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IMS: Biochemistry > Heme Metabolism > Flashcards

Heme Metabolism Flashcards

1
Q

Heme

Structure and Function

A
  • Consists of protoporphyrin IX (aka III) plus iron
  • Synthesis occurs in all cells except mature RBCs
  • Prosthetic group in a variety of proteins:
    • Hemoglobin and myoglobin
    • Cytochromes
    • Cytochrome P450 proteins
    • Catalase & peroxidase
    • NO synthase and guannylate cyclase
    • Tryptophan oxygenase
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2
Q

Porphyrin Structure

A
  • Four pyrroles joined by methene groups
  • Substitutions on rings
    • A = acetic acid
    • P = propionic acid
    • M = methyl
    • V = vinyl
  • Series I and III are physiologically important
    • III series displays asymmetry
  • Metalloporphyrins
    • Heme: Fe2+
    • Chlorophyll: Mg2+
    • Vit B12: Co2+
      *
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3
Q

Heme Synthesis

A
  1. Succinyl CoA + glycine → δ-aminolevulinic acid (ALA)
    • Catalyzed by mitochondrial ALA synthase
    • PLP (Vit B6) coenzyme
    • Committed and rate-limiting step in heme synthesis
  2. Two ALA combine to form porphobilinogen (a pyrrole)
    • Catalyzed by cytosolic porphobilinogen synthase (aka ALA Dehydratase)
    • Zn coenzyme
    • Inhibited by Pb which replaces Zn
  3. Four porphobilinogens condensed to hydroxymethylbilane (linear tetrapyrrole)
    • Catalyzed by Hydroxymethylbilane synthase (aka porphobilinogen deaminase)
  4. Uroporphyrinogen III synthase (cytosol) inverts one pyrrole group in hydroxymethylbilane and closes the ring to form uroporphyrinogen III.
  5. Decarboxylation of all acetic acid side chains to methyl groups on hydroxymethylbilane forms coproporphyrinogen.
    • Catalyzed by uroporphyrinogen decarboxylase (cytosol)
    • Enzyme catalyzes decarboxylation of both uroporphyrinogen I and III.
  6. Oxidative decarboxylation of two propionic side chains of coproporphyrinogen III to vinyl groups forms protoporphyrinogen IX.
    • Catalyzed by Coproporphyrinogen III oxidase (mitochondria)
    • The enzyme does not decarboxylate coproporphyrinogen I.
  7. Protoporphyrinogen IX oxidase (mitochondria) catalyzes oxidation of protoporphyrinogen IX to protoporphyrin IX.
  8. Ferrochelatase (mitochondria) catalyzes insertion of Fe2+ into protoporphyrin IX (III) to form heme.
    • Enzyme inhibited by lead.
    • Mitoferrin transporter moves iron into mitochondria from the cytosol.
    • An energy-dependent transporter (ABC class) likely transports heme out of mitochondria.
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4
Q

ALA Synthase

A

ALAS-I (hepatic)

  • Expressed in all tissues
  • Regulated by heme
    • high [heme] inhibits
      • gene transcription
      • protein transport into mitochondria
      • increases mRNA degradation
  • Inducible
    • Barbiturates and other xenobiotics (alcohol)
      • By increasing P450 activity in liver
  • Low [PLP] decreases ALAS activity

ALAS-II (erythroid)

  • Expressed in erythroid tissues
  • Regulated by iron:
    • As [iron] increases, mRNA translation increases
    • Acts through a 5’ IRE
    • When Fe abundant, ALAS-2 translated
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5
Q

Formation of Series I

A
  • Uroporphyrinogen I formed by spontaneous ring closure of hydroxymethylbilane without inversion.
    • Occurs primarily when there is a decrease in activity of uroporphyrinogen III synthase.
  • Uroporphyrinogen I is converted to coproporphyrinogen I by uroporphyrinogen decarboxylase.
  • Uroporphyrinogen I and coproporphyrinogen I are spontaneously auto-oxidized to uroporphyrin I and coproporphyrin I.
    • Not metabolized further and excreted.
    • Porphyrins are photoactive molecules.
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6
Q

Oxidation of Porphyrinogen to Porphyrin

A
  • Porphyrinogens (reduced) can be enzymatically and non-enzymatically oxidized (auto-oxidation) to porphyrins (oxidized)
  • Heme pathway
    • Protoporphyrinogen IX to protoporphyrin IX
  • Porphyrins are photoactive molecules
    • Due to resonance
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7
Q

Porphyrias

A

Defects in heme synthesis.

