Zinc

Protein synthesis and DNA and RNA synthesis require Zinc. Insulin is secrected from the pancreas and circulates in association with zinc. This secretion is diminished under conditions of zinc deficiency, leading to impaired ?. Zinc deficiency also affects ?, is associated with reductions of HDL.

(macro metabolism fxn) glucose metabolism lipid metabolism

What is Zn required for in the body?

- DNA synthesis - Cell division & growth - Protein synthesis - macro metabolism - development & function (sexual)

What other things pose a threat for Zn deficiency?

- Vegetarian diet - Preg and lactation - exclusively breastfed infants - hemoglobinopathies

What can Zn bound to in transport?

- blood = bound loosely to albumin - transferrin - alpha-2 macroglobulin - immunoglobulin - **Histidine & cysteine**

What are the storage sites for Zn?

- found in all organs - especially liver - kidneys - muscle - skin - bones

What are the three functions of Zn?

- mainly as a cofactor for numerous enzymes in cells - Stored in cells bound to metallothionein - As a part of the zinc finger transcription factor proteins, the expression of genes is inhibited or enhanced by Zn

How is Zn excreted

- mostly through feces - urine - shed skin cells - sweat, hair, menses, and semen

What are the sources of Zn?

- red meats, seafood, poultry, pork, dairy - whole grains, veggies - Supps

What are ways PZC as a biomarker of zinc nutrition can be assess in several ways?

1. Measure the PZC response after controlled manipulations of zinc intake, including both zinc-depletion/repletion studies and zinc supplementation trials. 2. Assess the relation between usual dietary zinc intake and PZC. 3. Compare PZCs between individuals by using clinical signs that are generally recognized as functional outcomes of severe zinc deficiency. 4. Compare initial PZCs between individuals who do or do not show a functional response to changes in their zinc intakes.

What are the 3 categories of basic function of Zn

1. enzyme catalyst 2. structural component 3. regulation of gene transcription

RDA: Men? Women? Preg? Lactation?

11mg, 8mg, 11mg, 12mg

Read over the recognition of Zn deficiency

21 year old man who looked like a 10 year old boy

Zinc is a catalyst or cofactor for how many different enzymes?

300

What is the UL of Zn?

40 mg

Clinically manifested by skin lesions, on the face, knees, and buttocks; impaired growth; and low plasma zinc concentrations. This condition can be treated with large doses of zinc, supporting the existence of paracellular transport at high intake levels.

Acrodermatitis enteropathica

It binds to thiol groups in proteins, making them less susceptible to oxidation. By displacing redox-reactive metals such as iron and copper from both proteins and lipids it can reduce the metal-induced formation of hydroxyl radicals and thus protect the macromolecules. Zn > MT increases, which scavenges hydroxyl radicals.

Antioxidant defense system

What are the two ways Zn is absorbed?

Carrier-mediated or passive diffusion & paracellular absorption

What is Zn an active site of? This is where Zn maintains enzymatic activity

CuZn superoxide dismutase (SOD)

Zinc serves as a necessary structural component of?

DNA binding and transcription factors that contains zinc fingers.

What is the Zn finger?

Each zinc atoms are coordinated by four cystein/histidine residues to stabilize a DNA binding structure.

What conditions pose a threat for Zn deficiency risk?

GI and metabolic disorders (-- inflammatory bowel disease, ulcerative colitis, Crohn disease, malabsorption syndrome -- chronic liver or renal disease, diabetes, malignancies, and other chronic illnesses -- chronic diarrhea/tropical enteropathy leading to excessive zinc loss)

Zn deficiency leads to a drop in food intake, a reduction in circulating concentrations of insulin-like growth factor (IGF-1), which may contribute to delayed ?

Growth

What are the physiological roles of Zn

Growth Immune function Reproduction Nervous system Antioxidant defense system Macronutrient metabolism, Carbohydrate metabolism

Lymphopenia and thymic atrophy; both cell-mediated and antibody-mediated responses are reduced; Generalized host defense; Thymulin, a zinc-dependent enzyme binds to T cells and stimulates development of T cells within the thymus.

