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144 Cards in this Set
- Front
- Back
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what is ferrous iron?
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Fe2+
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what is ferric iron?
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Fe3+
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which form of iron is favored in alkaline or neutral pH?
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ferrous (Fe2+)
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which form of iron is favored in acidic pH?
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ferric (3+)
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what is the structure in heme to which iron is chelated?
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protoporphyrin IX
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what type of iron is found in heme?
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ferrous iron (2+)
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why is excess iron bad?
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forms complexes that can aggregate, can bind to and interfere with macromolecule function
(forms adducts and precipitates) |
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what is hemosiderin?
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iron storage complex within cells that doesn't allow for the iron to be released efficiently
contain ferritin, denatured ferritin and other materials |
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how is dietary iron in heme absorbed?
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directly through enterocytes
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how is dietary free iron absorbed?
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reduced from ferric to ferrous and transported into enterocytes via divalent metal transporter (DMT1)
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what is DMT1?
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enterocyte-specific divalent metal transporter
transports metals (must be in 2+ form) across the basolateral membrane of enterocytes |
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how is iron stored intercellularly?
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in ferrous form (Fe2+), bound to ferritin
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what is ferritin?
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ubiquitous intracellular protein that can bind thousands of iron atoms per protein and release them in a controlled manner
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what protein allows iron to leave the cell? in what form does iron leave the cell?
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ferroportin (IREG1)
ferrous form (Fe2+) |
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what protein, associated with ferroportin, oxidizes extracellular ferrous iron as it is released?
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hephaestin (ferroxidase)
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what enzyme in enterocytes (specifically duodenum) reduces dietary ferric iron?
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duodenol cytochrome B (DCYTB)
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through what protein does dietary heme directly enter enterocytes?
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heme carrier protein 1 (HCP1)
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what enzyme degrades heme to release its ferrous iron?
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heme oxygenase
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what transport protein binds to iron, carries it through the blood, and helps other cells to absorb it?
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transferrin
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what ubiquitous protein allows all cells to internalize iron from the blood?
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transferrin receptor
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what enzyme in hepatocytes reduces free ferric iron in the blood?
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ferrireductase (not DCYTB)
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what is ceruloplasmin?
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free-floating protein which acts as a major copper sink and as a ferrioxidase (oxidizing ferrous iron to ferric iron and promoting binding to transferrin)
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in hepatocytes, what protein allows ferrous iron to leave the cell?
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ferroportin
(not IREG1, not associated with hephaestin) |
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in cells other than enterocytes, what enzyme replaces the function of hephaestin?
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ceruloplasmin
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how is transferrin-bound iron taken into cells?
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binds transferrin receptor, causing it to internalize into an endosome, which becomes acidic causing transferrin to release Fe3+ (but not the transferrin receptor), followed by reduction of Fe3+, and transport out of endosome via DMT1
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what is STEAP3?
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enzyme bound in the endosomal wall, which reduces ferric iron (Fe3+) to ferrous iron (Fe2+)
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how does iron leave an endosome after its been released from transferrin?
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divalent metal transporter 1 (DMT1)
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how is iron released from transferrin?
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acidic conditions of the endosome
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what happens to transferrin and the transferrin receptor after iron has been released in an endosome?
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both recycled (receptor to cell surface, and transferrin into blood)
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where is transferrin made?
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in liver
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what is ferritin called before it is bound to iron?
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apo-ferritin
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how many atoms of iron can one ferritin protein bind?
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2000 - 4500
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when/where is hemosiderin primarily found?
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in macrophages
following hemorrhagic events |
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what is the major mechanism of iron utilization regulation?
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iron-mediated control of translation
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what are IREs? where are they?
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iron regulatory elements
in transferrin receptor and ferritin mRNAs (secondary structures in RNA) |
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what is the main site of iron storage?
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liver
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what is the main site of iron utilization?
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bone marrow (about 70% is in hemoglobin)
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why is extensive dietary absorption of iron not necessary? how much is absorbed?
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body stores and recycles it effectively
1-2mg/day is absorbed from diet |
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what happens to excess dietary iron?
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excreted in feces
stored in enterocytes |
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what hepatic protein regulates the level of iron absorption?
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hepcidin
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when are hepcidin levels high? low?
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high iron diet
low iron diet |
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how does hepcidin function?
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inhibits presentation of DMT1 and IREG1 in intestinal membranes
(unknown if it is transcriptional regulation or localized regulation) |
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what is caused by loss of hepcidin?
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severe iron overload
hemochromatosis |
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what is hemochromatosis?
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defect in iron metabolism characterized by excessive absorption leading to saturation of iron-binding proteins, most notably transferrin
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what are the principal affected tissues by hemochromatosis?
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liver
pancreas skin |
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what is the effect of hemochromatosis on the liver?
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cirrhosis of the liver
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what is the effect of hemochromatosis on the pancreas?
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changes characteristics of beta cells and inhibits insulin secretion, causing bronze diabetes
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what is bronze diabetes?
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diabetes caused by hemochromatosis, which is associated with tanning or bronzing of the skin
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what are the names for HFE hemochromatosis?
