1. B io l o g ic a l F u n c t io n o f Z in c
Is f a h a n U n iv e r s it y o f M e d ic a l S c ie n c e , S c h o o l o f
P ha rma c y
D e p a r t m e n t o f C lin ic a l B io c h e m is t r y
2. B io l o g ic a l F u n c t io n o f Z in c
Z in c
B io lo g y
(An o v e r v ie w )
B y :e 2 6 ., N0 .1 2E m a m i R a z a v i
Ju n
A 2 T o t a l s l id e s : 7 8 2
3. B io l o g ic a l F u n c t io n o f Z in c
Outlines
Introduction
Sources, requirement and homeostasis
Zinc deficiency
Zinc toxicity
Biolochemical functions of zinc
Molecular biology of zinc
Immunological & Endocrinological Functions of zinc
Case report (acrodematitis enteropathica)
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4. B io l o g ic a l F u n c t io n o f Z in c
Z in c
In t r o d u c t io n
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5. B io l o g ic a l F u n c t io n o f Z in c
In ancient India the production of zinc metal
was very common. Many mine sites of Zawar
Mines, near Udaipur, Rajasthan;-Zawarmaala
were active even during 1300-1000 BC. There
are references of medicinal uses of zinc in the
Charaka Samhita (300 BC). The Rasaratna
Samuccaya (800 AD) explains the existence of
two types of ores for zinc metal, one of which is
ideal for metal extraction while the other is used
for medicinal purpose.
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6. B io l o g ic a l F u n c t io n o f Z in c
Pure metallic zinc was discovered by Andreas
Marggraf (Germany) in
1 746
Atomic number: 30
Atomic weight: 65.409
Valency: +2
Group #: 12
Periodic #: 4
State: solid metal at room
temperature
Isotopes: 21 isotopes (5
stable and 16 unstable)
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7. B io l o g ic a l F u n c t io n o f Z in c
Appearance
Bluish pale gray
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8. B io l o g ic a l F u n c t io n o f Z in c
What is zinc?
Zinc is an essential mineral that is found in
almost every cell. It stimulates the activity of
approximately 300 enzymes, which are
substances that promote biochemical reactions
in the body. Zinc supports a healthy immune
system , is needed for wound healing , helps
maintain the sense of taste and smell , and is
needed for DNA synthesis . Zinc also supports
normal growth and development during
pregnancy, childhood, and adolescence .
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9. B io l o g ic a l F u n c t io n o f Z in c
Z in c
S ourc e s ,
R e q u ie r m e n t &
H e m o s t a s is
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10. B io l o g ic a l F u n c t io n o f Z in c
Sources
Foods contain element zinc, much of it bound to
protein or DNA.
Oysters (> 70 mg per serving).
Meats (2-3 mg/100g).
Shellfish (2.7 mg/100g)
Other good food sources include:
beans, nuts, certain seafood, whole grains,
fortified breakfast cereals, and dairy products .
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11. B io l o g ic a l F u n c t io n o f Z in c
Zinc absorption is greater from a diet high in
animal protein than a diet rich in plant
proteins . Phytates, which are found in whole
grain breads, cereals, legumes and other
products, can decrease zinc absorption .
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12. B io l o g ic a l F u n c t io n o f Z in c
RDA
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13. B io l o g ic a l F u n c t io n o f Z in c
Absorption
GIT modulates the quantity of exogenous dietary zinc absorbed
and the quantity of endogenous zinc excreted
More than 70% of a small zinc dose (less than 3 mg) is absorbed
from the small intestine.
Maximum absorption occurs in duodenum
There is sustained release from enterocytes into portal
circulation for ~ 9h
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14. B io l o g ic a l F u n c t io n o f Z in c
Fractional Absorption
Inversely proportional to the amount of zinc in the meal
Does not depend on the ‘zinc status’ of the body
Increased by breast milk; Decreased by phytates
Protein hydrolysates and some amino acids, particularly
histidine and cysteine, increase fractional zinc absorption.
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15. B io l o g ic a l F u n c t io n o f Z in c
Transport and cellular uptake
ZIP4 (SLC39A4), a member of the ZIP family .
This transporter is expressed at the luminal side of enterocytes through
the small and large intestine.
hoRF1, may contribute to zinc uptake from the colon.
Genetic variants of this gen are associated with the rare familial
condition acrodermatitis enteropathica.
