mg for men (Food and Nutrition Board Institute of Medicine, 20021. Vegetarians and pregnant or breastfeeding women need slightly more. Sources: Oysters are exceptionally rich, other shellfish and meats also are good sources. Phytate from whole grains and some vegetables interfere with zinc absorption. Deficiency Low intake is associated with loss of appetite, scaling skin lesions, and impaired immune function.

Excessive intake: Consumption of more than 40mgd may deplete eoppcr stores, impair immune function, and lower 1101 levels.

Dietary sources

Foods contain elemental zinc, much of it bound to proteins or DNA. Meats (2-3mg.i(K)gl, and shelllish (cooked clams 2.7mg. 100g> provide most, oysters arc exceptionally rich (>70mg per serving). Plant foods are much poorer sources.

Digestion and absorption

More than 70% of a small zinc dose (less than 3 mg) is absorbed from the small intestine when there is no interference from other meal constituents (LÔnnerdal. 2000). Protein hydrotysates and some amino acids, particularly histidine and cysteine, increase fractional zinc absorption. Higher than minimal zinc doses, replete zinc status, and the presence of phytate in the same meal greatly decrease absorption efficiency. Concurrent high intakes of iron, calcium or other divalent metal cations do not appear to impact zinc absorption significantly (Sandstrom. 2001).

Significant amounts of zinc enter the intestinal lumen with secretions from the pancreas. Intraluminal digestion by proteases, DNAses and KNAses releases zinc from the food matrix. Zinc forms complexes w ith histidine. cysteine, and nucleotides that are absorbed better than zinc alone. Absorption is reduced by phytate (Lônncrdal, 20(H)).

The main mechanism for zinc uptake from the intestinal lumen is with Z1P4 (SLC39A4), a member of the ZIP family (Wang et a/., 2002). This transporter is expressed at the luminal side of enterocytes throughout the small and large intestine. A related protein, provisionally designated hORFI. may contribute to zinc uptake from the colon ( Wang et at,. 2002). Genetic variants of this gene are associated wilh the rare familial condition acrodermatitis enteropathies. The proton-coupled divalent cation transporter 1 (DMTI. SLCI1A2) appears to provide a minor uptake route. DMT I also transports iron, copper, cadmium, and other divalent metal ions that may compete with zinc (McMahon and Cousins. I<)9tf). This may be the basis for diminished zinc uptake in the presence of high amounts of calcium. Enterocyte intracellular iron concentration is the main determinant of DMT I expression and translocation to the apical membrane: low iron status upregulates DMTI expression, and more so if the subject is pregnant or has a familial hemochromatosis phenotype.

A possible alternative route for zinc uptake is v ia the hydrogen ion peptide cotrans-porter (SLC15A1. PepTI) when complcxed to small peptides (Tacnet et at., 1993). Uptake as a complex with indiv idual amino acids may explain why histidine and cysteine improve intestinal zinc absorption (L6nnerdal, 2000).

Metallothioneins are a ubiquitous family of cysteine-rich small peptides thai bind zinc and some other heavy metals with high capacity [up to 12 atoms per peptide).

DNA-Zn flNA-Zfi Ztl

DNA-Zn flNA-Zfi Ztl

(last wiiti lecas I

Intestinal lumen

Zn"

melallothiortein isequeatralmnj

(last wiiti lecas I

Intestinal lumen

Enterocyte

Brush border membrane

(ZnTt/jJ

Capillary lumen

S a sola! era I Capillary membrane endothelium

Figur» 11.11 Intestinal zinc absorption

A dozen genetically distinct metallothionein isoforms occur in liver, additional ones in brain, tongue and stomach. Metallothionein regulates zinc transfer into porta! blood through binding and retaining it within the enteroeyte until shedding into the intestina) lumen. High intracellular zinc concentration from luminal or endogenous increases metallothionein production and this, in turn, decreases net zinc absorption (Davis end.. 1998).

