Zinc

Reaction between carbohydrates and proteins; precents Zn from being absorbed by the intestine.

1) Similar to iron, Zn requires protein hydrolysis prior to absorption: Hydrochloric acid (antacids or proton pump blockers decrease Zn absorption); stomach and intestinal proteases and nucleases. 2) Absorption: Main site of absorption is proximal small intestine, most likely jejunum; ranges from about 15-60% of intake; paracellular diffusion occurs with high Zn intakes.

1) Several endogenous compounds are thought to serve as ligands with Zn enhancing its absorption: citiric and picolinic acid; histidine, cysteine, lysine, and glycine; glutathione (cysteine, glutamate, and glycine); tripeptides. 2) Low zinc status: Zn absorptive mehcanisms respond to Zn status; indicates homeostatic regulation.

Food compounds can complex with Zn and inhibit its absorption: phytate, oxalate, polyphenols, fibers, folic acid, iron, calcium and copper.

Zip 1-14; SLC39A gene family-transport Zn into cytoplasm. 1) High degree of homology from yeast to humans. 2) Tissue and cell-specific expression. 3) Localized to specific cellular compartments (can be at the plasma membrane or intracellular.

zinc may be used within the enterocyte; stored bound to protiens (MT and CRIPs); transproted through the cell and across the basolateral membrane (ZnT1).

Thionein: 1) small protein (MW. 6000) with a large number of sulfhydryl groups (cysteine residues) that chelate divalent cations. 2) Most divalent cations bound to metallothionein are Zn but MT binds copper and cadmium with high affinity. 3) Gene expression of thionein is induced by diets high in Zn. 4) MT-bound Zn is lost into the lumen when the mucosal cells are sloughed off.

1) Zinc not bound to MT or used within the enterocyte is transported across the plasma membrane by ZnTs (ZnT1). 2) Zn is found in all organs (2g/70kg BW): Liver, kidney, muscle, skin and bones; Content in soft tissue is relatively stable; not a mobilizable pool. 3) Zn-containing enzymes and MT (main storage form) partially provide Zn when dietary intake is insufficient to meet needs: catabolism of "less-essential" Zn-containing proteins. 4) Primary regulatory point is in the gut; absorption and excretion. 5) Excretion reflects endogenous Zn losses: Zn is in pancreativ fluid and results in a loss of 1-2mg Zn/d.

ZnT1-10: SLC30A gene family- Transport Zn from cytoplasm. 1) Tissue-specific expression. 2) Localized to very specific compartments in the cell. 3) Provide Zn for specific functions. 4) ZnT2 provides Zn for secretory vesicles (mammary gland and prostate). 5) ZnT3 provides Zn for synaptic vesicles (brain).

1) Zinc regulates thionein and ZnT1 gene expression. 2) Increased Zn leads to increased expression. 3) Metal regulatory elements (MREs): Specific nucleotide sequences in the promoter region of genes; Zinc interacts with metal transcription factor (MTF1) which binds to MREs and induces expression; Storage/efflux proteins increase during excess and decrease during deficiency- homeostasis.

1) Zinc and Trascription: Structural component of nuclear DNA-binding protiens (Zn finger transcription factors); Examples of proteins that contain Zn fingers are RAR, RXR, VDR, THR, etc. 2) Essential cellular functions: Cell growth, replication, bone formation, skin integrity, cell-mediated immunity and host defense; polymerases, kinases, nucleases, transferases, phosphorylases, and transcriptases all requires Zn.

1) Zn deficiency has rapid and extensive effects on immune system. 2) Affects both antibody- (B cell) and cell- (T cell) mediated responses: Regulates lymphopoiesis (apoptotic mechanisms); Zn deficiency increases stress response (glucocorticoids) and increases apoptosis.

delta-aminolevuliniv acid dehydratase: contains 8 subunits, each of which binds one Zn atom; Zn required for maintaining free thiols.

Protein digestion: 1) Aminopeptidase: cleaves amino acids from the amino (N) terminal of the polypeptide chain; Zinc is required for catalytic activity. 2) Carboxypeptidase A: Secreted by the pancreas into the duodenum; Necessary for hydrolysis of peptide bonds and C-terminal residues for digestion of aromatic/branched chain amino acids; 2 zinc atoms (one catalytic and one structural.

