Final Metabolism

How does Cu circulate in blood, and what is involved in uptake of Cu in tissues?

60-70% of circulating Cu is ceruloplasmin. This delivers Cu to tissues. Tissues take up Cu via Ctr1 on cell membranes.

Under what condition does Zn inhibit Cu absorption and why?

>40mg of Zn will inhibit absorption because it inhibits metallothionine

Discuss acute vs chronic toxicity with iron

Acute: exceeds transferrin capacity which leads to free iron (pro-oxidant as it will generate free radicals) Chronic: 2x normal absorption independent of Fe stores. Organ failure with Fe deposition.

What factors inhibit iron absorption?

Alkaline pH, Polyphenols, Oxalic acid, Phytic acid, Phosvitin, Divalent cations

Identify the risk factors for Cu deficiency

Anemia, Leukopenia, Impaired immunity

How is zinc (and copper) transported in the blood?

Bound to albumin and other proteins

List inhibitors of Zinc absorption

Ca and Fe supplements (>20mg), Phytates and Oxylates, Polyphenols from tea and coffee, Folate supplements

How is Metallothionein affected by Cd

Cd binds very tightly to MT which displaces Zn resulting in altered gene expression. Regulates Zn distribution to enzymes, gene-regulatory molecules.

How is nonheme iron absorbed across the apical membrane?

Digestion from food (ferric iron) in stomach and intestine. Ferric iron reduced to ferrous (brush border reductase). Ferrous absorbed into enterocyte by DMT1 (duodenal; transports other minerals)

Discuss ZIP14 for zinc

Facilitates liver uptake. An acute phase responder. Levels are increased in infection and trauma; keep zinc in liver, not bacteria

What protein is involved in the transport of iron?

Fe3+ is transported in the blood by transferrin (delivers Fe to body tissues)

What are the concerns of having free Fe and Cu in cells?

Free Cu is pro-oxidant that is bound to amino acids, GSH, Chaperones (deliver Cu to specific locations). Free Fe is also pro-oxidant

List the starting material for heme synthesis and indicate what nutrients are required for heme synthesis

Glycine and succinyl CoA make ALA which makes Heme (B6 and Zn dependent)

Discuss the presence of iron in heme and RBCs

Heme synthesis is the largest functional use of Fe in the body. RBCs = 2/3 of body Fe (Fe transferred to erythropoetic cells by transferrin, Fe from RBC turnover)

List the selected functions/molecules in which iron plays a role

Heme synthesis, Myoglobin (facilitate diffusion of O2 from Hb to muscle), Cytochromes and other enzymes of ETC; Catecholemne, Serotonin, Melatonin synthesis; Catalase 4 heme groups (antioxidant, break down peroxide); Thyroid hormone synthesis (Fe deficiency leads to low T3 and T4)

Food sources of Iron

Heme: Beef/Chicken liver, Oyster Clams, Mussels, Poultry Non-Heme: Lentils, Beans, Spinach, Molasses

Discuss the sources of plasma iron

Hemoglobin (Hb), Ferririn, Hemosiderin degradation (phagocytes of reticuloendothelial system (liver, spleen, bone marrow))

List the factors that increase the risk of iron deficiency. How is deficiency treated?

Hemorrage, Dialysis, Decreased GI transit time, Altered absorption due to parasites, PEM, and antacid use. Treatment with supplements.

In addition to ferritin, what other protein is involved in the storage of iron, and under what conditions is it involved?

Hemosiderin... dominates in iron overload

How is hepcidin involved in the regulation of iron absorption?

Hepcidin is the main regulator in iron absorption. If there are high stores of iron then there is an increased synthesis of hepcidin in the liver. Hepcidin causes degradation of ferroporin on the basolateral membrane (then unable to transport iron out of enterocytes). If there are low iron stores than there is only a little bit of hepcidin released from the liver (sufficient ferroportin for export).

How is heme iron absorbed across the apical membrane?

Hydrolyzed from globin to release heme; stomach and intestine. Heme (with iron bound) absorption into enterocyte is carrier dependent (in proximal small intestine). Ferrous iron hydrolyzes from heme within enterocyte.

How does copper status affect iron levels?

If there is a Cu deficiency than it leads to an accumulation of iron in the intestine and the liver.

List and discuss the functions of Cu

Iron Metabolism via ceruloplasmin: ferroxidase and antioxidant (prevents Fe acting as pro-oxidant); Cu transport; Oxidize Fe2+ to Fe3+ (required for Fe transferrin transport) Superoxide Dismutase antioxidant enzyme (Cu and Zn dependent; Cu in active site) Lysyl Oxidase: Connective Tissue Formation (collagen and elastin crosslinking; maintain the integrity of connective tissue in the heart and blood vessels and also plays a role in bone formation) Energy production (Cytochrome c oxidase in ETC) CNS function: Dopamine to Norepinephrine Cu regulates genes involved in control of oxidative stress

How is iron stored in cells? How is ferritin impacted by iron status?

Iron can be stored as ferritin by incorpotation into apo-ferritin. If iron not needed, ferritin excreted with short-lived enterocytes (2-3 days). High iron absorption leads to increased ferritin synthesis. Low iron absorption leads to decreased ferritin synthesis.

How does iron status impact DMT1?

