Hb synthesis and catabolism, choudhury Flashcards
structure of heme
porphyrin ring structure with one Fe atom chelated in center by 4 N atoms
reversible O2 attachement
1 Hb can carry how much O2
4 molecules
how does nonheme get absorbed
as Fe2+ so through DMT1 driven by H+ gradient
how is Fe2+ transported to basolateral membrane
mobilferrin
how is heme iron absorbed
duodenal epithelial cells via binding or endocytoses
what breaks down heme iron in enterocyte
heme oxygenase, release CO and biliverdin
What happens to dietary Fe3+ before absorption
recuded at extracell apical membrane by ferric reductase prior to absorption
Fe2+ exits enterocyte how and then what happens
ferroportin
converted back to Fe3+ by haphaestin and binds to transferrin
decreased apoferritin synthesis from liver disease changes iron levels how
elevated serum iron levels because apoferritin is the storage mech
what is hepcidin and its mech
peptide secreted by hepatocytes that causes degradation of ferroportin to reduce dietary iron absorption
what occurs in loss of hepcidin production
hemochromatosis. Fe overload
what happens in increase hepatice release of hepcidin
anemia of chronic disease by blocking Fe absorption
what is first step of heme synthesis and where does it occur
succinyl CoA and glycing make ALA in the mitochondria
how and where is porphobilinogen formed
2 ALA via ALA dehydratase make porphiliniogen in the cytosol
what disorders are cause by mutations in ALA dehydratase (porphobilinogen synthase)
porphyria and Pb poisoning
sideroblastic anemia is caused by a mutation where
aminolevulnic acid synthase (makes ALA) in mitochondria
porphyria can be caused by what mutations
ALA dehydratase and PBG deaminase
where and what converts protoporphyrin to heme
in mitochondria
ferrochelatase
too much of this substance can inhibit ferrochelatase
lead
what is the rate limiting step for heme synthesis
ALA synthase in mitochondria
what gives negative feedback on ALA synthesis
heme
protoporphyria is caused by mutation where
ferrochelatase
where does globin synthesis occur
cytoplasm of normoblasts and reticulocytes
which chromosome encodes for alpha globin? beta?
alpha on chrom 16
beta on 11
disruption in balance of globin chains is called what
thalassemia
what are the embryonic forms of Hb
Gower I and II
II has alpha 2 globin and epsilom
what are the fetal forms of Hb
Hb portland and HbF
most abundant fetal form Hb
HbF
what are the adult Hb
HbA2 and HbA1
most prevalent adult Hb and components
HbA1
2alpha and 2beta
where does heme join globin chains
cytoplasm in RBC of marrow
what is needed for normal Hb synthesis
Fe
what is the functional Fe pool
Hb, myoglobin, enzymes
what is the storage iron pool
ferritin, hemosiderin
Hb can only bind Fe in what form
ferrous 2+
how many bonds does Fe2+ make with hemoglobin
6
4 heme
1 globin
1 reversible to O2
most common cause anemia
Fe deficiency
how does heme iron enter enterocyte
endocytosis or binding then split into Fe3+ by heme oxygenase then enterocytes convert it to Fe2+
what are the energy metabolism mech of RBC
glycolysis!
pentose phosphate cycle
what is created in glycolysis in RBC
ATP for ion pumps and NADH for re-oxidation of Hb
what is created in pentose phosphate cycel
NADPH to maintain reduced state glutathione and sulfhydryl groups
how is hemolysis of RBC detected
hemoglobinemia annd hemoglobinuria
what is Hb degraded into and by what?
macrophages of reticuloendothelial system into 3 parts
Fe, protoporphyrin and globin
what happens to protoporphyrin ater heme breakdown
converted to biliverdin which is converted to unconjugated bilirubin
what is methemoglboin
Hb carrying ferric iron, cannot carry O2 now
hwo does body protect itself from increase methemoglobin levels
methemoglobin reductase from RBC
what is sulfhemoglobin
partially denatured Hb
usually from sulfa containing drugs or aromatic amine drugs
what is carboxyHb
CO Hb
What is structure of HbF
2 alpha, 2 gamma
how do we Tx infants with increased unconj bilirubin
light therapy changes trans to cis which is easily excreted in urine
what catalyzes unconj to conj bilirbuin in SER
UDPGT
When is urinary urobilinogen increased
hyperbilirubinemia
when you see increased urinary bilirbuin what does this indicate
increased serum conjugated bilirubin
water soluble bilirubin is same as what
conjugated
What is Gilberts and findings
enzyme mutation impairing hepatocellular funciton
hepatic jaundice
total serum bilirubin mainly unconjugated, increased urinary
what is Crigler-Najjar type I syndrome and findings
hepatic jaundice
enzyme mutation/defective conjugation
increased serum unconjugated bilirubin and increase urinary urobilinogen
what isdubin johnson syndrome and findings
haptic jaundice
defective secretion from hepatocyte
increased serum conjugated bilirubin
what can cause increase in direct and indirect bili
hepatitis with lowered conjugation or excretion
what are findings of post hepatic jaundice
increased serum and urine conjugated bili
dec urobilin and stercobilin
clay colored stools!!!!
no urinary urobilinogen
what causes sickle cell trait
missense mutation beta globin chain
position 6 valine for glutamic acid
Hb S replaces what Hb
HbF
occurs around 6 mo
what results from sickle cell disesase
hypozic tissue injury from microvascular occlusions from abnormal RBC shape
painful muscle aches and pains
sickle cell patients have what level bilirubin
increased, may have jaundice
what type of anemia is characteristic of thalassemias
microcytic hypochromic anemia with target cells!!! on peripheral smear
what is alpha thalassemia
impaired produciton alpha chains
what are types of alpha thalassemias
Hb H disease: 3 beta 1 alpha
Thalassemia major: loss all 4 alpha so results in hydrops fetalis
what occurs in beta thalassemia
elevated HbF and A2 because impaired beta globin synthesis
What is cooleys anemia
beta thalassemia major
homozygous
severe anemia that requires lifelong transfusions
what is Tx for beta thalassemia minor
heterozygous
genetic counseling but really nothing
clinical signs of beta thalaseemia
prominent protruding forehear and flattened nose
hyperplastic marrow?
“hair on end”
