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55 Cards in this Set
- Front
- Back
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What are the two major sites of heme synthesis? What do these organs make heme precursors for?
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Bone marrow and Liver; Hemoglobin and cytochrome enzymes, respectively.
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Heme has how many pyrrole rings? Heme is a particular pyrrole called:
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4. Heme is a Protoporphyrin IX
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Porphyrins have three groups that "decorate" the surface: What do these groups allow?
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Methyl, vinyl, and propionyl groups. It allows binding to various proteins.
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What is the difference bn Ferroprotoporhryin IX (heme) and Ferriprotoporphyrin IX (hemin)?
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Heme = Fe2+
Hemin = Fe3+ (the oxidized form) |
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What is the committed step in heme biosynthesis?
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Conversion of succinyl-CoA + Glycine to Aminolevulinate.
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What two molecules provide all of the C and N atoms to porphyrin molecules?
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Succinyl-CoA and Glycine
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Where is ALAS located? How does this enzyme get to its location?
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The inner mitochondrial membrane. Must be transported from nucleus to Mito membrane.
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What co-factor is required by ALAS?
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PLP - pyridoxal phosphate
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How is ALAS1 regulated? At what level(s) does it regulate?
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Via feed-back inhibition by FREE heme - it regulates at the translational, transcriptional, and translocational level.
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What is the difference between ALAS1 and ALAS2? (p337)
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They are regulated differently and:
ALAS1: Isoform in Liver ALAS2: Isoform in reticulocytes cells. |
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Unlike ALAS1, Heme does not inhibit ALAS2 in reticulocytes - instead it (Lecture 11/3 21:20):
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Heme stimulates synthesis of globin & ensures that heme and globin are synthesized in the correct ratio for assembly into hemoglobin.
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~100 drugs/metabolites increase ALAS1 activity. Why would you want this?
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Bc P450's requires porphyrin for its activity. Thus more ALAS activity = more P450's
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Describe the 2nd step of poryphoryin synthesis - i.e. what molecules/enzyme required; where does it happen; what kind of rxn is it. (p338)
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In the cytosol, 2 molecules of 5-Aminolevulinate are CONDENSED to Porphobilinogen (PBG) via ALA dehydratase (ALAD).
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What happens in the 3rd step? What enzyme is involved? What kind of rxn is it (happens 4 times) and what is liberated each time?
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1. Head to tail condensation of 4 porphobilinogen molecules to form a (hydroxymethyliblane (a linear tetrapyrrol).
2. Porphobilinogen deaminase (PBGD) 3. Condensation rxn with one ammonium ion being liberated each time. |
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What metal does ALA Dehydratase require? What's the significance of this?
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Zinc. Lead and other heavy metals can displace the Zn and eliminate ALAD's catalytic activity. As a result, there's an increase in ALA in the urine and clinical manifestations mimic acute porphyrias.
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When protoporphyrinogen oxidase is defective, what disease can it cause? What intermediate(s) accumulate and what are the two symptoms?
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Variegate Porphyria.
1. Protoporphyrinogen IX accumulates 2. Protoporphyrinogen IX and other intermediates show up in the urine 3. Pts are photosensitive |
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What is the role of Uroporphyrinogen III Cosynthase at step 3 of heme biosynthesis? (p338)
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It serves to direct the stereochemistry of the condensation rxn of the 4 hydroxymethylbilane molecules so that Uroporphyrinogen III is made vs the Uroporphyrinogen I molecule that is not in the heme biosynthesis pathway.
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What happens in Step 4 of heme biosynthesis? I.e. What is the enzyme? What is the major thing it does?
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Enzyme is Uroporphyrinogen Decarboxylase (UROD) and it catalyzes the decarboxylation of acetate side chains to methyl groups.
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In step 5 of heme biosynth, what does CPO do?
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Coproporphyrinogen III oxidase (CPO) converts Coproporphyrinogen III to Protoporphyrinogen IX by converting specific propionic acid side chains to vinyl groups.
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What happens in step six? What is it primarily doing?
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Protoporphrinogen IX is converted to Protoporphyrin IX via Protoporphyrinogen Oxidase that primarily moves double bonds.
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What happens in Step 7? What is the involved enzyme another target point for?
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Ferrochelatase inserts iron at a much higher rate than it would normally add spontaneously. The enzyme is a target for Lead
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What are porphyrias?
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A class of inherited or acquired disorders resulting from deficiency in the specific enzymes of the porphyrin biosynthetic pathway.
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Cyclic tetrapyrrole intermediates that accumulate due to step defect in heme synthesis results in what symptoms? Why?
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Cutaneous photosensitivity. The cyclic intermediates, in the presence of O2 and UV irradiation, generates reactive oxygen species that can produce cellular damage. Causes blistering, ulceration, scarring.
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When porphyrins are illuminated by ultraviolet light, what color do they exhibit? Where might you see this in pts?
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Red. You'll see this in their urine, teeth.
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Where in the Heme pathway can lead be a problem?
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At the ALA Dehydratase (Porphobilinogen) Step - it requires Zn+ but Pb can chelate instead. Also at the Ferrochelatase step where Fe is inserted into the compound.
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Variegate Porphyria is a disease with a defect in what enzyme? What are the symptoms? Who had this disease?