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primary hemochromatosis
type 1 hemochromatosis hemochromatosis |
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what is the most common inherited mutation leading to type I hemochromatosis?
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C282Y
(classically described in pathology) |
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what is the function of normal HFE1 complexes?
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bind to transferrin receptor controlling rate of iron transfer to cells
(inhibits iron uptake in cells) |
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what is encoded by the HFE1 gene?
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MHC class I alpha-chain protein with three Ig-like domains that dimerizes with beta2-microglobulin
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what is the result of a mutation in HFE1?
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protein remains trapped intracellularly and cannot interact with transferrin receptor
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how is HFE hemochromatosis treated?
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phlebotomy
iron-chelating drugs |
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in what populations is type I hemochromatosis most common?
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middle-aged
men alcoholics |
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what causes non-HFE hemochromatosis?
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mutations in hemojuvelin gene
mutations in hepcidin gene mutations in transferrin receptor-2 gene mutations in ferroportin gene |
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what two forms of non-HFE hemochromatosis are juvenile?
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type 2A
type 2B |
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what two forms of non-HFE hemochromatosis are not juvenile?
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type 3
type 4 |
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what shows up in a prussian-blue stain of hepatocytes in a hemochromatosis patient?
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blue spots which are hemosiderin
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what characterizes iron deficiency anemia?
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microcytic red blood cells
hypochromic red blood cells |
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what results in iron deficiency anemia?
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decreased globin synthesis
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what are the common causes of iron deficiency anemia?
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excessive menstruation
multiple births GI bleeding |
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what are the common causes of GI bleeds?
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hiatal hernia
peptic ulcer GI tumor gastritis due to alcoholism medications that cause ulcers or erosion |
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what is treatment for iron deficiency anemia?
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oral ferrous sulfate
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what is the most common cause of iron deficiency anemia?
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GI bleeds
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what protein transfers copper from the intestine to the plasma?
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ATP7A (a P-type ATPase protein)
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to what protein is dietary copper bound and transported in blood?
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albumin
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to where is dietary copper delivered?
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liver (primary site for copper storage)
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to what protein is copper bound and transported when it is released from the liver?
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ceruloplasmin
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what chaperone transfers copper to intracellular storage sites?
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ATOX1
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with what protein is copper bound and stored intracellularly?
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metallothionein
(cystein intracellular metal binding protein - not specific for copper) |
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where does copper go that is in excess of the binding capacity of metallothionein?
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excreted into the biliary canaliculi
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through the transport action of what protein is excess copper excreted into the biliary canaliculi?
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ATP7B
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what protein facilitates the transfer of copper to ceruloplasmin?
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ATP7B
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what is Menkes disease?
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inability to absorb copper from intestinal lumen
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what are the symptoms of Menkes disease? when do they usually present?
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**wiry brittle hair**
progressive neuro-degeneration connective tissue abnormalities present by 3 months |
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what causes Menkes disease?
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defect in ATP7A gene
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what is Wilson disease?
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inability to get rid of excess copper
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when do hepatic symptoms manifest in patients with Wilson disease?
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late childhood or adolescence
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when do neurological symptoms manifest in patients with Wilson disease?
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second to third decade of life
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what are the neurological symptoms of Wilson disease?
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extrapyramidal, cerebellar, and cerebral-related symptoms
Parkinsonian tremors, diminished facial expressions, diminished movements, dystonia, and choreoathetosis |
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what is dystonia?
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a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures
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what is choreoathetosis?
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brief, quasi-purposeful, irregular contractions that are not repetitive or rhythmic, but appear to flow from one muscle to the next
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what are the psychiatric disturbances exhibited by about 30% of Wilson Disease patients?
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changes in behavior
personality changes depression attention deficit hyperactivity disorder paranoid psychosis suicidal tendencies impulsivity |
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what is the most significant external diagnostic sign of Wilson disease?
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Kayser-Fleischer rings
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what are Kayser-Fleischer rings?
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copper deposition in Descemet's membrane of the cornea
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what are the purposes for heme?
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hemoglobin production (heme b)
cytochromes of oxidative phosphorylation cytochromes of oxygenases such as detoxifying enzymes |
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what are P450 class of enzymes?
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oxygenases, used as detoxifying enzymes
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where do the reactions of heme synthesis occur?
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first and last 3 are localized in mitochondria
intervening reactions are cytosolic |
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from where are all of the ring system atoms of heme derived?
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succinyl CoA
glycine |
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when does heme become fully colored?
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when it is fully conjugated
(about half way through the synthetic pathway) |
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what accumulations result from genetic enzyme deficiencies in heme synthesis?
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colored or colorless intermediates depending on the site of the metabolic block
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in heme synthesis, when are all of the reactions on the side groups of the ring system completed?
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before the molecule achieves its final colored state
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what is ALAS?
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delta-aminolevulinic acid synthase
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what type of ALAS is found in erythrocytes?
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type II
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what enzymes for heme metabolism are inhibited by heavy metal poisoning?
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ALA synthase
ALA dehydratase Ferrochelatase Heme oxygenase |
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what is the most common heavy metal poisoning?