DMT1,(SLCA11A2)
The proton coupled divalant cation transporter 1 appears to provide a
minor uptake route. DMT1 also transports iron, copper, cadmium and
other divalent metal ions that may compete with zinc.
PepT,(SLC15A1)
Hydrogen ion/peptide cotransporter is a posible alternative route for zinc
uptake when complex to small peptides.uptake as a complex with
individual amino acids may explain why histidine and cysteine improve
intestinal zinc absorption.
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16. B io l o g ic a l F u n c t io n o f Z in c
Metallothinein
Regulates zinc transfer into portal blood through binding and
retaining it within the enterocyte until shedding into the
intestinal lumen.
Zinc transporters
Zinc is exported from enterocytes into portal blood by Zinc
transporters 1 (ZnT-1,SLC30A1) and 2
(ZnT-2,SLC30A2).ZnT-1 is upregulated when zinc intake is
high.
Paracellular pathway
With increasing intra luminal concentrations, net zinc
movement across the tight junctions of the epithelial layer
becomes more significant. Regulatory mechanisms involving
DMT1 or metallotionein thus are bypassed when high-dose
supplement are ingested.
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17. B io l o g ic a l F u n c t io n o f Z in c
Intestinal zinc absorption
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18. B io l o g ic a l F u n c t io n o f Z in c
Excretion
Routes: intestine, kidneys, integument, and semen
After a meal, maximum zinc secretion occurs through
pancreatobiliary secretions
Maximum reabsorption occurs from mid-jejunum and ileum
Total amount excreted = Amount secreted – Amount reabsorbed
Excretion of endogenous zinc by the intestine depends on the
‘zinc status’ of the body.
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19. B io l o g ic a l F u n c t io n o f Z in c
Regulation
Metallothionein expression
The most important mechanism for maintaining zinc
adequacy.
Increased expression in the small intestine decreases
intestinal absorption
Increased expression in the liver expands stores.
Metallothionein expression is induced by the metal
response element-binding transcription
factor-1(MTF-1)
MTF-1 is bind to multiple metal response elements of the
metallothionein promoters when the free zinc ion
concentration is high.
MTF-1 also induces expression of ZnT-1
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20. B io l o g ic a l F u n c t io n o f Z in c
Metallothioneins
Major Zn2+ binding protein in mammalian
systems is metallothionein (MT)
MT contain Zn2+ coordinated to Cys by
mercaptide bonds
Binding of Zn2+ by MT depends on the
redox state of the cell – oxidization
releases Zn2+ from MT and vice versa.
Zn2+ + Apothionein → Metallothionein
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21. B io l o g ic a l F u n c t io n o f Z in c
Cellular Zn2+ sensors
The cellular Zn2+ sensor is
MTF-1 (Metal response
element binding transcription
factor-1)
Intracellular Zn2+ binds to
MTF-1
Zn-MTF-1 binds to MRE and
increases transcription of
Metallothionein and ZnT1
mRNA.
MT binds intracellular Zn2+
and removes it from the free
pool.
ZnT1 increases Zn2+ efflux
from cells
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22. B io l o g ic a l F u n c t io n o f Z in c
Compartments: Endogenous Zinc Pools (EZP)
Plasma
75% of Zn2+ is bound to albumin and 20% to α2-macroglobulin.
Most of the remaining Zn2+ is complexed to His & Cys rich proteins.
The free Zn2+ concentration of serum is in nM range.
Rapidly Exchanging Pool/ Endogenous Zinc Pool
(EZP)
Liver, spleen, kidneys, bone marrow, erythrocytes
exchanges with plasma zinc within 3 days
accounts for 10% of total body zinc
Slow Exchanging Pools
Nervous system, muscles, bones etc
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23. B io l o g ic a l F u n c t io n o f Z in c
Intracellular Distribution of Zn2+
30-40% in nucleus
50% in cytosol and cytosolic
organelles
10-20% in membranes.
The cytosolic free [Zn2+] is 1-2
nM
Zinquin fluorescence shows
Fluorescent cytosol
Non-fluorescent nucleus
Zincosomes (vesicles)
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24. B io l o g ic a l F u n c t io n o f Z in c
Intracellular Distribution of Zn2+
Confocal microphotographs of
mouse fibroblasts stained with
probes for DNA (blue),
microtubules (green). Next
generation zinc probes reveal
vesicular Zn(II) pools (purple).
Note the change in vesicular
distribution as the cell in the
upper right hand corner
undergoing mitosis.
