Heme Biochemistry Flashcards
What are the key features of porphyrin rings in heme?
Have four 5-membered rings containing N connected by single C bridges
Iron present in ferrous state
Oxidation to ferric states inactivates Hb (methemoglobin)
Where does biosynthesis of heme primarily occur?
In the liver and erythroid cells of bone marrow
What are the three phases of heme biosynthesis?
Phase I - in the mitochondria
Phase II - in the cytosol
Phase III -in the mitochondria
What happens in phase I of heme biosynthesis?
Gly + succinyl CoA —> ALA via ALA synthase and vitamin B6 (PLP)
Inhibited by heme and hemin
What happens in phase II of heme biosynthesis?
ALA —> porphobilinogen via ALA dehydratase
Prophobilinogen —> hydroxymethylbilane via porphobilinogen deaminase
End result is production of coproporphyrinogen II which has a porphyrin ring
What happens in phase III of heme synthesis?
Generation of protoporphyrin and introduction of iron to form heme via ferrochelatase
What inhibits both ALA dehydratase and ferrochelatase?
Pb (lead)
Describe lead poisoning
Lead inactivates ALA dehydratase and ferrochelatase causing accumulation of ALA and protoporphyrin IX
ALA is neurotoxic and heme production is lowered
Causes anemia (microcytic and hypochromic)
Also impacts ATP synthesis and energy metabolism
What are porphyrias?
Inherited metabolic disorders caused by defects in heme synthesis
Different types including acute hepatic (neurological sx) and erythropoietic (affects skin and causes photosensitivity)
Describe congenital erythropoietic porphyria
Erythropoietic
Deficiency in uroporphyrinogen III synthase in RBCs
Results in buildup of uroporphyrinogen I and its oxidation production uroporphyrin I (not a substrate for the next enzyme)
What are the sx associated with congenital erythropoietic porphyria?
Produces a red color in urine, red fluorescence in teeth, destruction of RBCs and skin photosensitivity
Describe variegate porphyria
Defective protoporphyrinogen IX oxidase Hepatic form Autosomal dominant Photosensitivity and neurologic sx and developmental delay in children “Celebrity porphyrias”
Describe porphyria cutanea tarda (PCT)
Defective uroporphyrinogen decarboxylase
Hepatoerythropoietic form
Leads to accumulation of uroporphyrinogen III which converts to uroporphyrinogen I
MC porphyria in the US
Photosensitivity resulting in vesicles and bullseye on skin of exposed area, wine red colored urine
Describe acute intermittent porphyria
Hepatic form
Defective PBG deaminase in liver
Deficiency leads to excessive production of ALA and PBG
Periodic attacks of abdominal pain and neurologic dysfunction
Describe heme degradation
Handled by the reticuloendothelial system which degrades hemoglobin into globin and heme
Globin broken down into amino acids and heme processed for degradation
What is the process for heme degradation?
Heme broken down into biliverdin via heme oxygenase which requires O2
-release CO and iron is oxidized from ferrous to ferric state
Biliverdin converted into bilirubin via biliverdin reductase which requires NADPH
What is jaundice?
Elevated levels of bilirubin in the bloodstream (hyperbilirubinemia)
Imbalance between production and excretion of bilirubin
Can be pre, intra or post hepatic
Describe pre-hepatic jaundice
Increased production of unconjugated bilirubin
Excess hemolysis (hemolytic anemias), Internal hemorrhage, problems with incompatibility of maternal-fetal blood groups (in neonates)
Capacity of liver to uptake exceeded
Describe intra hepatic jaundice
Impaired hepatic uptake, conjugation or secretion of conjugated bilirubin
Caused by generalized hepatic dysfunction
Ex. Liver cirrhosis, viral hepatitis, Criggler-Najjar syndrome, Gilbert syndrome
Describe post hepatic jaundice
Aka cholestatic jaundice or cholestasis (decreased bile flow)
Problems with bilirubin excretion
Caused by obstruction to biliary drainage, cholangiocarcinoma, gall stones, infiltrative liver disease, lesions, drugs
What findings occur in post hepatic jaundice?
Elevated blood levels of conjugated bilirubin
Conjugated bilirubin is present in urine (will be dark)
Elevated ALP and no stercobilin in feces (pale stool)
Small increase in unconjugated form
Describe type I Criggler-Najjar syndrome
Results from deficiency of UDP-GT
Complete absence of the gene
Severe hyperbilirubinemia
BR accumulates in the brain of babies and causes encephalopathy (kernictus) and brain damage
What forms of therapy are used in type I Criggler-Najjar syndrome?
Blood transfusions, phototherapy, heme oxygenase inhibitors, oral Ca phosphate and carbonate, liver transplantation
Describe type II Criggler-Najjar syndrome
Benign form
Results from mutation in the UDP-GT gene
Enzyme has less activity
Describe Gilbert syndrome
Relatively common benign disorder
Results from reduced activity of UDP-GT
Serum BR <6mg/dL but may increase with fasting, stress, or alcohol consumption
What is hepatitis?
Inflammation of the liver
Leads to liver dysfunction
Causes include viral hepatitis (Hep A, B and C), alcoholic cirrhosis, liver cancer
Increased levels of unconjugated and conjugated BR in blood
BR accumulates in skin and sclera of the eyes causing yellow discoloration
Dark, tea colored urine
Describe the color change that occurs in bruises
Red - heme
Green - biliverdin
Orange - bilirubin
Reddish brown - hemosiderin (iron)
What is neonatal jaundice?
Physiological jaundice Elevation of unconjugated bilirubin Immature hepatic metabolic pathways Deficiency of UDP-GT enzyme Breakdown of fetal Hb as it is replaced with adult Hb
Describe phototherapy used to treat jaundiced newborns
When exposed to blue fluorescent light BR undergoes photo conversion to form more soluble isomers
What is another line of Tx for neonatal jaundice?
Intramuscular injection of tin mesoporphyrin (strong inhibitor of heme oxygenase) to prevent heme breakdown to form bilirubin