Zinc is exported from enteroeytes into portal blood by zinc transporters I iZnT-l. SLC30A1) and 2 (ZnT-2, SLC30A2). ZnT-l expression is upregulated when zinc intake is high (McMahon and Cousins. 1998). Another pathway for zinc transport across the basolateral enteroeyte membrane is via the zinc-regulated transporter 1 (SLG39A11,

With increasing intraluminal concentrations net zinc movement across the tight junctions ofthe epithelial layer (paraeellular pathway) becomes more significant. Regulatory mechanisms involving DMTI or metallothionein thus are bypassed when high-dose supplements arc ingested.

Transport and cellular uptake

Blood circulation: Newly absorbed /inc in portal blond is bound to albumin (Cousins, 1986) and alpba-2-macroglobulm (Osterberg and Malmensten. 1984) as is the zinc in peripheral blood. Typical venous concentrations are between It) and 17 m.1110! 1. lower in people wiih severe zinc deficiency.

A hormone-responsive zinc Uptake transporter (SLC39A1) of the zinc- and iron-regulated protein (ZIP) family (Costello el al„ 1999) mediates the uptake into prostate cells. ZIP2 is another closely related transporter that may mediate cotransport of zinc and bicarbonate into cells (Gaither and Eide. 2000). ZnT-2 (SLC30A2) and be involved in zinc efflux or uptake into endosoraal and lysosomal v esicles in intestine, kidney, and testis, ZnT-3 (SJX30A3) is involved in zinc uptake into vesicles in neurons and in testis. ZnT-4 (SLC30A4) is another zinc exporter, which is highly expressed in mammary gland and brain. Transport of zinc across the plasma membrane of neurons is freely reversible and not ATP or ion-dependent (C'olv in. 1998).

In the mammary gland zinc is exponed into milk by ZnT-4; complexing with simultaneously secreted metallothionein greatly increases zinc bioavailability for the breastfed infant.

Zinc is presumably released again from metalloproteins, histones. and DMA when these arc broken down by intracellular (lysosomal) digestion.

Blood bram barrier: The mechanism for zinc uptake into brain capillary epithelial cells is unresolved. It is likely to involve mediation of uptake from blood by a zinc-histidinyl complex and DMTI (Takeda, 2000). Transport from blood into and out of cerebrospinal fluid via the choroid plexus is a major pathway for the maintenance of brain zinc homeostasis, but the molecular mechanisms at that site arc not any better understood than for brain capillary epithelium.

Matemo-fetal transfer: Zinc moves across the placental membrane by a slow process, that equally facilitates transfer in either direction depending on the prevailing concentration gradient (Beer et al.. 1992).

Storage

Zinc stores in replete women are about 1.5 g, and 2,5 g in men (King and Keen, 1994). Muscles ami bone contain most of the body s /inc. Turnover of zinc-containing proteins and UNA. which constitute the bulk of zinc in muscle and hone, is very slow, with a half-life of about 30(1 days (Wastney et a!,. 211(H)). This means that less than 6 mg are mobilized per day as zinc-containing structures are hroken down. In contrast, zinc associated with metal lothionein in the liver is turning over with a half-life of about two weeks and can be readily mobilized. This much smaller pool can cover for a sudden shortfall in dietary intake, therefore. However, due to the small size of this rapidly exchangeable pool (less than 170mg), zinc depletion can become functionally relevant within a week (Miller et al.. 1994).

Excretion

About 1 mg day appears to be lost w iih sweat, skin, and hair. Fecal losses (unabsorbed zinc from both diet and endogenous secretions) depend on zinc intakes and status (Lee et at, 1990). and can be less than I mg/day (Stan et at. 19%). Ejaculate contains about 1 mg. and menstrual losses range from 0.1 to 0.5 mg. Losses with urine have been estimated to be 0.4 -0.6 mg/day (2- 10"» of intake).