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25. B io l o g ic a l F u n c t io n o f Z in c
Zinc Transporters
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26. B io l o g ic a l F u n c t io n o f Z in c
Zinc deficiency
Deficiency Manifestation
Severe dermatitis, alopecia, diarrhea,
Causes: emotional disorder, weight loss,
infections, hypogonadism in males
Malnutrition
Alcoholism Moderate growth retardation and delayed puberty
Malabsorption in adolescents, hypogonadism in males,
rough skin, poor appetite, mental
Burns lethargy, delayed wound healing, taste
Chronic renal disease abnormalities and abnormal dark
Acrodermatitis adaptation
enteropathica
Mild oligospermia, slight weight loss and
hyperammonaemia
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27. B io l o g ic a l F u n c t io n o f Z in c
(Left) This boy has a zinc deficiency, and his hair is very thin and sparse; (right) after
treatment his hair is growing more strongly
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28. B io l o g ic a l F u n c t io n o f Z in c
Acrodermatitis Enteropathica
hZIP4 gene mutation
Erythematous, dry, scaly,
eczematous skin.
Periorificial and acral pattern on
the face, the scalp, the hands, the
feet, and the anogenital areas.
Infants may also experience
withdrawal, photophobia, and
loss of appetite.
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29. B io l o g ic a l F u n c t io n o f Z in c
Zinc deficiency as a cause of anorexia nervosa
Zinc deficiency causes a decrease in appetite -- which could
degenerate in anorexia nervosa (AN). Appetite disorders, in turn,
cause malnutrition and, notably, inadequate zinc nutriture. The
use of zinc in the treatment of anorexia nervosa has been
advocated since 1979 by Bakan. At least 5 trials showed that
zinc improved weight gain in anorexia. A 1994 randomized,
double-blind, placebo-controlled trial showed that zinc (14 mg
per day) doubled the rate of body mass increase in the treatment
of anorexia nervosa (AN). Deficiency of other nutrients such as
tyrosine and tryptophan (precursors of the monoamine
neurotransmitters norepinephrine and serotonin, respectively), as
well as vitamin B1 (thiamine) could contribute to this
phenomenon of malnutrition-induced malnutrition.
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30. B io l o g ic a l F u n c t io n o f Z in c
Zinc toxicity
Even though zinc is an essential requirement for a healthy body,
too much zinc can be harmful. Excessive absorption of zinc can
also suppress copper and iron absorption. The free zinc ion in
solution is highly toxic to plants, invertebrates, and even
vertebrate fish. The Free Ion Activity Model (FIAM) is well-
established in the literature, and shows that just micromolar
amounts of the free ion kills some organisms. A recent example
showed 6 micromolar killing 93% of all daphnia in water.
Swallowing an American one cent piece (98% zinc) can also
cause damage to the stomach lining due to the high solubility of
the zinc ion in the acidic stomach.
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31. B io l o g ic a l F u n c t io n o f Z in c
Zinc toxicity
Zinc toxicity, mostly in the form of the ingestion of US pennies
minted after 1982, is commonly fatal in dogs where it causes a
severe hemolytic anemia. In pet parrots zinc is highly toxic and
poisoning can often be fatal.
There is evidence of induced copper deficiency at low intakes of
100-300 mg Zn/d. The USDA RDA is 15 mg Zn/d. Even lower
levels, closer to the RDA, may interfere with the utilization of
copper and iron or to adversely affect cholesterol.
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32. B io l o g ic a l F u n c t io n o f Z in c
Physiological functions of zinc
Biochemical functions :
Cofactor for enzymes
Activity of zinc finger proteins
Cellular functions :
Growth & cell development
Cell membrane integrity
Tissue growth & repair
Wound healing
Endocrinological functions:
Reproduction: spermatogenesis & oogenesis
Thyroid function
Pancreatic function
Prolactin secretion
Thymopoetin synthesis
Immunological functions : function of neutrophils, T cells, B cells and NK cells
Neurological function: Cognition, memory, taste acuity, vision
Hematological function : coagulation factors
Skeletal function : Bone mineralization
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33. B io l o g ic a l F u n c t io n o f Z in c
Z in c
B io c h e m ic a l
f u n c t io n
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34. B io l o g ic a l F u n c t io n o f Z in c
Zn2+ containing enzymes
Zn2+ is an essential cofactor for ~ 300 enzymes from all 6
classes.
