University of Arizona



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 |Enzyme involved |Symptoms |Lab Tests |

|Acute intermittent porphyria |Uroporphyrinogen synthase |Abdominal pain, neuropsychiatric |Increased urinary porphobilinogen |

|Congenital erythropoietic porphyria|Uroporphyrinogen Cosynthase |Photosensitivity, dark urine, |Increased urinary uroporphyrinogen |

| | |hemolytic anemia, cutaneous lesions|I, but no change in porphobilinogen|

| | | |(already converted) |

|Erythropoietic protoporphyria |Ferrochelatase |Photosensitivity |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

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