Since \ irtually all zinc in blood is complexed to larger proteins (albumin, alpha-2-macroglobulin). relatively little gets into filtrate in the kidneys. The small amount that gets into ultraiiltrate is reabsorbed mainly from the distal renal tubule \ ia ZnT-1 (Victery etai. 1981).

Regulation

While zinc flux and concentration is regulated at various points, control of melallo-thionein expression is the most important mechanism for maintaining zinc adequacy. Increased metallothionein expression in the small intestine decreases intestinal absorption. increased expression in the fix or expands stores. Metallothionein expression is induced by the metal response element-binding transcription factor-1 < MTF-I). This zinc sensor with iis six zinc-coordinated peptide loops (zinc fingers) binds to multiple metal response elements of the metallothionein promoters when the free zinc ion concentration is high (Langmade ft al.. 2000). MTF-I also induces expression of ZnT-1. This latter change might be primarily responsible for increased excretion of zinc into bile and pancreas juice.

Binding of another transcription factor, upstream stimulatory factor family (DSF), to a separate promoter sequence (antioxidant response element) is involved in the induction of metallothionein expression in response to oxygen free radical (H:Oi) stress.

Function

Zinc is a cofactor of several hundred enzymes and is needed for the replication and function of DNA. Inadequate supplies impair food digestion and absorption, synaptic signaling, gene expression, control of oxidant stress, growth and wound healing, immune function, taste and appetite, and many other functions. I,ess than adequate zinc availability appears to interfere with organ formation during early pregnancy (Hurley. 19SI), It is ollen difficult to establish a tight link between individual /inc-dependent structures and functional status, because zinc impacts so many concurrent and sometimes competing processes. Only a limited selection will be touched on in the following.

Intestinal digestion Zinc is an essential cofactor of carbonic anhydrases, proteases, phosphatases and other enzymes involved in food digestion and absorption. The role of carbonic anhydrases for gastric acid production is described below. The car-box ypeptidases AI and A2 (EC3.4.2,1) are zinc-dependent digestive enzymes from the pancreas. Several peptidases of the intestinal brush border are zinc enzymes, including leucine arhinopeptidase (LAP. EC3.4.11,1). membrane alanine aminopepti-dase (aminopeptidasc N. EC3.4.I1.2), glutamyl aminopeptidasc (aminopeptidasc A. EC3.4.11.7). membrane dipeptrdase (EC3.4.13.19), angiotensin I-converting enzyme (EC3.4.15.1), neprilysin (EC3.4.24.II). and meprin A (EC3.4.24.1 K), Another zinc-containing brush border enzyme (pteroylpoly-gamma-glutamate carboxypepiidase. EC3.4.19.8) is needed to cleave off gam ma-glutamyl residues from dietary folate prior to absorption. Alkaline phosphatase (EC3.1.3,1, requires both zinc and magnesium) at the intestinal brush border digests complex forms of thiamin, riboflavin, and pantothenate. pH-Regulation: The conversion of carbon dioxide to its weak acid helps cells to adjust proton concentration w ith a readily available and easily removable reagent. This equilibrium reaction is catalyzed by the zinc enzyme carbonate anhydmse (EC4.2.I.I). The ten or more genetically distinct isoforms of this handy enzyme provide line tuned kinetic properties and regulatory characteristics for a w ide range of functions thai include acidification, signaling, promoting cell proliferation, bone resorption, and respiration. A long known role of the enzymes I, II. and IV is to provide protons for hydrochloric acid production in the stomach. Gastrin, histamine, and acetylcholine activate these isoenzymes, while somatostatin and several acid-suppressing drugs inhibit them. Carbonic anhydrase VI, gustin, is a special form in salivary glands, that helps to maintain taste bud growth (possibly by acting on bud stem cells) and function (I lenkin et uL, 1999). Adequate zinc intake appears to promote taste acuity. Nutrient metabolism: Zinc-containing alcohol dehydrogenases (ADM. EC 1.1,1.1) in the stomach wall and liver oxidize cthanol. A particular ADD isoenzyme is needed for the conversion of the transport and storage form retinol into the retinal form used for vision. Optimal zinc status may lower the risk of macular degeneration (Age-Related Eye Disease Study Research Group. 2001).