There are 3 primary types of Zn2+ sites: catalytic, structural & co-
catalytic
His, Glu, Asp and Cys are the main amino acids that supply
ligands to these sites.
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35. B io l o g ic a l F u n c t io n o f Z in c
Catalytic sites
3 protein ligands, bound
water
Conformational change during
catalysis activates Zn2+ bound
water
Ionization or polarization of water
→ acid base catalysis Carbonic anhydrase
Alcohol dehydrogenase
Carboxypeptidase
Displacement of water Matrix metalloproteinase
→ Lewis acid catalysis Thermolysin
β lactamase
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36. B io l o g ic a l F u n c t io n o f Z in c
Carbonic anhydrase
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37. B io l o g ic a l F u n c t io n o f Z in c
Zn 2+Polarizes H2O, making it a better nucleophile
His His
O O
..
His –Zn2+ O + C His –Zn2+ O C
O
H O H
His His
H2O
His Displaces HCO3-
O
..
His –Zn 2+
O + H+ + H O C
O
H
His Bicarbonate
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38. B io l o g ic a l F u n c t io n o f Z in c
Structural sites
4 protein ligands, no bound
water
Responsible for chemical
properties
Alcohol dehydrogenase
Protein kinase family
DNA, RNA polymerase
Matrix metalloproteinase
tRNA synthase family
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39. B io l o g ic a l F u n c t io n o f Z in c
R-alcohol Dehydrogenase from Lactobacillus brevis
Alcohol dehydrogenase
uses two molecular
tools to convert ethanol
to acetaldehyde. The
first is a zinc atom
which is used to hold
and position the alcohol
group on ethanol. The
second is a large NAD
cofactor, which actually
performs the reaction.
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40. B io l o g ic a l F u n c t io n o f Z in c
Co-catalytic sites
bridging of two metal sites by
an AA usually Asp
Responsible for the overall
fold of the protein as well as
catalysis
Superoxide dismutase
Phosphatase
Aminopeptidase
β-lactamase
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41. B io l o g ic a l F u n c t io n o f Z in c
Zinc fingers
A zinc finger is a protein domain
that can bind to DNA. A zinc finger
consists of two antiparallel β sheets,
and an α helix. The zinc ion is
crucial for the stability of this
domain type -in absence of the
metal ion the domain unfolds as it is
too small to have a hydrophobic
core
Zinc fingers are important in
regulation because when interacted
with DNA and zinc ion, they
provide a unique structural motif for
DNA-binding proteins.
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42. B io l o g ic a l F u n c t io n o f Z in c
Classes of zinc finger
C2H2 motif
2 Cys and 2 His residues bind
to one Zn2+ .
E.g. TFIIA, developmental/cell
cycle regulators, metabolic
regulators
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43. B io l o g ic a l F u n c t io n o f Z in c
Classes of zinc finger
C4 motif
Nuclear hormone
receptors
E.g. Estrogen Receptor
(ER). ER forms a dimer.
Each ER binds to 2 Zn2+ .
All steroid receptors
have the C4 motif
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44. B io l o g ic a l F u n c t io n o f Z in c
Classes of zinc finger
C6 motif
Gal4. Forms a dimer. 6
Cys residues bind to 2
Zn2+
E.g. metabolic
regulators
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45. B io l o g ic a l F u n c t io n o f Z in c
Zinc Finger Motifs: Protein-Protein Interaction
RING-finger
specialized Zn-finger involved
in mediating protein-protein
interactions
a series of His and Cys residues
with a characteristic spacing
that allows the coordination of
two zinc ions
Ubiquitin Ligase complex
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46. B io l o g ic a l F u n c t io n o f Z in c
Zinc Finger Motifs: Protein-Protein Interaction
LIM domain
2 tandemly repeating Zn-fingers
Homeobox proteins
Transcription regulatory proteins
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47. B io l o g ic a l F u n c t io n o f Z in c
Z in c
M o le c u la r b io lo g y
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48. B io l o g ic a l F u n c t io n o f Z in c
Zn2+ and cell signaling
Interaction with signal transduction pathways
Protein phosphorylation and dephosphorylation
Second messenger metabolism
Enzyme regulatory activity
Activity of transcription factors
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49. B io l o g ic a l F u n c t io n o f Z in c
