1. AA come together to form alpha and beta chains OR mRNA translation forms the alpha and beta chains
2. Gly and succinyl CoA form protoporphyrin IX
3. Ferric added to form heme (converted to ferrous)
4. heme combine with alpha and beta chains to form hemoglobin

• four pyrrole rings (5 member heterocyclic ring)
• pyrrole rings connected by one carbon bridges

• uroporphyrin- each pyrrole ring has acetate and proprionate side chain
• corproporphyrin- each ring with methyl and proprionate side chain
• protoporphyrin
  • two pyrrole rings have methyl and proprionate side chains
  • two pyrrole rins have methyl and vinyl side chains

• protoporphyrin (LEAST soluble)
• corpoporphyrin (limited solubility)
• uroporphyrin (MOST soluble)

1. synthesis of pyrrole ring
   1. Gly and succinyl CoA combine to form CoA, CO2 and 5-aminolevulinic acid   (5-ALA) via ALA synthase
      • RATE LIMITING STEP (5-ALA only used to make heme)
   2. two 5-ALA form 2 waters and 4 porphobilinogen via ALA dehydratase
      1. enzyme inhibited via Pb (lead)
   3. four porphobilinogens form 4NH3's and uroporphyrinogen III via synthase and cosynthase
      • synthase forms hydroxymethylbilane- a linear one carbon bridge with the four pyrrole rings
      • cosynthase takes the rings and forms the uroporphyrinogen III structure
2. synthesis of protoporphyrin
   1. uroporphyrinogen III form 4 CO2 and coproporphyrinogen III via decarboxylase
   2. corporphyrinogen III form 2CO2 and protoporphyrin via two oxidases
      • two propionate side chains converted to vinyl groups to form protoporphyrinogen IX via decarboxylation with first oxidase
      • second oxidase change oxidation state (double bonds at one carbon bridges)
3. synthesis of heme
   1. protoporphyrin IX and ferrous form heme protein via ferrochelatase

• medication that will:
  • decrease production of heme by inhibiting 5-ALA synthase
  • increase synthesis of alpha beta chain

• inhibits ferrochelotase and ALA dehydratase

Show increases in 5-ALA in the urine.

• two sets of symptoms
  • severe intestinal cramping
  • neuropsychiatric problems
• scarring
• increase hair growth (esp. on face)
• anemia

• build up of porphobilinogen and 5-ALA 
  • upregulation of 5-ALA synthase

Both of these compounds are very toxic to brain and intestines, so this is what causes neuropsychiatric and intestinal symptoms.

• build up of uroporphyrinogen I
• build up of 5-ALA and porphobilinogen, causing our neuropsyc. and GI symptoms
  • remember, the further down the pathway, the more lipid soluble we get
• these lipid soluble products in the skin
• UV light from sun cause production of free radicals
• leads to scarring seen
• place UV light on teeth, they turn red

Urine would have increase uropophyrinogen I.

1. iron separated from compound it is bound to by gastric acid to form ferrous
2. ferrous is able to move into the enterocyte
   1. ferric forms very stable complexes
3. apoferritin binds to ferrous ions to form ferritin (storage form of iron)
4. ferrous released from ferritin complex and go into blood
5. apotransferrin (empty protein carrier) and two ferrous ions bind to form transferrin (in ferric form)
   1. ferrous oxidized to ferric via ceruloplasmin
      1. copper transport protein, but has ferrous oxidase activity
6. transferrin go to various tissues where there are transferrin receptors
7. transferrin is endocytosed into cell
8. ferric dissociate from transferrin via lysosomal type particle to form apotransferrin
   1. pH of vesicle will go down (H pumped in)
   2. leaves ferric in the cel
   3. ferric binds to apoferritin to form ferriti
      1. has reduction and oxidation activity
9. apotransferrin exocytosed out of the cell so it can be recycled

1. endocytosed into macrophage
2. cell lysed
   1. forms membrane fragments and Hb
3. Hb splits to form heme and globin
   1. globins break down to form AA's
4. heme will become hemin
5. hemin, 2 oxygens, and NADPH form carbon monoxide, NADP, ferric, and billiverdin via heme oxygenase
   1. oxidize one of the bridge carbons
   2. leads to opening up of ring structure to form linear ring
   3. ferric go into ferritin
6. billiverdin and NADPH form NADP and billirubin via billiverdin reductase
   1. reduces the middle one carbon bridge
7. billirubin goes into blood and bound up by albumin
   1. because billirubin is water insoluble, it needs to be transported with protein
8. billirubin released from albumin and goes into hepatocytes
9. billirubin and UDP-glucoronide form 2 UDP's and billirubin diglucuronide via tranferase
   1. conjugation of the billirubin (remember, its very insoluble)
   2. glucuronic acids added to proprionates to make the compound water soluble
10. bilirubin diglucoronide used into bile
11. if it makes it into the large intestines, bacteria will deconjugate and oxidize the billirubin
12. excreted in feces (SEE GI physiology)

• sclera of eyes become yellow
• skin turns yellow
• because billirubin is lipid soluble, i will deposit it into the skin and eyes

JAUNDICE

• prehepatic
• genetic problems
  • Gilbret's syndrome (defect in transferase)
    • usually benign condition
    • Hct will show slightly darker color above after going through centrifuge
• problem within liver- build up of unconjugated billirubin
  • ex: cirrhosis, hepatitis
• post hepatic- obstructive jaundice w/gallstones

JAUNDICE common in premature babies (it takes a few weeks to build up and induce transferases), so we monitor the billirubin carefully (if it gets to high, it deposits into brain and causes severe brain damage).