1) Zinc is required for insulin packaging in pancreatic beta-cells: Zinc deficiency decreases insulin response, resulting in impaired glucose tolerance. 2) ZnT8 plays a role in Zn import into insulin-containing vesicles in pancreatic beta-cells: ZnT8 polymorphisms are associated with type 2 diabetes; ZnT8 autoantibodies have recently been detected in humans with type 1 diabetes.

Superoxide dismutase (SOD)-catalyzes the removal of superoxide radicals: located in the cytoplasm of cells, dimer; requires two atoms each of Zn and copper; Zinc provides a structural role in SOD.

Five General causes; occur in isolation or together: 1) Inadequate intake: low intake of bioavailable zinc (high phytate diets). 2) Increased requirements: growth, pregnancy, lactation. 3) Malabsorption. 4) Increased losses: alcoholism. 5) Impaired utilization: diabetes, chronic long-term infections.

1) less severe: Immune deficiencies, diarrhea and intesinal inflammation, impaired taste, delayed wound healing. 2) more severe: behavior disturbances, alopecia, and glossitis. 3) Most severe: growth retardation, delayed sexual maturation, impotence, hypogonadism, hypospermia. DEATH. 4) Reflects the role of Zn in the extraordinary number of functions.

1) Estimated that about 80% of world's population, including the US is marginally Zn deficient based on inrake data. 2) Zinc status is difficult to diagnose as plasma zinc level is tightly regulated and affected by eating, time of day, stress, infection, steroid and hormonal use.: Possible indicators suggested- RBC MT, urinary Zn, hair Zn, Zn-dependent enzyme activity, oral Zn tolerance test and WBC Zn transporter expression. 3) Pregnant and lactating women are at particular risk.

1) Large amount of zinc is transferred to the fetus during pregnancy 0.7 mg/d. 2) Larger amount of zinc is transferred into milk during lactation 1-2 mg/d.

1) Excessive intakes of Zn can cause toxicity. 2) An acute toxicity with 1-2 g of zinc sulfate (300 mg Zn) can produce the following symptoms: metallic taste, nausea and vomiting, epigastric pain, abdominal cramps, dizziness, and chills. 3) Chronic ingestion of Zn results in copper deficiency.

Chronic Zn toxicity can cause copper and iron deficiency: 1) Zinc at 25 mg/day impairs copper absorption. 2) high Zn intake increases the synthesis of MT. 3) Metallothionein will bind divalent ions with little degree of specificity when it is present in high amounts. 4) as a result, copper absorption is blocked. 5) as a result, iron deficiency anemia occurs because ceruloplasmin and hephaestin (copper are required as co-factors) are not functional.

Acrodermatitis enteropathica: genetic mutations in the Zn importer Zip4 result in severe Zn deficiency. 1) Patches and plaques of dry, scaly skin; eczema and subaceous pustules; alopecia. 2) Transient neonatal Zn deficiency: a mutation in ZnT2- Mother is not Zn deficient but milk Zn conventration is about 25% of normal, defect in ability to secrete Zn from the mammary gland into milk.

Carbonic anhydrase: 1) Located primarily in erythrocytes and in the renal tubule. 2) Essential for respiration. 3) Allows for the rapid disposal of carbon dioxide. 4) The hydrogen and bicarbonate ions and participate in buffering reactions.

1) Affects the activity of several membrane-bound enzymes. 2) stabalizes phospholipids. 3) Protects against lipid peroxidation.

Zinc deficiency can lead to a decrease in thyroid hormone synthesis and secretion.

1) Co-factor for polyglutamate hydrolase (gamma-glutamylhydrolase). 2) Digestion of folate in the intestinal tract. 3) Yeilds monoglutamate folate, which is actively transported into intestinal cells.

Cofactor for alkaline phosphatase: 1) Contains 4 zinc ions per enzyme molecule (2 are structural, 2 are catalytic). 2) Found primarily in bone and liver (small amounts in plasma). 3) Hydrolyzes monoesters of phosphates from various compounds.

Co-factor for alcohol dehydrogenase: 1) similar to alkaline phosphatase, it contains 4 zincs. 2) Converts alcohols to aldehydes (retinol to retinal). 3) NADH is also required.