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lead poisoning
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what is characteristic of lead poisoning?
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increased urinary ALA
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where does the majority of heme synthesis occur?
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erythrocytes
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what is hemin?
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heme with Fe3+ bound
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what is the feedback inhibitor of ALA synthase?
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hemin
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how does activate protein synthesis?
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through action of heme controlled repressor
(also regulates ferrochelatase and PBG deaminase) |
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what is important about the products of heme degradation?
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highly insoluble
need to be solubilized to be efficiently eliminated |
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why does iron need to be scavenged so effectively from heme?
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high rate of turnover of heme
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where does most heme catabolism occur?
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reticuloendothelial cells (mainly liver)
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to what is globin degraded?
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amino acids
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to what is heme degraded?
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bilirubin
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what substrate is required by heme oxygenase?
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heme (Fe2+)
any Fe3+ is reduced prior to degradation |
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to what is bilirubin bound in plasma?
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albumin
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what do hepatocytes convert bilirubin to? why?
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bilirubin diglucuronide (soluble)
bilirubin (insoluble) |
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what is required to degrade heme to bilirubin?
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NADPH
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why is bilirubin bad for cells?
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very hydrophobic and toxic
can disrupt membrane function can inhibit neural function |
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what degrades bilirubin in the body?
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UV light
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what is kernicterus?
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bilirubin poisoning of CNS
(unconjugated bilirubin in the neural cells) |
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what enzyme converts G-1-P to UDP-glucose?
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UDP-glucose pyrophosphorylase (UGP)
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what enzyme converts UDP-glucose to UDP-glucuronate?
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UDP glucose dehydrogenase (requiring NAD+)
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what enzyme adds UDP-glucuronates to bilirubin?
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bilirubin UDP-glucuronyltransferase (UGT1A1)
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how many glucuronates are attached to bilirubin in its conjugated form?
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two (attached to propyl groups)
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how is bilirubin usually excreted?
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diglucuronide is excreted into bile canaliculi and then excreted with feces
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what causes the typical yellow color of jaundice?
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extracellular accumulation of bilirubin, caused by blocking either the secretion of diglucuronide into the bile or preventing its formation
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what are bile pigments?
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intestinal bacteria products of bilirubin diglucuronide metabolism
includes urobilinogens and urobilins |
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when measuring direct bilirubin, what are you measuring?
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conjugated bilirubin
(bilirubin diglucuronide) |
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when measuring indirect bilirubin, what are you measuring? why is it called indirect bilirubin?
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unconjugated bilirubin
must treat with alcohol to release from serum albumin |
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which is worse in the body, direct or indirect bilirubin?
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indirect
inserts into plasma membranes and impairs cellular functions |
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which type of Crigler-Najjar Syndrome is generally benign?
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type II
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what causes Crigler-Najjar Syndrome?
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deficiency in hepatic UGT1A1 activity
(adds glucuronates to bilirubin) reduced - type II absent - type I |
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what is common in type I Crigler-Najjar Syndrome patients?
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severe kernicterus and death
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what causes Gilbert Syndrome?
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defect in UGT1A1 TATA-box
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what disorders in bilirubin metabolism result in unconjugated hyperbilirubinemia?
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Crigler Najjar Syndrome (CNS) types I and II
Gilbert Syndrome |
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what disorders in bilirubin metabolism are characterized by chronic conjugated hyperbilirubinemia?
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Rotor Syndrome
Dubin-Johnson Syndrome |
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what disorders in bilirubin metabolism are generally benign?
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Rotor Syndrome
Dubin-Johnson Syndrome Crigler-Najjar Syndrome type II Gilbert Syndrome |
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what causes Dubin-Johnson Syndrome?
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defects in bile canalicular multispecific organic anion transporter gene, CMOAT, leading to reduced biliary excretion
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what are the alternative names for the bile canalicular multispecific organic anion transporter?
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CMOAT
ABCC2 MRP2 |
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what causes X-linked sideroblastic anemia?
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defects in erythroid-specific ALAS2, which causes iron accumulation in erythroid marrow
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what are porphyrias?
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inherited and acquired disorders in heme metabolism
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what are the two classes of porphyrias? what are the other classifications?
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hepatic
erythroid acute cutaneous |
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what are the three types of pophyria cutanea tarda?
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type I - sporadic type (80%)
type II - UROD mutations type III - inherited defect secondarily affecting UROD (rare) |
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what is the most common type of porphyria?
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porphyria cutanea tarda (PCT)
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what is the most common hepatic porphyria?
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acute intermittent porphyria (AIP)
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what are the general symptoms of porphyrias?
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photosensitivity (benign to severe)
severe neurological failure severe hepatic failure |
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how is photosensitivity treated in porphyrias?
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avoiding sunlight
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what causes the symptoms of AIP?
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result from neurologic dysfunction, of unknown mechanism
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what is the most common symptom of AIP?
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poorly localized abdominal pain, with nausea and vomiting, that can be severe enough to require opiate treatment
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what can evoke symptoms of AIP?
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hormonal status
nutritional status certain drugs (barbituates, sulfonylureas, Ca2+ channel blockers) |