Immune Fxn

Explain the digestion of Zn

It is hydrolyzed from AA/nucleic acids in the stomach and small intestine - enzymes: proteases and nucleases

? stimulates transcription fter interacting with the MTF, which has acquired Zn in the cytosol or nucleus

MRE

(Zn homestasis) ? utilizes zinc by binding making protein very energized and then goes to bind with ? and drives gene transcription

MTF MRE {analogous to IRE binding to IRP}

An ? and ? in the promoter of the regulated gene are the basic components of zincs role

MTF and MRE

? facilitates translocation to the nucleus for MRE binding and stimulating transcription by interacting with dietary zinc that is transported into the cells

MTF-1

Depending on the cellular zinc status, it is thought that ? negatively or positively regulates numerous genes

MTF-1

a response to treatment showing improved growth and immune function, taste and smell acuity, and reproductive function.

Mild (marginal Zn def)

At the present time, ? is the only biomarker of status that can be used to measure zinc status in individuals with either a low or a high supply of dietary zinc, but with many limitations and constraints.

PZC - plasma zinc concentration

Although only 1% of the total body zinc is present in circulating blood, several expert committees have endorsed ? or ? as a useful biomarker of zinc status, especially for assessing the risk of zinc deficiency in ?

PZCs or SZCs (serum zinc concentration) populations

What is an example of another case of chronic Zn toxicity?

Patients with Wilson disease who were treated with 150 mg zinc/d developed hypocupremia, possibly due to a reduction in copper absorption

the original description in humans included lack of purbertal development. Spermatogenesis a zinc dependent process. Also required for normal fetal development and deficiency leads to abnormalities in humans and animals. Maternal zinc deficiency has been linked with pregnancy-associated morbidity, including pre-term delivery.

Reproduction fxn

delayed growth and sexual maturation and impotence, characteristic skin lesions, diarrea and deficits in taste and smell and behavioral changes (e.g. irritability and cognitive function).

Severe def

What is an important mechanism for Zn homeostasis

The endogenous secretion and the extent to which they are reabsorbed

What type of nutrient is Zn and what does this mean?

Type 2 nutrient - amount of the mineral in the body stays the same because being conserved but growth declines.

Where does feces Zn come from?

Unabsorbed dietary zinc, zinc contained within intestinal epithelial cells that have been sloughed off, and endogenous zinc secretions into the gut from pancreas, the gall bladder, and cells lining the GI tract.

What is Zn significance in nutrition?

Widely used in proteins due to size and charge (Zn2+); involved with enzymes and nuclear proteins

The ? work in opposition to, but in coordination with, the ? to regulate cellular Zn homeostasis

ZIP transporters ZnT transporters

What are the 2 known classes of Zn transporters?

ZIPs and ZnTs

an SLC30 family of transporters that move zinc and other metal ions, such as iron, from the cytoplasm to the outside of the cell or into the lumen of the intracellular organelles. There are 10 known transporters.

Zinc efflux transporters (ZnTs)

{Structure component} est the structural role for Zn; contains 4 cysteines that allow Zn to be bound in a tetrahedral complex, some have histidine

Zinc fingers - discovered in frogs in 1985

a solute carrier (SLC39) family of transporters that move zinc into the cytoplasm from cellular organelles or extracellular space. There are 14 known transporters

Zinc influx transporters (ZIPs)

{regulation role} ? containing protein controls reg of gene expression

Zn finger

What is Zns regulatory role in regards to the Zn finger

Zn goes into nucleus and can bind with Cys or Hist (AAs) finger-like structure; allows protein to go into nucleus and bind on promoter region of DNA and interact with transcription machinery by driving or inhibiting the process (pic on slide 12)

What mediates zinc efflux (the flowing out of) in intestinal cells

ZnT-1

What is the basolateral exporter of Zn to the circulation?

