IHL I - Hemoglobin Synthesis and Metabolism Flashcards
structure of heme
porphyrin ring with one iron chelated in the center by 4 nitrogens
iron has 6 binding sites
- 4 nitrogen - 1 to protein structure - 1 to oxygen
two major components of hemoglobin
heme and blogin
heme 3%
how many hemes per hemoglobin?
4 hemes (4 irons) each can carry 4 oxygen
16 O2 molecules per hemoglobin
porphobilinogen
first step in heme synthesis
-succinyl CoA and glycine decarboxylation eventually give porphobilinigen
delta-aminolevulinate synthase (ALA synthase)
committed step of heme synthesis
catalyzed reaction:
glycine and succinyl CoA > delta-aminolevulinic acid
(-) Heme - represses transcription of the enzyme
PBG Synthase (porphobilinogen synthase)
aka ALA dehydratase
catalyzes reaction:
2x delta-aminolevulinic acid > porphobilniogen
occurs in the mitochondria
protoporphyrin
condensation of four porphobilinogen > protoporphyrin
forms in the cytosol
iron is inserted into protoporphyrin by ferrochelatase
ferrochelotase
inserts the iron into the protoporphyrin ring
occurs in the mitochondria
sideroblastic anemia
due to mutation in the delta-aminolevulinic acid synthase (ALA synthase)
porphyria
due to mutations in ALA dehydratase or PBG deaminase
- results in accumulation of these in the skin - very photosensitive - red-colored urine
lead poisoning
inhibits ALA dehydratase and ferrochelatase
accumulation of molecules
- causes basophilic stiffling - little purple dots in the RBCs
globin synthesis
in the cytoplasm of immature RBCs
somehow there is a balance of heme and globin
-unknown mechanism
chromosome 16
alpha chains of globin
chromosome 11
beta globin chains, as well as delta and gamma
thalassemia
disruption of balance in the globin and heme synthesis
hemoglobin synthesis
combination of heme and globin in the immature RBCs in bone marrow
transferrin
transports iron in the body
location on heme synthesis
mitochondria
location of globin synthesis
cytoplasm ribosomes
Hb A
normal adult hemoglobin
2 alpha and 2 beta chains
variation in hemoglobin?
heme all the same
globin chains can be different
Hb F
2 alpha and 2 gamma
fetal hemoglobin
Hb A2
2 alpha and 2 delta
hemoglobin through development?
conception to 3 months -have Gower hemoglobin (e and zeta) -not in adult at 3 months until birth -Hb F forms (gamma chain production) -doesn't let oxygen go easily at birth - beta chain is synthesized -Hb A1 (normal adult hemoglobin) > around 6 months increased in delta chain is slight throughout life -increases Hb A2
deoxyhemoglobin
without oxygen
oxyhemoglobin
hemoglobin carrying oxygen
pulse oximetry
infrared light measures absorption of deoxy and oxyhemoglobin
-can compute the oxygen saturation levels
methemoglobin
when Fe2+ oxidized to Fe3+
-due to oxidizing drugs > nitrites, sulfonamides
cannot carry O2
methemoglobin reductase
converts methemoglobin to hemoglobin
sulfhemoglobin
partially denatured hemoglobin
- RBC desctruction and hemolysis - cannot carry O2
due to sulfur drugs and aromatic amine drugs
carboxyhemoglobin
hemoglobin carrying carbon monoxide
elevated in individuals with carbon monoxide poisoning
ferrous
Fe2+ binds oxygen
ferric
Fe3+ cannot carry O2
major sources of iron in the body?
heme and nonheme
nonheme
can be either ferric or ferrous
ferrous absorbed more readily
-reduced at the membrane by ferric reductase
ferric reductase
reduces iron at the membrane so it can be transported
DMT-I
cotransporter of Iron and H+ ions into the enterocyte
mobilferrin
binds to the free iron in the enterocyte and transport to basolateral membrane
hemochromatosis
too much iron
given phlebotomys and chelating agents (to bind iron)
iron storage locations?
spleen, liver, duodenum
spleen - old RBCs broken down
apoferritin
part of the iron buffer system
ferritin is the storage form of iron
RBC destruction
circulate for 120 days > then become senescent RBCs
erythrocyte energy production?
glycolysis and pentose phosphate
90% glucose in glycolysis
glycolysis in erythrocytes
formation of ATP which mantains the membrane ion pumps (ATP) and reoxidation of hemoglobin (NADH)
pentose phosphate pathway in erythrocytes
provides NADPH to maintain the reduced state of glutathione and sulfhydryl groups
spleen
“red cell graveyard”
red blood cells lose size and become rigid as they age
polycythemia
rate of RBC synthesis > degradation
anemia
RBC destruction > synthesis
hemoglobinemia
intravascular hemolysis of RBCs due to conditions such as hemolytic anemia, autoimmune processes, transfusion reactions, and drug-induced hemolysis
> free Hg in plasma
hemoglobinuria
increased Hg in the urine
excess Hg is nephrotoxic in kidneys***
three components of Hg breakdown
Fe, protoporphyrin, and globin
broken down heme oxygenase
-forms CO and biliverdin
biliverdin reduced to bilirubin
Hemoglobin S
sickle cell anemia
beta chain position 6 glutamic acid changed to valine***
missense mutation > results in Hg S synthesis
Sickle Cell Anemia
hemoglobin is susceptible to polymerization
- causes sickling - results in inflexibility and hemolysis
Thalassemias
quantitative defect
-imbalance in heme to globin ration
due to mutations in globin chain synthesis
microcytic hypochromic anemia
small in size and decrease in color
alpha thalassemia
decreased alpha globin synthesis
-results in excess of beta and gamma chains
hemoglobin H disease
loss of 3 out of 4 alpha globin genes in adult
-results in Hg H (hemoglobin tetramers)
thalassemia major
loss of all 4 alpha chain globin
results in formation of Hemoglobin barts (gamma tetramers)
-can cause hydrops fetalis
hydrops fetalis
incompatible with life
-hepatosplenomegaly
caused by loss of all 4 alpha globin chains
beta-thalassemia
excess of alpha globin chains
elevated Hg F and Hg A2
different ranges: minor > major
beta-thalassemia minor
heterozygous
-asymptomatic, may require genetic counseling
beta-thalassemia major
homozygous disorder
significant imbalance of alpha and beta chains
-sever anemia in early life
requires life-long RBC transfusion
untreated, death in first decade
aka cooley’s anemia
