intestinal absorption of minerals ii
DESCRIPTION
Intestinal Absorption of Minerals II. Iron and other micro-metals. Handling the metal internally. Expelling the metal from the enterocyte. Ferritin (Fe). Metallothionein (Zn, Cu, Cd). Serosal Side. Efflux system for export. - PowerPoint PPT PresentationTRANSCRIPT
Intestinal Absorption of Minerals II
Iron and other micro-metals
Handling the metal internally
Expelling the metal from the enterocyte
Serosal Side
Ferritin (Fe)
Metallothionein(Zn, Cu, Cd)
Efflux system for export
A metal ion upon entering the enterocytes is either delayed in transit or released quickly from antiluminal
(basolateral) surface into the system
Binding to internal stationary factors such as proteins and vesicles allows the metal to be sequestered for safety purposes and for regulating the flow of that metal into the system.
The above scenario plays out for Fe, Zn and Cu, where storage and transport proteins have been identified.
Metallothionein: Binds Cu, Zn, and Cd. Will not bind Fe
Ferritin: Binds Fe exclusively
Binding to Internal Factors
Ferritin
Gold are gated pores that control iron release from the inner core
24 subunits, with 2 distinct isoforms: H ferritin
and L ferritin To release iron, the Fe3+ must first be reduced to Fe2+.
H: predominates in heartL: predominates in liver
To store iron, the Fe2+ must first be oxidized to Fe3+
b.
Iron is stored in ferritin as Fe(III) in the mineral [FeO(OH)]8[FeO(H2PO4)]. This mineral
can be represented by ferrihydrite, FeO(OH) (shown above). Note: the name "ferrihydrite" is used for both [FeO(OH)]8[FeO(H2PO4)] and FeO(OH). Note: Iron (III)
ions are shown in brown, and oxygen (II) ions are shown in red.
Ferrihydrite
Iron Export from Mucosal Cells
Duodenal Lumen Duodenal Mucosa Plasma
Heme-Protein
Heme+
Polypeptides
Mucin(gastroferrin)
Fe3+
Fe3+
Fe3+
B2-microglobulin
HFE Biliverdin Bilirubin Bilirubin
CO COHeme
Oxygenase
Heme
FeFe2+2+
FeFe33
++
DCT-1
B3 integrin
paraferrin
Mobilferrin (vesicles)
FeFe2+2+ FeFe2+2+
FeFe33
++
Iron Absorption (heme and non-heme)
Ferroportin
Ferritin
FeFe3+3+
FR FeFe3+3+Haephestin
Transferrin
Ferroportin, the only way iron can escape from the cell.
Adriana Donovan and Nancy Andrews were the first to show the importance of ferroportin
Knockout mouse cells lacking the gene for ferroportin are unable to release iron
(blue)
Ferroportin appears to be the portal for releasing iron from the cell. Also called IREG1 and MPT1
FP
Ferroportin
Hc
Hepcidin (Hc) downregulates the surface concentration of ferroportin thereby controlling the concentration of the iron exported from the cell. Hc Considered the master regulator of cellular iron export
Hephaestin (a Cu protein):
Iron exported from the enterocyte at the basal surface is primarily Fe2+. In order to transfer Fe2+ to transferrin it must be oxidized to Fe3+.
Oxidation of Fe2+ to Fe3+ on the serosal side of the intestine is catalyzed by a copper protein, haephestin.
