GI 2 Heme Synthesis
Terms
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- summary of Heme synthesis
-
glycine & SCoA
delta aminolevulinate
(from mito into cyto)
porphobilinogen
proprophorinogen III
(then into mito for M, P & V)
protoporphoryn IX
Heme
build porphoryn ring
-linear pyrrole
-cyclize to porphyrinogen - enzymes for heme synthesis
-
ALA synthase
ALA dehydratase
Uroporphyrinogen I synthase w/Uro III cosynthase
ferrochetolase - summary of heme degredation
-
heme
biliverdin (via heme oxegynase + O2 & NADPH)
bilirubin (via biliverdin reductase)
bilirubin diglucuronide (via UDP glucuronyl transferase)(conjugated) - Fe2+ protoporphyrin IX
- heme
- iron state in heme
- Fe2+
- location of heme synth
-
all cells
(not recycled-toxic)
no storage
mito then cyto then mito again - rate limiting step of heme synthesis
-
ALA synthase
in mitochondria
two isoforms:
-E erythroid
-N non-erythroid - regulation of heme synthesis
-
ALAS-E
-IRE in 5'
-increased Fe gives increased ALAS-e
(like ferritin)
ALAS-N
-negative feedback
-by heme & glucose
-induced by many drugs
insertion into mito is another poit of reg - porphobilinogen synthetase
-
aka ALA dehydratase
-in cyto
-zinc enzyme
-lead poisoning (b/c displaced) - function of Uro III cosynthase
-
to prevent spontaneous ring formation
(need AP AP AP PA)
with PBG deaminase
gives coproporphyrinogen III - substrate that returns to mito (in heme synth)
-
coproporphyrinogen III
(from PGB deaminase & cosynthase) - fate of coproporphyrinogen III
-
return to mito
oxidized
convert 2 propyl side chains to vinyl - characteristics of protoporphyrin IX
-
oxidized
fully conjugated ring system
from protoporphyrinogen IX
(colorless)
receives iron to become Fe 2+ protoporphyrin IX - ferrochetolase
- adds iron to protoporphyrin IX
- types of heme
-
a, b & c
differ by side chains & linkage to protein (covalent or non)
all have protoporphyrin - causes of porphyrias
-
no dz assoc ALA synthase mut
any other enzyme
nervous system
skin
variagate= have to stay out of the light - variagate porphyria
-
have to stay out of the light
mut in PGen IX oxidase
affects NS, skin - heme oxygenase
-
(catabolism)
in macrophages
opens ring
uses NADPH & O2
gives CO (only rxn in body), Fe3+ & NADP+
gives biliverdin -
reaction producing CO
(NOT CO2) -
heme oxygenase
degrade heme
open ring
in MPs
releases iron (Fe3+) - glucuronic acid
-
produced in liver
to conjugate bilirubin
from UDP glucose & 2 NAD - bilirubin UDP glucuronyltransferase
-
transfer UDP glucuronic acid onto bilirubin
not ready til birth
(premies jaundiced, babies take a while to activate) - bilirubin produced by
-
reduction of biliverdin
(via reductase)
uses NADPH - 2 types hyperbilirubinemia
-
prehepatic
-excess heme destruction
-excess of conjugated
-Rotor's
-Dubin Johnson
hepatobiliary
-lost ability to conjugate
-Crigler Najjar
-Gilbert's - vanden burg reaction
-
measures bilirubin
(direct vs indirect)
(prefixes go together) -
benign congenital liver disorder
males more than females
teens - early 30s (onset) -
Gilbert's
tx w/phenobarb
(stimulates UDP g transferase activity) - severe unconjugated hyperbilirubinemia at birth
-
Crigler-Najjar
fatal when enzyme absent
(UDP g transferace) - mild conjugated hyperbilirubinemia
- Dubin-Johnson or Rotor's
- purpose of bilirubin
-
antioxident
-supress oxidation of lysosomes
-protect myocardium & nervous tissue - phototherapy for jaundice
-
opens H bonds
increases solubility - heptaglobin
- picks up Hgb (if RBC lyses) & transport to liver
- hemopexin
- picks up loose heme