Several zinc-dependent folate hydrolases in lysosomes. membranes, and cytosol are essential for folate metabolism and transport in tissues.

DNA replication and transcription: Zinc lingers are DNA-binding domains of transcription factors in which the zinc ion is tetrahedrally coordinated to cysteine and,or histidine residues. These zinc-complexing structures are very ubiquitous features that give zinc a central role in expression of virtually any type of protein. Zinc is a cofactor of many enzymes participating in the synthesis of DNA and RNA during cell div ision and gene expression. Important zinc enzymes include DNA polymerase (EC2.7.7.7) and

DNA-dependent RNA polymerase (EC2.7.7.6); many others are regulated through zinc-finger proteins.

RNA editing: Zinc is a cofactor of the apolipoprotein B RNA editing complex, which deaminates specific cytidine moieties in a few mRNA species, most prominently of apolipoprotein B. but also of tumor necrosis factor-«, c-myc and other centrally important regulators of growth and differentiation (Anant and Davidson, 2000). The same complex also extensively edits the translational repressor NATI. which is involved in postnatal heart development (Pak and Pang, l 999).

Immune function: The zinc-dependent peptide hormone (hymulin comes from the thymus. Thymulin helps to maintain immune function by activating T-lvmphocytcs and enltancing the cytotoxicity of natural killer cells. Zinc may also act directly by promoting the proliferation of lymphocytes and decrease susceptibility to programmed cell death (apoptosis). Since zinc is an essential cofactor of many enzymes involved in proliferation of any rapidly dividing cell, it becomes very difficult to differentiate this from a more specific role as a direct effector. Whatever the proximate mechanism, there is no doubt that counts of both natural killer cells and 1111 lymphocytes decline with zinc deficiency. Related to suboptimal zinc are also low production of interlcukin-2. tumor necrosis factor-«, and interferon-y (Prasad. 1998). and possibly of 11-6. Fuel metabolism: The interactions of zinc with players in carbohydrate metabolism are numerous and not yet fully understood. Only a few are to be mentioned here. Zinc chelates insulin during storage and thus plays a role in control of its secretion. Glucagon rapidly lowers the intracellular concentration of the free zinc ion. Zinc itself opposes the effect ofcAMP on glycolysis.

Free radical metabolism: Zinc contributes importantly to the defense against oxidative stress. It docs so partly as a cofactor of superoxide dismutases (SOD, EC 1.15,1.1) in cy to plasma (SODl) and in the extracellular space (SOD3). Protection of sulfhydryl groups and other direct effects of zinc on redox reactions have been demonstrated (Powell. 2000).

Other functions: A link of zinc to vascular function is established through its rote as a cofacior of nitric oxide synthases (ECl.14.13.39).

References

Age-Related I ve Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E. hcia carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. Arch Ophthalmol 2001;] 19:1417 36 Anant S. Davidson NO An Al -rich sequence element (ULfl N[ A I J]l i downstream of the edited C in apolipoprotein B mRNA is a high-affinity binding silc for Apobee-1: binding of Apobee-1 to this motif in the 3' untranslated region of c-myc increases mRNA stability. Ma! Cell Biol 2000:20:1982 02 Beer WH. Johnson RF. Guentzel MN. Lozano J. Henderson Gl. Schenker S. Human placental transfer of zinc: normal characteristics and rule of ethanol. Ale Clin Exp Res 1992:16:98-105

Colv in RA. Characterization of a plasma membrane zinc transporter in rat brain. Neumsci Lett !9ys;247:l47-50

Cosiello LC. Liu Y. Zou J, Franklin RB. Evidence Ibra /inc uptake transporter in human prostate cancer cells which is regulated by prolactin and testosterone../ Biol Chew 1999:274:17499- 504

Cousins RJ. Toward a molecular understanding of zinc metabolism. Clin Physiol Biochem 1986;4:20-30

Davis SR. McMahon RJ. Cousins RJ. Metallothionein knockout and transgenic mice exhibit altered intestinal processing of zinc with uniform zinc-dependent zinc transporter-! expression. J Nutr 1998;128:825-31 Food and Nutrition Hoard Institute of Medicine. Dietary Reference Intakes for vitamin A, vitamin K. arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. National Academy Press. Washington. DC, 2002 tiaither LA, Eide DJ. Functional expression ofthe human hZlP2 zinc transporter,./ Bio!

