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Metabolism > Porphyrin metabolism > Flashcards

Porphyrin metabolism Flashcards

1
Q

Describe structure of porphyrin

A
  • 4 pyrrole rings with methenyl bridges
  • conjugated double bonds throughout
  • each ring has two side chains
  • the 8 side chains are asymmetrical under normal phys. conditions
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2
Q

porphyrin central pocket occupied by?

A
  • Iron - makes heme
  • Cobalt - makes cobalamine (vitamin B12)
  • Magnesium - makes chlorophyll in plants
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3
Q

4 physiological roles of heme proteins

A

1) Mitochondrial cytochromes - make H+ gradient for ATP synth in ETC
2) Hemoglobin and myoglobin - O2 transport in blood and muscle
3) Cytochrome P450 enzymes - metab of fat sol compounds, formation of cholesterol, steroids, arachidonic acid, important for drug interactions
4) Catalase - antioxidant enzyme hyrdrolyzes H2O2

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4
Q

Heme biosynth reaction 1

A
  • ALA sythase
  • condensation of glycine and succinyl CoA to form delta-aminolevulinic acid (ALA)
  • 1st of two rate limiting steps
  • irreversible
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5
Q

transcription of ALA synthase is inhibited by?

A
  • hemin (oxidized form of heme)

- glucose

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6
Q

Heme biosynth reaction 2

A
  • ALA dehydrase

- 2 molecules of ALA form the pyrrole compound porphobilinogen (PBG)

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7
Q

Heme biosynth reaction 3

A
  • Hydroxymethylbilane synthase
  • 4 PBG form hydroxymethylbilane
  • 2nd of 2 rate limiting steps
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8
Q

Heme biosynth reaction 4

A
  • uroporphyrinogen synthase

- ring closure of hydroymethylbilane to form uroporphyrinogen I

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9
Q

Heme biosynth reaction 5

A
  • uroporphyrinogen III cosynthase

- isomerizes D ring side chains of uroporphyrinogen I to form the III version

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10
Q

Uroporphyrinogen III is precursor to?

A
  • chlorophyll
  • cobalamine
  • heme
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11
Q

Heme biosynth reaction to create protoporphyrin IX

A
  • series of oxidation and decarboxylation reactions
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12
Q

Visible difference between porphyrins vs PBG and porphyrinogens?

A
  • porphyrins are purple and fluorescent whereas the others are colorless
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13
Q

Final heme biosynth reaction

A
  • ferrochelatase

- introduction of iron (Fe2+) into protoporphyrin IX to form heme

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14
Q

4 major disease states caused by abnormal heme sythesis

A
  • acute porphyrias
  • non-acute porphyrias
  • lead poisoning
  • iron-deficiency anemia
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15
Q

mechanism of acute porphyria?

A
  • autosomal dominant
  • blockade of early rate limiting steps of heme biosynth pathway
  • decreased production of heme
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16
Q

example of acute porphyria?

A
  • AIP - acute intermittent porphyria
  • intermittent attacks of abdominal pain, often following ingestion of drugs or chemicals
  • induced production of CYP enzymes which consume heme
  • triggers increase in ALA synthase levels and accumulation of ALA and PBG
  • pain caused by ALA accumulation in liver
  • ALA antagonizes GABA receptors causing neuropsychiatric symptoms
17
Q

acute intermittent porphyria diagnosis and treatment

A
  • AIP urine turns purple when left to sit (presence of PBG)
  • treat with intravenous hemin and glucose
  • avoid precipitating drugs
18
Q

mechanism of non-acute porphyria

A
  • blockade of normal heme biosynth pathway after formation of hydroxymethylbilane
  • accumulation of abnormal porphyrin derivatives in liver and skin
  • liver damage, skin rashes
  • no neuropsychiatric symptoms because ALA is normal
19
Q

example of non-acute porphyria

A
  • porphyria cutanea tarda (PCT)
  • reduced activity of enzymes leading to protoporphyrin IX
  • accumulation of uroporphyrins
20
Q

porphyria cutanea tarda treatment

A
  • regular phlebotomy

- avoid alcohol, liver toxins, excess sunlight

21
Q

mechanism of lead poisoning

A
  • lead inhibits ALA dehydrase and ferrochelatase

- same symptoms as acute intermittent porphyria because decreased ALA dehydrase leads to accumulation of ALA

22
Q

mechanism of iron-deficiency anemia

A
  • translation of erythroid ALA synthase mRNA is stimulated by iron
  • lack of iron decreases erythroid heme synthesis, causing anemia
23
Q

where does heme degradation take place

A

mostly in the spleen and liver

24
Q

degradation of heme steps 1 and 2

A
  • heme oxygenase for both steps
  • NADPH and O2 convert heme to biliverdin
  • biliverdin is green
  • iron released
25
Q

degradation of heme step 3

A
  • biliverdin reductase
  • NADPH used to reduce biliverdin to bilirubin
  • bilirubin is red/yellow
26
Q

what carries bilirubin through bloodstream to liver?

A

albumin

27
Q

degradation of heme step 4

A
  • in liver
  • bilirubin glucuronyltransferase
  • attaches 2 molecules of glucuronic acid to bilirubin to form bilirubin diglucuronide (water soluble)
28
Q

Intestinal fate of bilirubin glucuronide

A
  • converted by bacteria to urobilinogen

- urobilinogen is colorless

29
Q

fate of urobilinogen in intestine

A
  • most is oxidized to stercobilin (brown feces)

- some reabsorbed into blood and transported to kidney where converted to urobilin (yellow urine)

30
Q

what biochemical assay measures levels of both conjugated and unconjugated bilirubin in blood?

A

van den Bergh reaction

31
Q

what is the major symptom of abnormal heme degradation?

A

jaundice

32
Q

4 types of jaundice

A

1) hemolytic - red cell lysis like sickle cell anemia, abnormally high unconjugated bilirubin
2) obstructive - blockage of bile ducts like by gallstones, high conjugated bilirubin
3) hepatocellular - liver cell damage like by hepatitis, high liver enzymes (AST, ALT)
4) neonatal - low levels of bilirubin glucuronyltransferase activity during early infancy, treated by admin of blue fluorescent light to convert bilirubin into water-soluble metabolites

Metabolism (9 decks)

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