Porphyrin Metabolism Flashcards
The overall synthesis of heme requires what?
8 enzymes, pyridoxal phosphate, Mg2+, O2, and reducing substances
What are the byproducts of heme synthesis?
8 CoA, 14 CO2, 4 NH4
Where is heme synthesis located?
liver and erythropoietic tissue
Erythropoietic tissue forms heme for ____. Liver forms heme for incorporation into ____.
hemoglobin; cytochromes
The first step and the last three steps of heme synthesis are located where?
mitochondria; the rest are cytosolic
This is a mitochondrial enzyme coded for by nuclear genes, synthesized on cytosolic ribosomes, and transported into the mitochondria. It requires pyridoxal phosphate and Mg2+.
Delta-Aminolevulinic acid synthetase
This is a cytosolic enzyme. It allows two molecules of Aminolevulinic Acid (ALA) - formed by D-ALA syntehetase -to condense and form porphobilinogen. It is very sensitive to heavy metals (Pb).
Delta-Aminolevulinate dehydratase
This enzyme and coenzyme allow four molecules of porphobilinogen to condense head-to-tail, and become cyclized to form uroporphyrinogen.
Uroporphyrinogen I synthase I and Uroporphyrinogen III co-synthase (cytosolic)
In the absence of uroporphyrinogen III co-synthase, what occurs, in regards to production of uroporphyrinogen.
In the absence of Uroporphyrinogen III co-synthase, large amounts of uroporphyrinogen I are formed, while in the presence of Uroporphyrinogen III co-synthase, essentially only isomer III is produced.
Urophyrinogen decarboxylase (cytosolic) catalyzes the sequential decarboxylation of the four acetic acid side chains to methyl groups. What is this enzyme inhibited by?
iron salts
What is the role of corproporphyrinogen oxidase, what does it require, and where is it located?
converts the propionic acid groups of ring A and B to vinyl groups. It is specific for the type III isomer.
It requires O2 but no other cofactor or metal
It is located in the mitochondria
This enzyme is specific for protoporphyrinogen IX, requires O2, and reducing substances. The product, protoporphyrin IX is more water insoluble than previous precursors.
protoporphyringoen oxidase (mitochondrial)
This is the last enzyme found in heme synthesis. It inserts ferrous iron into protoporphyrin IX to yield heme. It is sensitive to heavy metals and is membrane associated.
Ferrochelatase (mitochondria)
What is the rate limiting step of heme synthesis in the liver?
D-ALA synthetase
Heme inhibits ALA synthetase at three points. What are they?
inhibition of the synthesis of the enzyme
inhibition of transport of the enzyme into the mitochondria
allosteric inhibitor of the enzyme activity
Repression of the synthesis of ALA synthetase is very efficient. Why?
the half-life is short, about 60 min
If a patient came in with ALA dehydrase deficiency due to a defect in ALA dehydrase, what would be the major symptom and biochemical finding?
symptom: neurological
biochemical finding: ALA urine
If a patient came in with acute intermittent porphyria and a defect in uroporphyrinogen I synthase, what would be the major symptom and biochemical finding?
symptom: neurological
biochemical finding: ALA, PBG urine
If a patient came in with congenital erythropoietic porphyria and a defect in uroporphyrinogen III cosynthase, what would be the major symptom and biochemical finding?
symptom: photosensitivity
biochemical finding: uroporphyrin urine, serum and feces
If a patient came in with porphyria cutanea tarda and a defect in uroporphyrinogen III decarboxylase, what would be the major symptom and biochemical finding?
symptom: photosensitivity
biochemical finding: uroporphyrin, urine and feces
hereditary coproporphyria/defect in coproporphyrinogen oxidase
symptom: photosensitivity and neurological
biochemical finding: ALA, PBG, coproporphyrin urine; coproporphyrin feces
variegate porphyria/defect in protoporphyrinogen oxidase
symptom: photosensitivity and neurological
biochemical finding: ALA, PBG, coproporphyrin urine; protoporphyrin feces
erythropoietic protoporphyria/ferrochelatase
symptoms: photosensitivity
biochemical finding: protoporphyrin erythrocytes and feces
Describe heme catabolism
- Heme oxygenase of the reticuloendothelial cells - heme is released and converted to biliverdin
- Biliverdin is converted to bilirubin by biliverdin reductase
- Bilirubin is transported through the blood to the liver bound to albumin
- Bilirubin is conjugated to form a diglucoronide in the liver
- In the colon, bilirubin diglucoronide is converted to urobilinogen by intestinal bacteria
What is the only known source of endogenous CO?
Heme oxygenase
In the feces, urobilinogen becomes _____; In the urine, uroblinogen becomes ____
stercobilinogens; urobilins
Jaundice is yellowing of the skin due to increased plasma ____
bilirubin
Pre hepatic jaundice is due to production of bilirubin in excess of liver capacity to conjugate. Describe the status of serum, stools, and urine.
serum: increased total bilirubin with increased unconjugated bilirubin (direct)
stools: increased stercobilin excretion - normal color
urine: increased urobilin excretion
Hepatic jaundice is due to failure of liver to conjugate bilirubin. Describe the status of serum, stools, and urine
serum: increased total bilirubin with increased unconjugated bilirubin (indirect)
stools: decreased stercobilin - light color
urine: decreased urobilin excretion
Post hepatic jaundice is due to regurgitation of conjugated bilirubin into blood. Describe the status of serum, stools, and urine.
serum: increased total bilirubin with increased conjugated bilirubin (direct)
stools: decreased stercobilin - light color
urine: decreased urobilin - conjugated bilirubin is filtered by kidney and causes dark brown pigmentation of urine
Liver of neonate has limited capacity to conjugate bilirubin. True or false?
true