Chem 2000:275:5560-4 Henkln Rl. Martin BM, Aganva) Rp. Efficacy of exogenous onil /inc in treatment of patients with carbonic anhydrase VI deficiency. Am J Med Sei 1999:318:392 405 Hurley I 5. Zinc deficiency and central nervous system malformations in humans. Am J

Clin Nutr 198J;34:2864 5 King JC, Keen CL. Zinc. In Shiis MF., Olson JA. Shike M. Modern Nutrition in Health and Disease, 8ih edn. I ,ea &. Febiger. Philadelphia. 1994. pp.214 30 Langmade SJ. Ravindra R. Daniels PJ. Andrews GK. The transcription factor MTF-1 mediates metal regulation of the mouse ZnTI gene, J Biol Chem 2000:275: 34803-9

Lee HH, Hill GM. Sikha VK. Brewer GJ, Prasad AS. Owyang C. Pancreaticobiliary secretion of zinc and copper in normal persons and patients with Wilson's disease../ Lah Clin Meil 1^90:116:283 8 Lönnerdal B. Dietary factors influencing zinc absorption.J Mar 2000; 131): 1378S I3X3S McMahon RJ. Cousins RJ. Mammalian zinc transporters. J Nutr 1998:128:667 70 Miller LV. Hambidge KM, Naake VL. Hong Z. Westeott JL. Fennessey PV. Size ofthe zinc pools that exchange rapidly with plasma zinc in humans: alternative techniques for measuring and relation to dietary zinc intake. J Nutr 1994; 124:268 76 Osterberg R. Malmensten B, Methylamine-induced conformational change of alpha - 2-macroglobulin and its zinc(ll) binding capacity. An x-ray scattering study. Eur J Biochem 1984; 143:541 4 Pak BJ. Pang SC. Developmental regulation of the translational repressor NATI during cardiac development../ Mol Cell Cardiol 1999:31:1717-24 Powell SR. The antioxidant properties of zinc. J Nutr 2000:130:1447S 1454S Prasad AS, Zinc: an overview. Nutrition 19lJ5:l l(Suppl);93 9 Prasad AS, Zinc and immunity. Mol Cell Biochem 1998:188:63 -9 Sandström B. Micronutrient interactions: effects on absorption and bioavailability. Brd Nutr 200l;85:S)81-5

Sian L, Mingyan X. Miller LV.Tong L, Krebs NF. Hambidge KM. Zinc absorption and intestinal losses of endogenous zinc in young Chinese women with marginal zinc intakes. Am J Clin Nutr 1996;63:348-53 Tacnet F. Lauthier F. Ripoche P. Mechanisms of zinc transport into pig small intestine brush border membrane vesicles../ Physiol 1993:465:57-72

Takeda A Movement of zinc and its functional significance in the brain, tint in Res Rev 2000;34:137-48

Victory W, Smith JM, VandcrAJ Renal tubular handling of zinc in the dog ImJ Physiol l981;24l:F532-9

Wang K. Zhou B. Kuo YM, /e man sky J. Gitschiirr J. A novel member of a zinc transporter family is defective in acrodermatitis cnterpathica. Am .1 Hum Genet 20(12: 71:66-73

Wastney ME, House WA, Barnes RM, Subramanian KN Kinetics of zinc metabolism: variation with diet, genetics and disease../ Nutr 2000; 130:1355S 1359S

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