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Protoporphyrinogen Oxidase. Symptoms include cutaneous photosensitivity and intermediates prior to the block accumulate in the urine. Often asymptomatic until a drug is used or and anemia that overwhelms the deficient enzyme. Also causes odd behavior, prolonged periods of insomnia, bluish-red urine, blindness. King George III
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Excess ALA will be toxic to
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Neuro - excess is a neurotoxin.
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Heme is degrade to:
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Bilirubin
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During the metabolism of Heme, the body has to deal with two challenges:
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1. Handling hydrophobic products of prophyrin ring cleavage.
2. Retention, safe mobilization, and re-utilization of iron. |
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How is bilirubin excreted?
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It's excreted into bile by the liver.
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How are old RBCs disposed of? What system?
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Macrophages take them up in the reticuloendothelial system of the liver and spleen. (i.e. the rxn takes place in the endoplasmic reticulum of the MA)
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Bilirubin is harmful but it binds to this:
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Albumin
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The first step of heme catabolism takes place in the macrophage. What is it converted to and what color is it?
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Biliverdin - green
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The 1st catabolic step that produces biliverdin is mediated by what enzyme? What does it produce and what is required?
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Heme oxygenase.
Requires O2 and NADPH; Produces F3+ and Carbon Monoxide |
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What is biliverdin
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A linear tetrapyrrol
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What enzyme converts Biliverdin to Bilirubin? Where does this rxn take place? What energy source does it use? What does the rxn achieve? What does bilirubin complex to?
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Biliverdin Reductase. Occurs in the Cytoplasm of MA. Enzyme uses NADH or NADPH. Rxn basically just moves double bonds around.
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Once bilirubin is in the circulation, what keeps it solubilized?
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Albumin
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Where are these MA's that are breaking down heme?
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In the spleen and bone marrow.
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When the bilirubin is bound to albumin, what takes it up? Does albumin dissociate before or after being absorbed?
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Liver. Albumin dissociate before being absorbed into the enterocytes.
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Once bilirubin is inside the hepatocyte, what keeps it soluble?
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Ligandins
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Inside the enterocyte, the bilirubin is conjugated to ligandin. Then what is it transferred to before being excreted from the hapatocyte? Where does this take place?
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Bilirubin is conjugated to either one or two molecules of Glucuronic Acid via UDPGT. Rxn takes place in the ER of the hepatocyte.
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How is glucuronic acid-conjugated bilirubin released from enterocytes?
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Via MOAT (Multiorganic Anion Transporter). Requires ATP
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When the bilirubin reaches the intestinal tract, it is converted to what, by what?
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Converted to Urobilinogen by intestinal bacteria. (colorless)
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Some of the urobiliniogen is absorbed but 80% is further degraded to what by what? What color is it?
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Further degraded to Stercobilin by bacteria - it's the major pigment of feces.
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Some of the urobilinogen can be absorbed and sent to this organ: What is it converted to and what is the color?
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Sent to the kidneys to form Urobilin - giving urine it's yellow color.
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Hyperbilirubinemias (or jaundice) are classified into two types:
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1. Unconjugated
2. Conjugated |
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What does the van den bergh assay evaluate? How does it work?
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It measures the amount of conjugated bilirubin. Works by mixing a dye in a sample of both conjugated and unconjugated bilirubin. The conjugated form react very quickly, and unconjugated slowly. Another sample is reacted but in methanol where both conjugated and unconjugated react rapidly. The amount of unconjugated is equal to: TOTAL - Direct (conjugated) = Indirect (Unconjugated)
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What is Kernicterus?
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It is hyperbilirubinemia in neonates due to unconjugated bilirubin. This problem results from a delayed maturation of the liver and low activity of UDPGT. This can cause brain damage, hearing loss, cerebral palsy.
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How can Kernicterus be prevented?
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By exposing neonate to UV-light - this changes the bilirubin a form that can be excreted without conjugation.
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What is Crigler-Najjar Syndrome Type I, Type II and Gilbert Syndrom?
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In decreasing severity, they are inherited disorders in UDPGT expression which result in lowered hepatic conjugation of bilirubin.
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What disease is associated with MOAT defect? Note: This is a conjugated hyperbilirubinemia
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Dubin-Johnson.
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What is the name of the other disease associated with conjugated hyperlipidemia? (the first one is Dubin-Johnson)
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Rotor Syndrome
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How might hemolytic jaundice happen? Why? Is there excessive amounts of conjugated or unconjugated bilirubin?
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Major trauma causing extensive bleeding. The liver can't handle conjugating all of that free bilirubin and therefore you have an excessive amount of unconjugated/indirect bilirubin.
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If the bile ducts are blocked, it might cause this type of jaunice. Is there excessive amounts of conjugated or unconjugated bilirubin?
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Obstructive Jaundice. Since the conjugate form cannot be released, you see an excess of conjugated/direct bilirubin in the liver.
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If the liver is damaged by toxins, poisons, cardiac failure, or acute or chronic disease, you might get this type of jaundice: Is there excessive amounts of conjugated or unconjugated bilirubin?
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Hepatocellular Jaundice. This causes an excess of unconjugated/indirect bilirubin b/c the liver is damaged and cannot conjugate the bilirubin.
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