Gi 2 Heme Synthesis

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summary of Heme synthesis

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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

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enzymes for heme synthesis

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ALA synthase
ALA dehydratase
Uroporphyrinogen I synthase w/Uro III cosynthase
ferrochetolase

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summary of heme degredation

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heme
biliverdin (via heme oxegynase + O2 & NADPH)
bilirubin (via biliverdin reductase)
bilirubin diglucuronide (via UDP glucuronyl transferase)(conjugated)

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Fe2+ protoporphyrin IX

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heme

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iron state in heme

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Fe2+

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location of heme synth

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all cells
(not recycled-toxic)
no storage

mito then cyto then mito again

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rate limiting step of heme synthesis

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ALA synthase
in mitochondria

two isoforms:
-E erythroid
-N non-erythroid

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regulation of heme synthesis

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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

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porphobilinogen synthetase

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aka ALA dehydratase
-in cyto
-zinc enzyme
-lead poisoning (b/c displaced)

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function of Uro III cosynthase

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to prevent spontaneous ring formation
(need AP AP AP PA)

with PBG deaminase
gives coproporphyrinogen III

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substrate that returns to mito (in heme synth)

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coproporphyrinogen III
(from PGB deaminase & cosynthase)

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fate of coproporphyrinogen III

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return to mito
oxidized
convert 2 propyl side chains to vinyl

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characteristics of protoporphyrin IX

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oxidized
fully conjugated ring system
from protoporphyrinogen IX
(colorless)
receives iron to become Fe 2+ protoporphyrin IX

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ferrochetolase

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adds iron to protoporphyrin IX

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types of heme

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a, b & c
differ by side chains & linkage to protein (covalent or non)
all have protoporphyrin

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causes of porphyrias

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no dz assoc ALA synthase mut

any other enzyme
nervous system
skin

variagate= have to stay out of the light

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variagate porphyria

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have to stay out of the light
mut in PGen IX oxidase

affects NS, skin

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heme oxygenase

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(catabolism)

in macrophages
opens ring
uses NADPH & O2
gives CO (only rxn in body), Fe3+ & NADP+
gives biliverdin

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reaction producing CO
(NOT CO2)

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heme oxygenase
degrade heme
open ring
in MPs
releases iron (Fe3+)

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glucuronic acid

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produced in liver
to conjugate bilirubin
from UDP glucose & 2 NAD

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bilirubin UDP glucuronyltransferase

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transfer UDP glucuronic acid onto bilirubin

not ready til birth
(premies jaundiced, babies take a while to activate)

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bilirubin produced by

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reduction of biliverdin
(via reductase)
uses NADPH

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2 types hyperbilirubinemia

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prehepatic
-excess heme destruction
-excess of conjugated
-Rotor's
-Dubin Johnson

hepatobiliary
-lost ability to conjugate
-Crigler Najjar
-Gilbert's

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vanden burg reaction

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measures bilirubin
(direct vs indirect)
(prefixes go together)

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benign congenital liver disorder
males more than females
teens - early 30s (onset)

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Gilbert's
tx w/phenobarb
(stimulates UDP g transferase activity)

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severe unconjugated hyperbilirubinemia at birth

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Crigler-Najjar
fatal when enzyme absent
(UDP g transferace)

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mild conjugated hyperbilirubinemia

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Dubin-Johnson or Rotor's

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purpose of bilirubin

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antioxident
-supress oxidation of lysosomes
-protect myocardium & nervous tissue

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phototherapy for jaundice

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opens H bonds
increases solubility

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heptaglobin

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picks up Hgb (if RBC lyses) & transport to liver

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hemopexin

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picks up loose heme