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Flashcards in porphyrin metabolism Deck (73)
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cyclic compounds that bind metal ions tightly
most important = heme
formed by linkage of 4 pyrrole rings through methenyl bridges
two double bonds are conjugated throughout system
ones in humans have asymmetrical rings - can have symmetrical ones in disorders



iron-binding compound responsible for:
- O2 transport in blood and muscle
- electron transport in mitochondria
- metabolism of fat-soluble compounds in the liver


pyrrole rings

form porphyrins
each ring has two side chains which are distributed around entire porphyrin molecule
Roman numerals specify the arrangement of side chains - asymmetrical when porphyrin is produced under normal physiological conditions


central pocket

of a porphyrin
can be occupied by a metal ion
iron is in heme
cobalt is in cobalamine (vitamin B12)
magnesium is in the chlorophyll in plants


physiological roles of heme proteins (list)

as mitochondrial cytochromes - in electron transport chain
in Hb and Mb to transport O2
as catalases
in cytochrome P450 proteins - drug metabolism
removal of H2O2 - catalase


heme proteins as mitochondrial cytochromes
what inhibits?

generate membrane H+ gradient required for ATP synthesis via electron transport chain
cyanide poisoning causes irreversible inhibition of mitochondrial cytochrome a3


heme in cytochrome P450 enzymes

needed for metabolism of fat-soluble compounds, formation of cholesterol, steroids, and arachidonic acid metabolites


heme in catalase

antioxidant enzyme hydrolyzes H2O2


steps in heme synthesis

1: ALA synthase catalyzes condensation of glycine and succinyl CoA to make delta-aminolevulinic acid (ALA)
2: ALA dehydrase condenses two molecules of ALA to make pyrrole compound porphobilinogen (PBG)
3: hydroxymethylbilane synthase condenses four molecules of PBG to make hydroxymethylbilane
4: uroporphyrinogen synthase catalyzes ring closure of hydroxymethylbilane to make uroporphyrinogen I
5: uroporphyrinogen III cosynthase isomerizes the D ring side chains of uroporphyrinogen I to make uroporhyrinogen III
6: decarboxylation and oxidation reactions convert uroporphyrinogen III to protoporphyrin IX
7: ferrochelatase catalyzes introduction of iron into protoporphyrin IX to make heme


where is heme synthesized?

primarily by liver and bone marrow specific isoforms of the necessary enzymes


ALA synthase

enzyme that catalyzes the first step of heme synthesis
condenses glycine and succinyl CoA to make delta-aminolevulininc acid (ALA)
releases CoA and CO2
irreversible reaction
hemin, oxidized form of heme (Fe3+), and glucose suppress transcription of ALA synthase gene - allows negatative feedback


what suppresses ALA synthase?

hemin, oxidized form of heme, and glucose
note: these suppress the synthesis of the mRNA, not the activity of the enzyme


ALA dehydrase

enzyme responsible for second step of heme synthesis = pyrole compound
condenses 2 molecules of ALA to make porphobilinogen (PBG)
releases two H2O
lead inhibits


hydroxymethylbilane synthase

enzyme responsible for 3rd step in heme synthesis
condenses 4 molecules of PBG to make hydroxymethylbilane
regulate reaction
second rate-limiting step
releases 4NH3


uroporphyrinogen synthase

enzyme responsible for 4th step in heme synthesis
catalyzes ring closure of hydroxymethylbilane to make uroporphyrinogen I - symmetrical


uroporphyrinogen III cosynthase

enzyme responsible for 5th step in heme synthesis
isomerizes the D ring side chains of uroporphyrinogen I to make uroporphyrinogen III - so that it's not a symmetrical heme and can be used biologically


uroporphyrinogen III

molecule made in 5th step of heme synthesis by enzyme uroporphyrinogen III cosynthase from uroporphyrinogen I
common precursor for chlorophyll, cobalamine, and heme in organisms that make those compounds
several steps make it into protoporphyrin IX, which has lots of conjugated double bonds that allow them to fluoresce


how could you tell the difference between porphyrins and their precursors?

porphyrins are purple and fluorescent
PBG and other porphyrinogens are colorless and don't fluoresce until they're oxidized



enzyme responsible for 7th step of heme synthesis
catalyzes the introduction of iron (Fe2+) into protoporphyrin IX to make heme
lead inhibits
releases 2 H+


classes of disease associated with abnormal heme synthesis (4 - list)

1: acute porphyrias
2: non-acute porphyrias
3: lead poisoning
4: iron-deficiency anemia


what steps of heme synthesis are disrupted by lead?

the enzymes ALA dehydrase and ferrochalatase are inhibited by lead
the first condenses two molecules of ALA to make PBG
the second catalyzes the addition of iron to make the final heme


acute porphyrias

autosomal dominant disorders characterized by blockade of the early, rate-limiting steps of heme biosynthetic pathway
results in decreased production of heme (and hemin)
example = acute intermittent porphyria (AIP)


acute intermittent porphyria (AIP) (everything we've learned about it)

due to deficiency in hydroxymethylbilane synthase
clinical signs: intermittent attacks of abdominal pain and neuropsychiatric symptoms (that go away with bowel movements)
attack precipitated by ingestion of drugs and other compounds
compounds induce production of CYP enzymes => consumption of heme => increase in ALA synthase levels and accumulation of ALA and PBG - ALA committed step
lack of negative feed back makes things worse
ALA causes abdominal pain because of its massive accumulation in the liver
neuropsychiatric symptoms due to similarity between ALA and GABA => ALA antagonizes GABA receptors
diagnosis is made by detection of excess PBG in urine - when urine stands, it oxidizes and turns purple
treat with intravenous hemin and glucose
patients should avoid precipitating drugs
can identify affected family members by PCR


what deficiency causes acute intermittent porphyria?
what is the result of this deficiency (what will build up)?

deficiency of hydroxymethylbiane synthase enzyme, which condenses 4 molecules of PBG to make hydroxymethylbilane

this will result in the build up of PBG and ALA (the precursor for PBG)


what are the clinical symptoms of acute intermittent porphyria (AIP)?

abdominal pain
neuropsyciatric symptoms


what usually triggers an attack of acute intermittent porphyria (AIP)?
why does this trigger an attack?

attacks are usually triggered by ingestion of drugs and other symptoms
this is because these compounds induce the production of CYP enzymes => heme consumption => increases in ALA synthase activity => increases in ALA and PBG
the ALA and PBG builds up in liver
patients with AIP are advised to avoid precipitating drugs


what causes the abdominal pain that patients with acute intermittent porphyria (AIP) experience?

buildup of ALA in the liver


what causes the neuropsyciatric symptoms that patients with acute intermittent porphyria (AIP) experience?

ALA and the neurotrasmitter GABA have very similar structures
ALA antagonzies GABA receptors


how do you diagnose acute intermittent porphyria (AIP)?

detect excess PBG in urine
leave urine to stand so that it can oxidize
if the patient has AIP, the urine will turn purple (because when the PBG oxidizes it becomes porphyrin, which is purple)


how do you treat acute intermittent porphyria (AIP)?

with intravenous hemin and glucose - ala synthase also negatively regulated by glucose
(get rid of/avoid inducers - cytochrome P450 can't work - so anything that needs those)
can consume blood - will alleviate symptoms