heme synthesis and porphyrias Flashcards
where does heme synthesis start and what are the starting substrates?
mitochondrial matrix
glycine + succinal CoA ==> ALA (dela-aminolevulenic acid)
via ALA synthase
where does the second step of heme synthesis take place and what is the enzyme and product?
cytosol
ALA is converted to porphobilinogen via ALA dehydratase
where does the third step of heme synthesis take place and what is the enzyme and product?
cytosol
prophobilinogen is converted to hydroxymethylbilane via prophobilinogen daminase (aka hydroxymethylbilane synthase)
where does the final step of heme synthesis take place and what is the rxn? enzyme?
protoporphorin IX + Ferrous (Fe2+) ironis converted to heme via ferrochelatase in the mitochondrial matrix
what co-factor is required for ALA synthase?
B6 (pyridoxine)
what drugs directly inhibit ALA synthase?
Drugs that interfere with vitamin B6
penicillamine, chloramphenicol and isoniazid
both interfere with pyridoxal phosphate
how is ALA synthase affected by P450 inducers?
activated
what effect do steroids have on ALA synthase?
steroids induce ALA synthase transcription
what inhibits ALA synthase?
heme, hemin, hmatin, and glucose
used as treatments for acute intermittent porphyi
what causes acute intermittent porphyria?
autosomal dominant defect in porphobilinogen deaminase, leading to accumulation of porphobilinogen and ALA which can be detected in urine
what are the 5 Ps of acute intermittent porphyria?
pain in abdomen lasting several days
peripheral neuropathy
purple-red urine
pyschological disorders (especially depressino)
precipittation of attacks by alcohol, drugs or starvation
what type of diet should be given to pt with acute intermittent porphyria?
high carb diet - glucose inhibits ALA synthase
should be given with hemin so as to replenish the depleted heme pool from defective porphobilinogen deaminase
what enzyme is partially defective in porphyria cutanea tarda?
uroporphyrinogen decarboxylase ==> high levels of uroporphorinogen III
what is the most common type of porphyria?
porphyria cutanea tarda
what is a characteristic symptom of porphyria cutanea tarda?
photosensitivity and subseqently fragile skin that blisters with minimal sun exposure
what drug can be given to treat porphyria cutanea tarda?
hydroxychloroquine
what is the MOA of hydroxychloroqine treatment in porphyria cutanea tarda?
mobilizes phyrins that have accumulated in the liver
is porphyria caused by defective heme synthesis steps in the cytoplasm or mitochondria?
cytoplasm
how do barbituates trigger exacerbations of pophyrias?
P450 inducers cause consumption of heme and thus remove the negative feedback on ALA synthase, resulting in increased production of heme intermediates
what does a defect in mitochondrial enezymes of heme sysnthesis cause?
sideroblastic anemia (especially ALA synthase and ferrochelatase)
e.g. X-linked hereditary sideroblastic anemia due to defect in ALA synthase-2 gene
what two heme synthsis enzymes are inhibited by lead?
ALA dehyratase and ferrochelatase
what pigment is responsible for the green pigment of bruises?
biliverdin – intermediate between heme and unconjugeated bilirubin
