Heme synthesis and degradation Flashcards
describe the structure of the heme
poryphyrin 5-membered ring complex N atoms face the Fe2+
where is heme synthesized?
liver and erythroid cells of bone marrow
what are the three phases of heme synthesis?
1-mitochondria-make ALA from Gly and succinyl CoA
2-cytosol-2ALA combine to PBG, 4 of these make CPP3
3-mitochondria-two oxygenation rxn to install side chain=protoporphyrinogen9 and make conjugated ring, insertion of Fe2+
What is ALA?
in mitochondria: delta-aminolevulinic acid (ALA synthase)
What is CPP3?
coproporphyrinogen 3-cytosol to mitochondria (uro.. dehydrogenase 3)
What is PBG?
porphobilinogen-cytosol (ALA dehydrogenase)
Describe ALA synthase
needs B6 (pyridoxal phosphate or PLP)
2 isoforms ALAS1(ubiquitous) and ALAS2 (erythroid cells)
Heme inhibits (feedback)
Iron increases transcription and translation
Decarboxylation rxn
What are the 4 most important enzymes to know regarding heme synthesis? Where are they located?
ALA synthase mito
ALA dehydrogenase cyto
Porphobilinogen deaminase cyto
Ferrochelatase mito
What enzymes does Pb interact with? What molecules accumulate?
ALA dehydratase
ferrochelatase
ALA and Protoporphyrin IX accumulate
What enzymes can have a defect and cause a porphyria?
ALA synthase porphobilinogen deaminase uroporphyrinogen 3 cosynthase uroporphyrinogen decarboxylase protoporphyrinogen oxidase
What type of poryphria would a defect in PBG deaminase (liver) cause?
Acute intermittent hepatic
What type of poryphria would a defect in uroporphyrinogen 3 synthase (erythrocytes) cause?
congenital
What type of poryphria would a defect in uroporphyrinogen decarboxylase cause?
porphyria cutanea tarda
most common
hepatoerythropoietic
What type of poryphria would a defect in protoporphyrinogen IX oxidase cause?
Variegate porphyria
hepatic
What phenotype is attributed to a deficiency in uroporphyrinogen 3 synthase?
a build-up of uroporphyrinogen I
red in urine, red flourescence in teeth, skin photosensitivity
What enzyme is involved in generating bilirubin from heme?
heme oxygenase cleave the cycle and makes it into a linear form
requires oxygen,
Describe biliverdin synthesis
heme oxidase
iron oxidized from ferrous to ferric
What is the second eznyme involved in bilirubin synthesis?
biliverdin reductase
eliminates double bond
Describe free BR
unconjugated/indirect (insoluble)
bound to albumin
Describe direct BR
conjugated with glucoronic acid (soluble)
describe conjugation
UDP glucose converted to UDP-glucuronic acid
UDP-glu transferase conjucate free BR and UDPGlu acid
does this twice to add two sugars (X2)
What is the rate limiting step of BR removal?
UDP glucuronyl transferase
What form is iron in heme? What form does it take after the action of heme oxygenase?
In Hb it is ferrous (Fe2+)
after oxygenase it is ferric (Fe3+)
What is the cause of green pigmentation in heme breakdown?
conversion of ferrous to ferric
Fe2+ to Fe3+
What carries bilirubin in the blood?
albumin
What steps are needed and where in BR excretion?
BR->urobilinogen in intistine
urobilinogen taken by kidney->urobilin
urobilinogen stays in gut->stercobilin
what are characteristics of pre-hepatic jaundice?
hemolytic anemias
liver cannot uptake excrete, or conjugate
fetal incompatability
glucose 6 phosphate dehydrogenase deficiency
What are findings of pre-hepatic jaundice?
elevated unconjugated BR in blood, normal conjugated levels normal serum levels urobilinogen in urine direct BR not in urine
What are findings in intra-hepatic jaundice?
unconj and conj BR level=depends
increase in serum ALT and AST levels
urobilinogen levels in urine is normal
conjugated BR in urine
Describe characteristics of post-hepatic jaundice
BR cannot be excreted
bile might not flow
What are findings in post-hepatic jaundice?
elevated conjugated BR levels in blood
normal AST and ALT levels
conjugated BR is present in urine (dark)
describe neonatal jaundice
elevation of
describe neonatal jaundice
elevation of un-conjugated BR deficiency of UDP-GT enzyme breakdown of fetal Hb, replaced with adult Hb BR can cause encephalopathy` varies in severity due to causes
What does phototherapy do?
blue fluorescent light causes BR to convert to more soluble isomers
also heme oxygenase inhibitor may be used