Interaction with signal transduction pathways &
Protein phosphorylation / dephosphorylation
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50. B io l o g ic a l F u n c t io n o f Z in c
Interaction with signal transduction pathways: Ca2+
signaling pathways
Electrical stimulation of cardiac cells can cause Zn2+ entry through voltage
gated Ca2+ channels
Elevation of extracellular Zn2+ can act via HHS-R to mobilize Ca2+ from
hormone sensitive Ca2+ stores → increases intracellular [Ca2+]
Ca2+ -Calmodulin dependent PK activity:
Low [Zn2+] increase calmodulin independent activity
High [Zn2+] inhibit the binding of Ca2+ -Calmodulin
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51. B io l o g ic a l F u n c t io n o f Z in c
Second messenger metabolism: Cyclic Nucleotides
cGMP PDE is activated by
Zn2+ upto 1µM; at > 1µM
cGMP PDE is inhibited
Increase in intracellular Zn2+ >
1µM increases cGMP
Increase in cGMP in turn
downregulates Zn2+ uptake
NO, an activator of guanylyl
cyclase enhances the
downregulation of Zn uptake
2+
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52. B io l o g ic a l F u n c t io n o f Z in c
Enzyme regulatory activity : Protein Kinase C function
PKC contain 2 Zn2+ binding motifs in the regulatory region
Zn2+ in nM concentrations can activate PKC and increase its
translocation to the cell membrane and cytoskeleton
The cellular redox state can affect PKC activity: Oxidation
causes release of Zn2+ from Zn2+ binding motifs of PKC →
increases autonomous activity of PKC,
decreases sensitivity to regulating cofactors.
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53. B io l o g ic a l F u n c t io n o f Z in c
Activity of transcription factors
Regulation through zinc finger domains:
MTF-1 (metal transcription factor-1)
CREB (cAMP response element binding protein)
Steroid receptors
Gal-4
Direct regulation:
Activation of NF-κB
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54. B io l o g ic a l F u n c t io n o f Z in c
Neuronal Zn2+ signals
There are three types of neuronal Zn2+ signals:
Zn2+ -SYN
Zn2+ -TRANS
Zn2+ -INT
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55. B io l o g ic a l F u n c t io n o f Z in c
Zn2+ -SYN
Synaptic vesicular Zn2+ in the presynaptic boutons is released on
axonal depolarization.
Zn2+ can reach 10-30μM in the extracellular fluid
Zn2+ -SYN reaches multiple Zn2+ modulated postsynaptic sites
Amino acid receptors: glutamate- and GABA- R
Tonic defacilitation of glutamate receptors: absence of synaptic Zn2+
increases seizures
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56. B io l o g ic a l F u n c t io n o f Z in c
Zn2+ -TRANS
Transmembrane flux of Zn2+. Zn2+-TRANS is analogous to
transmembrane Ca2+ flux.
The Zn2+ channels are Ca-AK channels and NMDA channels
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57. B io l o g ic a l F u n c t io n o f Z in c
Zn2+ -INT
Analogous to intracellular Ca2+ signal, but no organelle
analogous to SR/ER has been identified for Zn2+
Likely source of Zn2+ -INT is MT
NO is one of the main inducers of Zn2+ -INT signal
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58. B io l o g ic a l F u n c t io n o f Z in c
Role of Zn2+ in cell proliferation
Zn2+ increases IGF-1. IGF-1
causes G1→S transition.
Zn2+ stimulates GF-R which
act via MAPK pathway
Zn2+ increases phosphorylation
of Jun & ATF-2
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59. B io l o g ic a l F u n c t io n o f Z in c
Role of metallothioneins in Zn2+ mediated cell proliferation
& differentiation
Cellular MT levels oscillate during the cell cycle reaching a
maximum at G1→S transition.
MT translocates to nucleus during S phase in rapidly
proliferating cells.
The nuclear translocation of MT is a vehicle for achieving high
nuclear zinc level in the S-phase of the cell cycle.
Similarly MT translocates into the nucleus of differentiating
cells. E.g. preadipocytes, myoblasts. After differentiation, MT
translocates back to the cytoplasm.
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60. B io l o g ic a l F u n c t io n o f Z in c
Zn2+ inhibits apoptosis
Mitochondria releases ROS which causes
lipid peroxidation, DNA damage, Protein
SH oxidation
Mitochondria channel input signal
pathways to the central pathway of
Bcl-2(anti-apoptotic) or Bax (pro-
apoptotic) genes.
Bcl2/Bax ratio determines whether cells
are apoptosed or not.
