Metabolism 12: Heme Metabolism Flashcards
Which tissues have the highest rate of heme synthesis and where do they incorporate it into?
Bone Marrow: hemoglobin incorporation in erythrocytes
Liver: Cytochrome incorporation (P-450 enzymes)
What enzyme is rate limiting and highly regulated in heme biosynthesis?
ALA Synthase (1st step)
What reaction does ALA synthase catalyze?
Succinyl CoA + Glycine -> ALA
What’s the difference between porphyrinogen and porphyrins?
Porphyrinogen: No double bonds at bridging carbons, colorless
Porphyrin: double bods at bridging carbons, colored
How can porphyrinogens be converted to porphyrins?
Non-enzymatically oxidized by light
What are the two ALA Synthases and where are tehy present in?
ALAS1: all tissues
ALAS2: bone marrow erythroid cell
How does regulation of heme biosynthesis differ between bone marrow and liver?
Liver: heme inhibits its own synthesis by decreasing ALAS1 activity
Bone Marrow: ALAS2: not regulated by heme
What is the sequence of heme synthesis?
Succinyl CoA + Glycine -> ALA ->Porphobilinogen -> Hydroxymethylbilane -> Uroprophyrinogen III -> Coproporphyrinogen III -> Protoporphyrinogen III -> Protoporphyrin III -> Heme
What is porphyria?
disease caused by partial deficiency of one of the enzymes in heme biosynthesis. Sx caused by increase in metabolic intermediates rather than lack of heme production
What enzyme is deficient in acute intermittent porphyria?
Porphobilinogen deaminase. Leads to increased levels of ALA and porphobilinogen and lower concentration of heme in liver
How does the lower rate of heme synthesis affect pts with acute intermittent porphyria?
Lower heme production reduces the feedback inhibition o ALA Synthase -> leads to more ALA and PBG to exacerbate the disease
What is the treatment for acute intermittent porphyria?
Glucose infusion and IV heme to suppress ALA Synthase
What is deficient in variegate porphyria?
Deficient in protoporphyrinogen oxidase -> leads to increased levels of protoporphyrinogen III and coproporphyrinogen III in liver
Why does blistering and skin lesions occur with variegate porphyria?
protoporphyrinogen and coproporphyrinogen are deposited in skin and converted to porphyrins by sunlight. The porphyrins are then degraded by light and generate tissue damaging singlet oxygen
What is seen in both variegate porphyria and acute intermittent porphyria?
Reduce heme syntehsis leading to increased ALA Synthase activity leading to increased ALA and PBG
What enzymes are inhibited in lead poisoning?
ALA Dehydratase, coproporphyrinogen oxidase, ferrochelatase
What is elevated with lead poisoning?
ALA, coproporphyrinogen, protoporphyrin III
How is erythrocyte destroyed?
Taken up by phagocytic cells of the reticuloendothelial system and destroyed
What is generated with hemoglobin degradation?
Heme(Fe and bilirubin) and globin(free amino acids)
What is the degraded product of heme degradation?
Unconjugated bilirubin (insoluble)
How is unconjugated bilirubin delivered to the liveR?
Carried in plasma complexed with albumin and then taken up by the liver via active transport for conjugation
How does the liver conjugate bilirubin?
Attaches 2 glucuronic acid groups to the unconjugated bilirubin
What happens to the conjugated bilirubin formed in the liver?
It is soluble and is secreted actively into bile canaliculus
What is another name for conjugated bilirubin?
bilirubin diglucuronide
What stool its brown color?
Presence of stercobilins which is generated when conjugated bilirubin in the intestine is digested by bacterial flora and then oxidized
What gives urine its yellow color?
Urobilin: oxidized form of urobilinogen
What is hyperbilirubinemia?
Elevated bilirubin in serum (>1 mg/dL)
Both unconjugated and conjugated
How does bilirubinemia cause jaundice?
Elevated bilirubin diffuses into tissue and makes them yellow.
When is jaundice detectable in the eye?
Serum bilirubin >2-2.5mg/dl
What are the clinical significances of conjugated/unconjugated bilirubinemia?
Conjugated Hyperbilirubinemia: benign
Unconjugated Hyperbilirubinemia: benign when <25mg/dL (Albumin binding capacity)
What happens when unconjugated hyperbilirubinemia exceeds 25 mg/dL?
free unconjugated bilirubin can enter brain and cause toxic encephalopathy (kernicterus)
What causes jaundice?
Hemolysis
Biliary Obstruction
Hepatitis/Cirrhosis
What does hemolysis result in?
increased blood unconjugated bilirubin
What does biliary obstruciton lead to?
increased blood conjugated bilirubin -> dark urine
Chalky white stool due to lack of stercobilins
How does hepatitis/cirrhosis cause jaundice?
Liver damage leads to decreased conjugation and thus decreased excretion of bilirubin
Mixed hyperbilirubinemia
What causes neonatal physiological jaundice?
fragile erythrocytes
immature hepatic system- decreased uptake, conjugation, and excretion of bilirubin
What results in neonatal physiological jaundice?
increased blood unconjugated bilirubin
If too high (>15mg/dl) can lead to kernicterus
What is the treatment for neonatal physiological jaundice?
Blue light: convert insoluble and BBB permeable unconjugated bilirubin to isomers that are soluble and impermeable to BBB -> excreted in urine or bile