  • Types
    • Non-erythropoietic
      • Acute
      • Chronic
    • Erythropoietic (all are chronic)
  • Caused by enzymatic blocks
    • Genetic or acquired
  • Results in:
    • increase in heme precursors in blood and urine
      • helps to identify the location of the block
    • decrease in heme
      • IV heme is a treatment for the acute porphyrins such as AIP
      • Phlebotomy to reduce cutaneous symptoms in the cutaneous porphyrins such as PCT
  • Presenting signs and symptoms
    • Early block in the pathway (prior to tetrapyrrole formation)
      • See nervous system effects
      • Ex. Acute intermittent porphyria (AIP)
    • Block is later in the pathway
      • See cutaneous effects/photosensitivity
        • Due to the presence of non-metalloporphyrins (photoactive molecules)
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8
Q

Acute Intermittent Porphyria

(AIP)

A
  • Defect in HMB Synthase
    • Causes increased ALA synthase activity
  • Affects non-erythropoietic tissues
  • Nervous system symptoms
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9
Q

Porphyria Cutanea Tarda

(PCT)

A
  • Defective Uroporphyrinogen Decarboxylase (UROD)
    • Causes increased ALAS activity
  • Can be induced by chronic liver disease
  • Clinical expression commonly requires exposure to environmental or infectious agents
    • Alcohol
    • Hepatitis
  • Affects non-erythropoietic tissues
  • Porphyrins accumulate
    • Photosensitivity
    • Discolored urine
  • Most common porphyria
  • Onset typically in the 4th to 5th decade
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10
Q

Lead Poisoning

A
  • Induces Porphobilinogen Synthase & Ferrochelatase dysfunction
    • ALA synthase increased
  • Can result in GI and neurobehavioral symptoms
  • Causes a hypochromic microcytic anemia
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11
Q

Sideroblastic Anemia

A
  • Caused by inactivating mutations in ALAS-II
  • Defect in heme synthesis results in stainable deposits of iron in erythroblasts = sideroblasts
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12
Q

Heme Transport

A

Free heme transported in the blood bound to hemopexin.

Free hemoglobin transported bound to haptoglobin.

Heme and Hb arise from intravascular hemolysis.

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13
Q

Heme Degradation

A

Heme is not reutilized.

Degradation occurs in the cytosol of phagocytic cells of the Reticuloendothelial System eg macrophages.

  1. Heme converted to Biliverdin by Heme oxygenase-1 in an O2 and NADPH dependent reaction.
    • HO-1 is an inducible enzyme of the ER
      • Hypoxia
      • Inflammation
      • Oxidative stress
    • CO produced
      • Appears to have anti-inflammatory effects
      • Functions as a signaling molecule
  2. Biliverdin converted by Biliverdin Reductase to Bilirubin in an NADPH dependent reaction.
  3. Bilirubin transported bound to albumin to the liver.
    • Free bilirubin = unconjugated/indirect
  4. Bilirubin successively conjugated with two UDP-glucuronic acids by Bilirubin UDP-Glucuronosyltransferase (UGT) to form Bilirubin diglucuronide (conjugated/direct)
    • Increases solubility & decreases toxicity
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14
Q

Bilirubin Assays

A

First total bilirubin (TB) and conjugated bilirubin (CB) measured.

CB subtracted from TB to indirectly measure the unconjugated bilirubin (UCB).