When cells pass the Bcl2/Bax
checkpoint, Cytochrome C is released
Cyt C activates the caspase cascade.
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61. B io l o g ic a l F u n c t io n o f Z in c
Zn2+ inactivates the
caspase cascade
Zn2+ binds to Cys163 and
prevents disulfide bond
formation
This prevents dimerization
of Caspase-3 and inhibits
its activity.
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62. B io l o g ic a l F u n c t io n o f Z in c
Z in c
Im m u n o lo g y
E n d o c r in o lo g y
f u n c t io n
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63. B io l o g ic a l F u n c t io n o f Z in c
Immunological function of Zn2+
Effect of Zn2+ deficiency on neutrophils:
Decreases bone marrow production
Decreases chemotaxis and adhesion
Impairs phagocytosis and oxidative burst
Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 63
64. B io l o g ic a l F u n c t io n o f Z in c
Decreases NK cell lytic activity and IFNα production
Decreases monocyte/macrophage activation, phagocytosis
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65. B io l o g ic a l F u n c t io n o f Z in c
In B cells Zn2+ deficiency produces apoptosis
In T cells Zn2+ deficiency produces thymic atrophy → impaired
T cell development and decreased counts.
Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 65
66. B io l o g ic a l F u n c t io n o f Z in c
Endocrinological function of Zn2+
Insulin is stored in pancreatic islets as osmotically stable zinc-
insulin complex (2 Zn2+ : 6 insulin)
The hexamers are formed in the trans-Golgi complex.
Stimulating the islets by glucose and other stimulators result in
the release of the hexamer which immediately dissociates into
insulin and Zn2+.
Zn2+ ions released from β cells stimulate the secretion of
glucagon from α cells by a paracrine mechanism.
Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 66
67. B io l o g ic a l F u n c t io n o f Z in c
Zn2+ and Diabetes Mellitus
Plasma Zn2+ concentration is decreased
Glucose-mediated hyperzincuria and decreased gastrointestinal absorption of
zinc are responsible. Hyperzincuria responds partly to insulin treatment.
Hyperglycemia interferes with the active transport of Zn back into the renal
tubular cells.
Zinc supplementation reduces blood glucose level in type 1 diabetics.
At the molecular level:
Zn2+ inhibits post insulin receptor intracellular events which results in a decreased
glucose tolerance, and a relative decrease in insulin secretion.
Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 67
68. B io l o g ic a l F u n c t io n o f Z in c
Zn2+ and Type 1 Diabetes Mellitus
Type I DM is an autoimmune destruction of islets of pancreas
mediated by free radicals.
Zn2+ is required for the function of Superoxide dismutase,
catalase and peroxidase.
Zn-metallothionein complex in the islet cell provides protection
against free radicals.
Zn2+ deficiency impairs the function of these enzymes and
increases autoimmune destruction.
Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 68
69. B io l o g ic a l F u n c t io n o f Z in c
Zn2+ and Type 2 Diabetes Mellitus
In Type 2 DM there is insulin resistance
at the receptor level.
In the initial stages this leads to
increased insulin secretion
Excessive Zn2+ ions are co-secreted
with insulin during hyperglycemia
Zn2+ induces islet cell death
Endogenous Zn2+ translocates to other
islet cells, probably leading to their
death
Chelation of released Zn2+ inhibits islet
cell death in vitro and diabetes in vivo
Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 69
70. B io l o g ic a l F u n c t io n o f Z in c
Summary
Zn2+ is an essential micronutrient that is maintained in the physiological range
by various homeostatic mechanisms
Zn2+ is essential for the function of enzymes and zinc finger proteins
Metallothioneins, MTF-1 & ZnT1 regulate the intracellular level of Zn2+
Zn2+ plays an important role in various signaling pathways
Zn2+ is essential for cell proliferation, differentiation and apoptosis
Zn2+ deficiency can decrease the function of the immune system
Zn2+ is essential for the normal function of the pancreas
Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 70
71. B io l o g ic a l F u n c t io n o f Z in c
Z in c
C a s e R e port
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72. B io l o g ic a l F u n c t io n o f Z in c
ACRODERMATITIS ENTEROPATHICA TYPE OF
DERMATOSIS
ZINC DEFICIENCY PRESENT
Bilateral, erythematous areas,
some of which are weeping, plus
vesicles, pustules and ulcers of the
lower extremities
Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 72
73. B io l o g ic a l F u n c t io n o f Z in c
Note the weeping nature of
some of the lesions on the
dorsum of the foot. Yellowish
foci probably correspond to
pustules histologically. One of
the small blisters it at the tip of
the arrow. Erosions are present.
Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 73
74. B io l o g ic a l F u n c t io n o f Z in c
Low power view, biopsy #1. The keratinocytes in the upper 1/3
of the epidermis are slightly pale when compared to those in the
lower epidermis. All of the keratinocytes are much larger than
normal.
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75. B io l o g ic a l F u n c t io n o f Z in c
High power view of above (biopsy #1). Dyskeratosis of the type
that has been described as being the result of condensation of
tonofilaments in other diseases is apparently present here
(arrows). Spongiosis and edema of the papillary dermis are also
present.
Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 75
76. B io l o g ic a l F u n c t io n o f Z in c
High power view of the superficial part of biopsy #1 showing
polymorphonuclear leukocytes within the upper levels of the
epidermis. More of these would have resulted in a pustule. The
pallor of the keratinocytes in this area may be the result of
increased cytoplasmic volume. The parakeratotic cap would
account for a scaly lesion.
Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 76
77. B io l o g ic a l F u n c t io n o f Z in c
Low power view of biopsy #2. The pallor of the superficial part
of the epidermis is striking. Intraepidermal vesicles may result
from severe ballooning of keratinocytes (intracellular edema in
this case) or the coalescence of ballooned keratinocytes.
Spongiotic vesicles also are forming.
Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 77
78. B io l o g ic a l F u n c t io n o f Z in c
High power view of biopsy #2. The keratinocytes, even those in
the basal layer, are huge, and some seem about to explode. There
are small defects at the dermoepidermal junction in this area.
Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 78
79. B io l o g ic a l F u n c t io n o f Z in c
Very high power view of the dermoepidermal junction in biopsy
#2.
Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 79
80. B io l o g ic a l F u n c t io n o f Z in c
Q u e s t io n s ?
Ju n e 2 6 , 2 0 1 2 T o t a l s l id e s : 7 8 80
Notes de l'éditeur
In ancient India the production of zinc metal was very common. Many mine sites of Zawar Mines, near Udaipur, Rajasthan;- Zawarmaala were active even during 1300-1000 BC. There are references of medicinal uses of zinc in the Charaka Samhita (300 BC). The Rasaratna Samuccaya (800 AD) explains the existence of two types of ores for zinc metal, one of which is ideal for metal extraction while the other is used for medicinal purpose. [ citation needed ] Zinc alloys have been used for centuries, as brass goods dating to 1000 – 1400 BC have been found in Israel and zinc objects with 87% zinc have been found in prehistoric Transylvania . Because of the low boiling point and high chemical reactivity of this metal (isolated zinc would tend to go up the chimney rather than be captured), the true nature of this metal was not understood in ancient times. The manufacture of brass was known to the Ebi by about 30 BC , using a technique where calamine and copper were heated together in a crucible. The zinc oxides in calamine were reduced, and the free zinc metal was trapped by the copper, forming an alloy . The resulting calamine brass was either cast or hammered into shape. Smelting and extraction of impure forms of zinc was accomplished as early as 1000 AD in India and China . In the West, impure zinc as a remnant in melting ovens was known since Antiquity, but usually discarded as worthless. Strabo mentions it as pseudo-arguros — "mock silver". The Berne zinc tablet is a votive plaque dating to Roman Gaul , probably made from such zinc remnants. Metallic zinc in the West The English metallurgist Libavius received in 1597 a quantity of zinc metal in its pure form, which was unknown in the West before then. Libavius identified it as Indian/Malabar lead. Paracelsus ( 1516 ) was credited with the name "zinc". It was regularly imported to Europe from the orient in the 17th century , but was at times very expensive. The isolation of metallic zinc in the West may have been achieved independently by several people: Dr John Lane is said to have carried out experiments, probably at Landore , prior to his bankruptcy in 1726 . Postlewayt 's Universal Dictionary, the most authentic source of all technological information in Europe, did not mention zinc before 1751. In 1738 , William Champion patented in Great Britain a process to extract zinc from calamine in a smelter, using a technology somewhat similar to that used at Zawar zinc mines in Rajasthan . However, there is no evidence that he visited the orient. [2] The discovery of pure metallic zinc is also often credited to the German Andreas Marggraf , in the year 1746 , though the whole story is disputed. [ citation needed ] Before the discovery of the zinc sulfide flotation technique, calamine was the mineral source of zinc metal. Foods and spices that contain the essential mineral zinc