Haephestin (name after the Greek god of metals) was isolated as the gene product of a genetic defect in mice called Sex-Linked Anemia (SLA). Mice with the defect were iron deficient causing a pronounced anemia
Regulation of Iron Uptake
Exogenous dietary factors
Role of IRPs (Iron regulatory proteins)
Dietary Factors that Influence Iron Absorption
Amino Acids Organic Acids Sugars
CysteineGlycineHistidineLysineMethionine
AscorbateCitrateLactateMalatetartaric
FructoseSorbitol
Facilitate
Inhibit
BranHemicelluloseCellulosePectinGuar gum
Fibers PolyphenolicsFlavonoidsAnthrocyaninsIsoflavonoids
Others
OxalatesCarbonatePhosvitin (iron-binding protein in egg yolk)
Iron, a “one-way” metal
Excretion of iron from the body is not regulated
Iron status of the system is controlled only at the absorption stage
Intestinal iron transport is influenced by the amount of iron in the diet. Sequestering by ferritin when iron is in abundant supply is one mechanism. Another is regulating the surface density of the importing and exporting factors. DMT-1 and ferroprotin 1(FPN1), respectively. Both are subject to mobilizing effects in response to iron. When iron is low DMT1 is rich on the cell surface primed to input more iron. FPN1 in low iron is localize to the cytosol. When iron is enriched DMT1 is down-regulated, meaning it shifts to the cytosol. The opposite occurs with FPN1 where movement in response to iron is to the membrane preparing the cell to
release more iron.
How do you interpret these observations?
(iron-dependent enzyme in the cytosol)
Iron storage protein
No iron, no ferritin
Regulation at the level of transferrin receptor and ferritin mRNA
Iron regulatory protein (IRP)
Iron regulatory protein (IRP)
Iron response elements
Iron response elements
Transferrin receptor is believed to be the factor that tunes iron status of the body
to iron absorption in the intestine
Addendum
IRPs control the expression of DMT-1 (DCT-1, Nramp2) mRNA and protein and are critically important to secure physiological levels of ferroportin, the iron export protein. IRPs thus coordinate the synthesis of key iron metabolism proteins in the duodenum.
Galy et al, 2008
Vesicle Transport of Metals
Zn Cu
Metallothionein
A small metal binding protein with an unusually high amount of cysteine residues. One third of the residues are cysteine
Binding sites for Zn2+ and Cu+ in different locations of the protein
Primary role was considered to be detoxification, not nutrition
Metallothionein
6 copper atoms inside bound to cysteines
Cu
Cysteine
Storage and Release of Metals from Metallothionein
Reduced glutathione controls the storage of copper and zinc by glutathione; oxidized controls the release
Reduced
Absorption
Mucosa Serosa
Zn++ Zn++
NSBP
MTI
MTI-Zn
CRIP
CRIP-Zn
Zn++ Zn++
Zn++-Albumin
Albumin
CRIP=cysteine-rich intestinal protein; MTI=metallothionine; NSBP, non-specfic binding protein
Non-saturable = Passive Diffusion
Saturable =Bound to
form transportligand Zn++-Albumin
A 13-year-old girl presented with a history of red scaly plaques involving the chest, arms and legs beginning in infancy. Punch biopsy revealed psoriasiform hyperplasia and pallor of the epidermis. The patient's serum zinc level was 36 μg/dl [nl. 66-144 μg/dl]. A diagnosis of acrodermatitis enteropathica was established and the patient responded well to zinc replacement therapy. Acrodermatitis enteropathica is a rare autosomal recessive disorder caused by mutations in SLC39A4, which encodes the tissue-specific zinc transporter ZIP4
Cellular access
protein
Glucose, amino acid transporters
K+ channel protein, Na/K ATPase
CaT1 DCT-1 (DMT-1)?
Cytosol storage protein
None None Vesicles None
Cytosol
trafficking protein
None None Calbindin None
Basal export protein
Na/K ATPase None Ca-ATPase None
Plasma trafficking protein
None None Albumin Albumin
Sodium Potassium Calcium Magnesium
Proteins Involved in the Absorption and Transport of Macro-metals
Process
Cellular access
protein
Mobilferrin
DCT-1 (DMT-1)
Zip4 Ctr1
Cytosol storage protein
Ferritin Metallothionein Metallothionein
Cytosol
trafficking protein
Mobilferrin Zip4-containing vesicles, CRIP
Atox1
Basal export protein
Ferroportin ZnT1 ATP7A
Plasma trafficking protein
Transferrin 2- macroglobulin albumin
Albumin,
transcuprein, ceruloplasmin
Process Iron Zinc Copper
Proteins Involved in the Absorption and Transport of Micro-metals