ZnT1

What are the carrier mediated proteins for Zn

Zrt & Irt-like protein (ZIP) 4 {zinc-regulated transporter; iron regulated transporter

What type of Zn toxicity effects include nausea, vomiting, loss of appetite, abdominal cramps, diarrhea, and headache; (mostly GI tract upset)

acute

Copper/Zinc superoxide dismutase is an important antioxidant enzyme. In general, animals studies have revealed an association between zinc deficiency and increased oxidative stress.

antioxidant defense system

What is the best method for estimating zinc exposure in individuals and populations

assessment of dietary zinc intake

In zinc's catalytic role, what is the enzyme Zn works with and where is that enzyme located?

carbonic anhydrase in erythrocytes and renal tubule cells

Symptoms of ? include gastric problems, a reduction in immune function, decreased HDL cholesterol, and low serum copper concentrations

chronic Zn toxicity

The usual zinc intake of individuals can be estimated from a ? or an ?

diet history or FFQ

What are the routes for deficiency of Zn?

dietary inadequacy, acrodermatitis enteropathica, the genetic disorder of zinc, malabsorption and more generalized malabsorption syndromes. Also from inappropriate intravenous feeding and the use of chelation therapy.

What are the 3 recommended zinc biomarkers for research, clinical, and program use?

dietary intakes, PZCs or SZCs, and stunting (measure of growth)

The zinc intake of populations can be estimated from ? data provided by the ?

food balance-sheet or FAO

How are biomarkers graded?

for their strnegth of their use for assessing zinc exposure, zinc status, zinc fxn, and zinc effects

What biomarkers for Zn are considered "potential" - shows promise, but data are insufficient to est cut offs indicating Zn inadequacy in populations

hair zinc, urinary zn, neurobehavioral fxn

Where do Zn fingers occur?

in nuclear proteins involved in signal transduction, cellular differentiation or proliferation, cellular adhesion, and transcription

{Zn homeostasis} Zn increases --> MT mRNA increases, ZnT1 mRNA increases --> ?

increase intracellular Zn storage and increased efflux across the plasma membrane

What is the storage protein for Zn

metallothionein storage

How was the carrier mediated process discovered?

mutation in ZIP 4 led to skin lesions, impaired growth, GI issues known as Acrodermatitis enteropathica

What biomarkers for Zn are considered "emerging"

nail zn, zn-dependent proteins, oxidative stress and DNA integrity, zn kinetics, taste acuity

The links between the biochemical (enzymes) roles of zinc within proteins and its physiological function are often?

not understood

Zn has a unique role as a?

nuclear protein/transcriptional factor

How was the discovery of passive diffusion and paracellular absorption of Zn discovered?

pts with the ZIP 4 mutation given large amounts of supps and it corrected the deficiency which indicated there was another route besides ZIP4

Carbonic anhydrase allows?

rapid disposal of CO2

What is the role of superoxide dismutase?

serves as an imp antioxidant defense by removing superoxide radicals (2O2)

In zinc's structural role, what enzyme does Zn work with and where is it found

superoxide dismutase in cell cytosol or extracellular

What is Zn usually stored bound to?

thionein Metallothionein

How is Zn homeostasis achieved?

through metallothionein (MT) and ZnT1; MTF1 and MRE

{catalyst fxn} Direct links between Zn def symptoms and the fxn of an individual enzyme have?

yet to be identified and are unlikely - only occur if the ZN-dependent enzyme were acting at a rate-limiting step in a critical pathway

How was the UL of Zn established

zinc intakes >50 mg/d in adults reduced the activity of the copper-dependent enzyme erythrocyte Cu, Zn superoxide dismutase. After adjustment for an uncertainty factor, the UL was set for 40 mg/d for adults. (to prevent accidental Cu def) - Zn competes with DMT1 transporter with Cu

{catalyst fxn} Under conditions of zinc deficiency, ? have decreased activity but their protein structure ?; how do you restore enzyme activity?

zinc metalloenzymes structure does not change adding back zinc restores activity

What biomarkers for Zn are considered "not useful"

zinc-dependent enzymes, RBC and leukocytes