Download Objectives 19 - u.arizona.edu

1. HEME SYNTHESIS
- heme is an iron containing prosthetic group found in hemoglobin, myoglobin, and
cytochromes
- heme binds O2, participates in electron transfer, or oxidizes exogenous molecule
- reaction for synthesis occur both in cytoplasm and mitochondrial matrix; final step of
pathway  incorporation of iron (Fe2+) into molecule
- delta-aminolevulinate synthase (delta-ALA synthase) is initial reaction in heme synthesis:
combines succinyl CoA (carbon backbone) and glycine (nitrogen) delta-aminolevulinic acid
(delta-ALA); pyridoxal phosphate as a cofactor; committed, regulated step of porphyrin
biosynthesis; mitochondrial reaction because succinyl CoA comes from citric acid cycle,
amino acids, and odd-chain fatty acids via methylmalonyl CoA; delta-ALA transported from
mitochondria  cytoplasm
- ALA dehydratase (8 subunits, in cytoplasm, zinc cofactor, lead inhibition) combines 2
molecules of delta-ALA  porphobilinogen
- uroporphyrinogen synthase/uroporphyrinogen cosynthase form uroporphyrinogen III by
first combining 4 molecules of porphobilinogen  uroporphyrinogen I via
uroporphyrinogen synthase; then uroporphyrinogen I  uroporphyrinogen III by
uroporphyrinogen cosynthase
- a decarboxylase form coproporphyrinogen III from uroporphyrinogen III;
coproporphyrinogen III transported to mitochondria
- two oxidase reactions convert coproporphyrinogen III to protoporphyrin IX (hydrophobic)
- chelation of Fe2+ by ferrochelatase acting on protoporphyrin IX (in mitochondria);
ferrochelatase required ascorbate (vitamin C) as a cofactor; enzyme inhibited by lead; defect
in ferrochelatase  accumulation of protoporphyrin IX  its measurement in RBCs used to
identify iron deficiency or lead poisoning; heme is final product in mitochondria
- lead causes anemia due to inability to synthesize heme leading to reduction in functional
RBCs
Coordinated regulation of heme and globin synthesis
- heme is the major feedback regulator of the pathway, Heme:
1.) inhibits activity of pre-existing delta-ALA synthase (important)
2.) diminishes transport of delta-ALA synthase from cytoplasm  mitochondria after enzyme
synthesis
3.) repressed production of delta-ALA synthase by regulating gene transcription
4.) stimulates globin synthesis to keep free heme levels low (important)
Porphyrias are genetic deficiencies of enzymes in heme synthetic pathway; intermediates are
photosensitive due to unsaturated, cyclic molecular structure
Type
Acute intermittent
porphyria
Congenital
erythropoietic
porphyria
Enzyme involved
Uroporphyrinogen
synthase
Uroporphyrinogen
Cosynthase
Symptoms
Abdominal pain,
neuropsychiatric
Photosensitivity, dark
urine, hemolytic
anemia, cutaneous
lesions
Erythropoietic
protoporphyria
Ferrochelatase
Photosensitivity
Lab Tests
Increased urinary
porphobilinogen
Increased urinary
uroporphyrinogen I,
but no change in
porphobilinogen
(already converted)
Increased fecal
protoporphyrin IX,
red cell/plasma
protoporphyrin IX
2. HEME CATABOLISM
- RBC life is 120 days  hemoglobin degraded; amino acids from globins and iron recycled;
porphyrin is degraded  bilirubin is end product of heme catabolism
Blood cells
- hemoglobin broken down to globin and heme
- heme oxygenase converts heme backbone  biliverdin IXalpha; produces carbon
monoxide (CO)
- biliverdin reductase (NADPH  NADP+) converts biliverdin IXalpha  bilirubin (not
water soluble, unconjugated)  bilirubin transported from reticuloendothelial cell in to plasma
 binds to albumin  transported to hepatocyte (liver) via blood
Liver
- in hepatocyte  UDP-glucuronyltransferase conjugates bilirubin with 2 molecules of
glucuronic acid (derived from UDP-glucuronic acid)  bilirubin diglucuronide (water
soluble, conjugated)
Post-hepatic metabolism
- bilirubin diglucuronide excreted into bile duct to intestines
- lumen of intestine  bacterial enzymes act on conjugated bilirubin; first, glucuronic acid
residues removed; then, bilirubin backbone reduced to urobilinogen; some urobilinogen
absorbed by intestinal cells and set via blood to kidney where it is excreted in urine as urobilin
(yellow urine color); most urobilinogen oxidized to stercobilin  major excreted product from
heme (brown color to feces)
3.
- direct hyperbilirubinemia  elevated levels of conjugated, water-soluble bilirubin
- indirect hyperbilirubinemia  elevated levels of unconjugated, water-insoluble bilirubin
- mixed means elevation of both forms; jaundice  yellow skin/eyes due to deposition of
unconjugated bilirubin in skin and conjunctiva
- disorders of bilirubin metabolism categorized into: increased production, decreased
conjugation, and decreased excretion
Hemolytic anemia
- jaundice from hemolysis results from accelerated destruction of RBCs (hereditary
spherocytosis, sickle cell disease, hemoglobin turnover in newborns)
- production of bilirubin increases; no block in bilirubin conjugation and excretion 
bilirubin diglucuronide (conjugated) excreted into intestine increases; amount of bilirubin
produced far exceeds conjugating capacity of liver  unconjugated hyperbilirubinemia (in
blood)
- increased conjugated bilirubin released into bile duct (less increase than unconjugated form)
- production of bilirubin-UDP glucuronyltransferase delayed in newborn infants 
physiologic jaundice during 1st week of life
- unconjugated bilirubin deposited in skin  UV light photolyzes unconjugated bilirubin to
water soluble products
- capacity of liver to conjugate bilirubin increases during first few days of life
Hepatitis
- liver damage  destruction of hepatocytes; infectious hepatitis and acetaminophen poisoning
- jaundice results from impaired capacity to conjugate and secrete bilirubin diglucuronide into
bile
- high levels of unconjugated bilirubin (in blood); residual hepatic capacity to conjugate
bilirubin so a mixed hyperbilirubinemia is found  occurs because not all of conjugated
bilirubin can be excreted by the damaged hepatocytes causing it to exit cells into blood 
increased conjugated bilirubin in blood (equal to increase of unconjugated form)
Obstruction of biliary passage
- bile duct obstruction  failure of bile to reach lumen of bowel; gallstone in lumen of bile duct
- early stages  liver function normal  liver secretes conjugated bilirubin  direct
hyperbilirubinemia
- prolonged biliary obstruction  liver damage  direct and indirect hyperbilirubinemia
- stool is gray colored; conjugated bilirubin excreted in urine in large amounts
- small increase in unconjugated bilirubin in blood
- larger increase in conjugated bilirubin in blood
4. GENETIC DISORDERS
- Crigler-Najjar syndrome  inactivity of liver bilirubin-UDP glucuronyltransferase;
patients have very high levels of unconjugated bilirubin; I and II types, II is less sever
- unconjugated bilirubin is hydrophobic  increases causes bilirubin to be deposited in lipid
of brain  neurologic damage called kernicterus; profound jaundice
- Gilbert syndrome  milder defect in bilirubin-UDP glucuronyltransferase; mildly
increased level of unconjugated bilirubin; slight jaundice, illness
- Dubin-Johnson syndrome  defects of impaired biliary secretion (abnormal transport of
conjugated bilirubin into biliary system) produces elevated levels of conjugated bilirubin;
moderate jaundice