heme synthesis and porphyrias

Question 1

where does heme synthesis start and what are the starting substrates?

Answer 1

mitochondrial matrix

glycine + succinal CoA ==> ALA (dela-aminolevulenic acid)
via ALA synthase

Question 2

where does the second step of heme synthesis take place and what is the enzyme and product?

Answer 2

cytosol

ALA is converted to porphobilinogen via ALA dehydratase

Question 3

where does the third step of heme synthesis take place and what is the enzyme and product?

Answer 3

cytosol

prophobilinogen is converted to hydroxymethylbilane via prophobilinogen daminase (aka hydroxymethylbilane synthase)

Question 4

where does the final step of heme synthesis take place and what is the rxn? enzyme?

Answer 4

protoporphorin IX + Ferrous (Fe2+) ironis converted to heme via ferrochelatase in the mitochondrial matrix

Question 5

what co-factor is required for ALA synthase?

Answer 5

B6 (pyridoxine)

Question 6

what drugs directly inhibit ALA synthase?

Answer 6

Drugs that interfere with vitamin B6

penicillamine, chloramphenicol and isoniazid

both interfere with pyridoxal phosphate

Question 7

how is ALA synthase affected by P450 inducers?

Answer 7

activated

Question 8

what effect do steroids have on ALA synthase?

Answer 8

steroids induce ALA synthase transcription

Question 9

what inhibits ALA synthase?

Answer 9

heme, hemin, hmatin, and glucose

used as treatments for acute intermittent porphyi

Question 10

what causes acute intermittent porphyria?

Answer 10

autosomal dominant defect in porphobilinogen deaminase, leading to accumulation of porphobilinogen and ALA which can be detected in urine

Question 11

what are the 5 Ps of acute intermittent porphyria?

Answer 11

pain in abdomen lasting several days
peripheral neuropathy
purple-red urine
pyschological disorders (especially depressino)
precipittation of attacks by alcohol, drugs or starvation

Question 12

what type of diet should be given to pt with acute intermittent porphyria?

Answer 12

high carb diet - glucose inhibits ALA synthase

should be given with hemin so as to replenish the depleted heme pool from defective porphobilinogen deaminase

Question 13

what enzyme is partially defective in porphyria cutanea tarda?

Answer 13

uroporphyrinogen decarboxylase ==> high levels of uroporphorinogen III

Question 14

what is the most common type of porphyria?

Answer 14

porphyria cutanea tarda

Question 15

what is a characteristic symptom of porphyria cutanea tarda?

Answer 15

photosensitivity and subseqently fragile skin that blisters with minimal sun exposure

Question 16

what drug can be given to treat porphyria cutanea tarda?

Answer 16

hydroxychloroquine

Question 17

what is the MOA of hydroxychloroqine treatment in porphyria cutanea tarda?

Answer 17

mobilizes phyrins that have accumulated in the liver

Question 18

is porphyria caused by defective heme synthesis steps in the cytoplasm or mitochondria?

Answer 18

cytoplasm

Question 19

how do barbituates trigger exacerbations of pophyrias?

Answer 19

P450 inducers cause consumption of heme and thus remove the negative feedback on ALA synthase, resulting in increased production of heme intermediates

Question 20

what does a defect in mitochondrial enezymes of heme sysnthesis cause?

Answer 20

sideroblastic anemia (especially ALA synthase and ferrochelatase)

e.g. X-linked hereditary sideroblastic anemia due to defect in ALA synthase-2 gene

Question 21

what two heme synthsis enzymes are inhibited by lead?

Answer 21

ALA dehyratase and ferrochelatase

Question 22

what pigment is responsible for the green pigment of bruises?

Answer 22

biliverdin – intermediate between heme and unconjugeated bilirubin