Low iron stores lead to increased DMT1 synthesis. Adequate/high iron stores lead to decreased DMT1 synthesis.

How does Metallothionein act as an acute phase responder?

MT as an acute phase responder: increased gene expression during infection, promotes Zn storage; prevent bacterial usage.

What is Metallothionein (MT)?

Main storage protein for Zn.

List the selected functions of zinc

Metalloenzyme component, Gene expression, Membrane/cytoskeletal stabilization, Immune function, Sexual maturation, Fertility and reproduction

List the food sources of copper

Organ meats, Shellfish, Legumes, Nuts, Whole grains

List food sources of zinc

Oysters, Red meat, Poultry, Beans, Whole/fortified grains

Discuss the concerns for vegetarians obtaining zinc in their diet

Phytates in whole-grain breads, cereals, and legumes will bind zinc and inhibit its absorption

How Cu status is assessed and identify any necessary precautions to be taken

Plasma Cu, Serum [ceruloplasmin]/activity (+/- supplementation), SOD in RBCs, Platelet Cu, Skin lysyl oxidase

Discuss Cu homeostasis and identify the key player. Include a discussion of Wilson's disease (defect, effects, treatment).

Primarily regulated by biliary excretion from liver to feces. (High bile Cu excretion with hi Cu intake; Low bile Cu excretion with low Cu intake).

Discuss how Cu deficiency leads to iron deficiency

Reduced hephaestin and ceruloplasmin activity...these are both Cu dependent proteins; oxidize Fe before export from enterocytes via ferroportin. Fe becomes trapped in enterocyte.

How is zinc status assessed?

Serum/Plasma Zn (influenced by multiple factors), Serum metallothionine (acute phase responder), Urinary Zn excretion, Carbonic anhydrase or alkaline phosphatase activity

Regarding zinc, copper and iron, what generally happens with these absorbed minerals within the intestinal cell?

Store, Use, Export

How is Cu stored in cells?

Stored with metallothionine temporarily and then lost in the feces 2-3 days later

How do gene defects in hepcidin affect iron status?

-Overproduction of hepcidin leads to iron refractory iron deficiency anemia -Absence of hepcidin leads to iron toxicity

What factors enhance iron absorption?

Sugars, Acids, Acidic pH, Mucin, Meat, Fish, and Poultry

How is Mo of therapeutic value?

Therapeutic in treatment of Wilson's disease in that it causes Cu excretions.

Who is at risk for developing a zinc deficiency? what are symptoms?

Those with GI disorders, Vegetarians, Pregnant and lactating women with marginal status, Alcoholics Skin Rash, Poor wound healing, Impaired growth and development (children), Depression (Adults)

What proteins are involved in the transport of iron across the basolateral membrane of enterocyte?

To be transported across the basolateral membrane, Iron must first be oxidized (Fe2+ to Fe3+). Oxidation is Cu-dependent hephaestins (or ceruloplasmin).Fe3+ is then transported across the basolateral membrane by ferroportin ("iron door")

How is Metallothionein regulated by Zn and how does high Zn affect Cu?

Transcriptionally regulated by Zn: High levels of Zn increase the expression of the thioneine gene which then increases MT levels. Also traps Cu in enterocytes (MT also stores Cu with high affinity)

Identify the brush border carriers for Cu absorption; discuss interactions with Fe

Cu Reductase, Ctr1, DMT1 DMT1 is a shared carrier with Fe and thus there is competition for absorption

How do Cu, Zn, Vitamin A, and Pb affect iron status?

Cu deficiency leads to Fe deficiency anemia (allows Fe to be used for Hb). Zn and Fe inhibit each others absorption. Low Vitamin A leads to iron accumulation in organs. Pb poisoning leads to Fe deficiency anemia.

How is Cu transported across the basolateral membrane? Name the players here and discuss Menkes disease.

Cu is actively transported across the basolateral membrane; facilitated by chaperones. If there is a mutation in the transporter ATP7A then Menkes disease will occur.

How is Cu delivered to the liver, and what happens to Cu in the liver? Indicate the important players here and effects of genetic disorder.

Cu is delivered to the liver via albumin. Once in the liver it is incorporated into Ceruloplasmin (facilitated by Atox1 and ATP7B). Liver also stores Cu in metallothioneine.

Discuss the primary carrier for zinc absorption and its regulation

ZIP4; high zinc, ZIP4 mRNA instability...decreased ZIP4 Low zinc, increased transcription and ZIP4 mRNA stability...increased zinc absorption

How does Zn function with insulin?

Zn and insulin granules are both in pancreatic β-cells; when there is low Zn there is a decreased insulin response which then leads to impaired glucose tolerance

How does Zn function in gene expression?

Zn binding to transcription factors called Zn fingers. The Zn fingers of transcription factors interact with MREs (metal response/regulatory element) in promoter region of selected gene. This will increase or decrease transcription. Some Zn fingers interact with mRNA to repress translation.

How does Zn function with immunity?

Zn is needed for the development and activation of T-cells

How does Zn function with wound healing?

Zn promotes health of skin and mucous membranes

Discuss Zn metalloenzymes and examples

Zn stabilizes tertiary structure and Zn functions at the caralytic site. Superoxide dismutase, Carboxypeptidase A & B; Aminopeptidase, Alcohol dehydrogenase, Δ ALA dehydratase