Oyster > 70 mg per serving Meats =2-3 mg per 100g Shellfish =2.7 mg per 100 g
The main mechanism for zinc uptake from the intestinal lumen is with ZIP4 (SLC39A4), a member of the ZIP family .This transporter is expressed at the luminal side of enterocytes through the small and large intestine.A related protein, provisionally designated hoRF1 , may contribute to zinc uptake from the colon. Genetic variants of this gen are associated with the rare familial condition acrodermatitis enteropathica. The proton coupled divalant cation transporter 1 ( DMT1 ,SLCA11A2)appears to provide a minor uptake route. DMT1 also transports iron, copper, cadmium and other divalent metal ions that may compete with zinc. Hydrogen ion/peptide cotransporter (PepT,SLC15A1) is a posible alternative route for zinc uptake when complex to small peptides.uptake as a complex with individual amino acids may explain why histidine and cysteine improve intestinal zinc absorption. Metallothinein regulates zinc transfer into portal blood through binding and retaining it within the enterocyte until shedding into the intestinal lumen. Zinc is exported from enterocytes into portal blood by transporters 1 (ZnT-1,SLC30A1) and 2 (ZnT-2,SLC30A2).ZnT-1 is upregulated when zinc intake is high. With increasing intra luminal concentrations, net zinc movement across the tight junctions of the epithelial lyer(paracellular pathway) becomes more significant.regulatory mechanisms involving DMT1 or metallotionein thus are bypassed when high-dose supplement are ingested.
Alcohol dehydrogenase uses two molecular tools to convert ethanol to acetaldehyde. The first is a zinc atom which is used to hold and position the alcohol group on ethanol. The second is a large NAD cofactor, which actually performs the reaction. The molecule on the left contains ethanol molecules bound to the two active sites. The ethanol, shown in green and magenta, binds to the zinc and is positioned next to the NAD cofactor. A hydrogen binds to the ethanol carbon and the zinc polarizes the oxygen of the alcohol group. The ethanol carbon loses a hydrogen to NAD and is now acetaldehyde.
Picture:Cartoon representation of the protein Zif268 (blue) containing three zinc fingers in complex with DNA (orange). The coordinating amino acid residues of the middle zinc ion (green) are highlighted.
Clinical information abstracted from the presentation by Anneli Bowen, M.D., Glen Bowen, M.D., and Payam Tristani, M.D. of the University of Utah Department of Dermatology They also provided the clinical photographs. April 2000 This 68 year male, with a history of arterial insufficiency of the lower extremities, was admitted for the evaluation of non-healing ulcers. There is a history of 'blisters' preceding the ulcers. There is a history of alcohol abuse in the past but not recently. His wife indicated that he eats well. There is no history of inflammatory bowel disease. There is an unexplained recent history of thirty pound weight loss. Physical examination revealed erythema, blisters, pustules, ulcers, and weeping yellowish areas of both lower extremities. Following two biopsies and the demonstration of abnormally low zinc levels on two occasions, the patient was placed on zinc supplementation. Levels of niacin, glucagon, and folate were normal. All of his lesions, with the exception of the ulcers, disappeared over a two week period. The persistence of the ulcers (one of which went into his Achilles tendon) and continued poor perfusion in spite of a right femoral artery bypass prompted the surgeons to amputate both legs. The histology of the skin from the amputation specimens (away from the ulcers) was normal. The cause for his zinc deficiency is not explained.
DISCUSSION Acrodermatitis enteropathica is classically a disease of infancy or childhood related to the malabsorption of zinc. Zinc deficiency can be an acquired condition in adults as a result of inflammatory bowel disease or as a result of nutritional deprivation of zinc. Eczematous, psoriasiform, and vesicular lesions have been described, and most of these occur in acral locations and, sometimes, additionally on the face. The dermatosis ('nutritional dermatosis') associated with zinc deficiency is stated to have the same pathology as that associated with niacin deficiency and that which is associated with the glucagonoma syndrome (necrolytic migratory erythema). Pallor of the superficial keratinocytes is seen in each of these. Spongiosis, infiltrates of polymorphonuclear leukocytes, intracellular edema, and intraepidermal vesicle formation have been described. It is likely that a variety of pathologic patterns may be observed as counterparts to the variety of clinical lesions observed.