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15
Q

Bilirubin Excretion

A
  1. Bilirubin diglucuronide actively secreted across bile canicular membrane in the liver.
  2. Excreted as part of the bile into intestines.
  3. Gut bacteria remove diglucuronides.
  4. Bilirubin converted to Urobilinogen (+ others) by bacterial action.
  5. Urobilinogen:
    • Converted by colonic bacteria to stercobilin (bile pigment)
      • Gives stool brown color
    • Small amount reabsorbed in the gut
    • Majority returned to liver via circulation (enterohepatic recycling)
    • Remainder converted in the kidney to urobilin (bile pigment)
      • Gives urine yellow color
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16
Q

Effects of Bilirubin

A
  • Elevated plasma levels of unconjugated bilirubuin (UCB) toxic
    • Especially for developing neurological tissues
  • Low levels of UCB in plasma antioxidant
    • UCB auto-oxidized to biliverdin
    • Protect tissues from ROS and free radicals
    • Protective effect on cardiovascular disease and cancer
17
Q

Hyperbilirubinemia

A

An increase of bilirubin about normal for total serum bilirubin (TSB) of 1 mg/dL.

>95% of the TSB is UCB under normal conditions.

  • Symptoms
    • Jaundice
    • Kernicterus: deposition of UCB within neurons of the brain resulting in bilirubin encephalopathy
  • Caused by:
    • Excessive production of bilirubin (pre-hepatic)
    • Distrubance in conjugation of bilirubin (hepatic)
    • Interference in excretion of CB (hepatic or post-hepatic)
18
Q

Apoferritin

A
  • Found in most cells
  • 24 protein subunits
    • FtH (heavy)
      • Has ferroxidase activity (Fe2+ to Fe3+)
    • FtL (light)
  • Binds up to 4500 atoms of Fe3+
  • Apoferritin-Fe3+ complex termed ferritin
19
Q

Transferrin

A
  • Glycoprotein in the blood
  • Transports iron as Fe3+
  • Binds 2 atoms of Fe3+
  • Very high affinity
  • Normally only 1/3 saturated
20
Q

Hemosiderin

A
  • Amorphous deposit of iron hydroxide, iron phosphate, and protein
    • Golden brown granules
  • Occurs when intracellular [iron] exceeds binding capacity of ferritin
21
Q

Iron Metabolism

A
  • Duodenal enterocytes absorp ~ 1-2 mg iron/day
    • Compensates for iron loss from epithelial exfoliation
    • No regulated method of iron excretion
  • Iron transported into enterocytes as heme and non-heme iron
    • Heme iron better absorbed but lower concentration
22
Q

Enterocyte Iron Transport

A
  1. Heme imported by heme transporter on apical membrane.
    • Fe2+ released from heme intracellularly by heme oxygenase.
  2. Iron crosses membranes only as Fe2+
    • Fe3+ reduced to Fe2+ by Ferrireductase in intestinal lumen.
      • Enzyme requires Vit C
      • Vit C deficiency can lead to anemia
    • Fe2+ transported into cell by DMT-1 (Divalent metal transporter)
      • Symporter with H+
      • Excessive PPI use inhibits
    • Inside the cell, Fe2+ can either be:
      • Converted to Fe3+ for storage on Ferritin
      • Exported on the basolateral side by Ferroportin (IREG in physio)
        • Only known iron exporter.
23
Q

Plasma Iron Transport

A

Iron is only transported/stored in the Fe3+ state and only crosses membranes as Fe2+.

  • Fe2+ transported out of cells by Ferroportin.
    • Regulated by Hepcidin
  • Fe2+ is converted to Fe3+
    • By Hephaestin for enterocytes
      • Cu-containing feroxidase associated with enterocyte membrane
    • By Ceruloplasmin for non-enterocytes
      • Also contains Cu
  • Fe3+ bound by Transferrin
  • Transferrin-Fe3+ carries 2 iron molecules to the periphery.
24
Q

Hepcidin

A

The central molecule of iron homeostasis.

  • Binds to Ferroportin:
    • Induces internalization
    • Induces lysosomal degradation
  • Synthesized by the liver:
    • Excess iron → hepcidin synthesis increased → decrease in Ferroportin → decrease in release of iron from enterocytes
    • Deficient iron → hepcidin synthesis decreased → increased Ferroportin → increased release of iron from enterocytes.
  • Hepciden decreased in anemia and hypoxia.
25
Q

Hereditary Hemochromatosis

A
  • Pathological disease of excess iron
    • Most stored in ferritin and hemosiderin
  • Characterized by iron overload in the liver, heart, and other organs
  • All the result of inappropriately low levels of hepcidin
    • Autosomal recessive
    • Most commonly due to defects in HFE (high iron) gene
  • Symptoms:
    • cirrhosis
    • hepatic cancer
    • cardiomyopathy
    • DM
    • arthritis
    • skin pigmentation
  • Treated with phlebotomy to remove excess iron
26
Q

Iron Poisoning

A

Typically occurs in children due to accidental ingestion of vitamins containg iron.

Symptoms include GI distrubance to severe hydration.

Treatment with iron chelator such as deferoxamine.

27
Q

Iron Deficiency Anemia

A

Microcytic Hypochromic Anemia

  • Decreased heme synthesis in RBC
  • Treatd with iron supplements
28
Q

Anemia of Chronic Disease

A
  • Attributed to increased expression of Hepcidin
  • Leads to suppresion of Ferroportin
  • Decreased release of Fe from enteorcytes
  • Defense against iron-requiring pathogens
  • Ferritin levels increase
29
Q

Iron Recycling

A
  • Splenic macrophages phagocytize:
    • Old or damaged RBC
    • Hb (bound to haptoglobin)
    • Heme (bound to hemopexin)
  • Other cells use specific scavenger systems.
  • RBC → Hb → Heme → iron
  • Iron exported from macrophage by ferroportin (+ceruloplasmin)
  • Binds to transferring
  • Recycled iron meets ~ 90% daily need
30
Q

Cellular Iron Uptake

A

Uptake of iron involves the transferrin/transferrin receptor1 (Tf/TfR1) system.

of TfR1 on the membrane controls the rate of cellular iron uptake.

  • TfR1 binds transferrin-Fe3+
  • Receptor-ligand complex enters cells at clathrin-coated pits by receptor-mediated endocytosis
  • Acidification releases Fe3+ from Tf
  • Fe3+ → Fe2+ which is then transported out of the cell by DMT-1
  • Release of iron greatly reduces affinit of TfR for Tf causing dissociation
  • Transferrin and TfR1 recycled back to the membrane.
31
Q

Erythroblasts

A

Most iron in the body used by erythroblasts for synthesis of hemoglobin.

Mitochondria are the principal sites of iron utilization within the cell.

  • Iron carried into mitochondria by mitoferrin
  • Stored in the mitochondria on frataxin
32
Q

Apoferritin Regulation

A

Controlled at level of translation.

  • mRNA has one IRE in the 5’ UTR
  • IRP bound to 5’ IRE blocks translation
  • IRP degraded in conditions of high [iron] → mRNA uninhibited → Apoferritin translated
33
Q

Transferritin Receptor Regulation

A

Controlled at the level of translation.

  • mRNA has multiple IREs in the 3’ UTR
  • IRP binding IRE stabilizes mRNA allowing translation of more receptors.
  • Without bound IRP, mRNA unstable and quickly degraded
34
Q

Cellular Iron Homeostasis

A

Through control of cellular concentrations of TfR and apoferritin via control of translation:

IRE (iron regulatory elements) → cis-acting

IRP (iron regulatory proteins) → trans-acting

  • When [Fe3+] low, free IRP maintained and can bind to IREs.
  • When [Fe3+] high, free IRP decreased as a result of proteasomal degradation.
35
Q

Clinical Iron Tests

A

Serum iron: measurs iron bound to Tf in blood

Total iron binding capacity: the amount of iron needed to fully saturate Tf

Percent transferrin saturation: % of Tf saturated with iron ⇒ serum iron/TIBC x 100

Serum ferritin: measures the amount of ferritin in the blood, correlates with how much stored in cells

IMS: Biochemistry (10 decks)

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