Heme Synthesis & Hemoglobin Flashcards
What are the 3 main functions of heme?
transport of O2
electron transport
oxidation-reduction reactions (cyps)
Where is heme produced?
bone marrow-hemoglobin
liver-cyps
all other cells EXCEPT mature erythrocytes
What is a porphyrin?
cyclic tetrapyrroles capable of chelating to various metals to form essential prosthetitic groups for various biological molecules
What is heme?
Ferroprotoporphyrin IX
Does heme contain Fe3+ or Fe2+?
Fe2+
Where is ALAS localized to?
inner mitochondiral membrane
What is ALAS dependent on as a cofactor?
PLP (pyridoxal phosphate)
What are the 2 isoforms of ALAS? Location?
1-liver
2-erythroid/reticulocyte
Which isoform of ALAS undergoes feedback inhibition?
ALAS1-feedback inhibition by heme (at translational and transcriptional levels & mitochondrial import)
ALAS2-NOT regulated by feedback inhibition
How can lead poisoning affect the ALAD reaction?
Pb2+ can displace Zn2+ and eliminate catalytic activity, this leads to increased ALA in urine
What does lead poisoning mimic?
Acute porphyrias
What affects does ALA have on the brain?
it is toxic, causes the neurological effects of lead poisoning, Pb2+ may also directly affect nervous system
What does UROS do?
step 3 pt 2
converts uroporphyinogen III to the right isomer
What does ALAS do?
step 1
condenses glycine and succinyl Co-A to yield ALA
What does ALAD do?
step 2
condenses 2 molecules of ALA to form one molecule of PBG
What does PBGD do?
step 3 pt 1
form a linear tetrapyrrole
What does UROD do?
step 4
decarboxylates acetate side chains to methyl group
What does CPO do?
step 5
converts propionic acid side chains to vinyl groups
What does PPO do?
step 6
converts rpotoporphyrinogen IX to protoporphyrin IX
What does ferrochelatase do?
enhance the rate of Fe2+ into protoporphyrin IX insertion
What can inhibit ferrochelatase?
lead (increase protoporphyrin in urine)
iron deficiency
What is porphyria?
defect in heme biosynthesis
inherited or acquired
Inheritance of porphyria?
Al are AD except congential erythropoietic prophyria (AR)
What is the most common porphyria?
Porphyria cutanea tarda (PCT)
Most common acute porphyria?
Acute Intermittant Porphyria (AIP)
Most common erythropoietic porphyria?
Erythropoietic protoporphyria (EEP) most common porphyria in childhood
What are symptoms of porphyrias with early defects?
accumulation of ALA, neurologic dysfunction
What are symptoms of porphyras with late defects?
sunlight induced cutaneous lesions, due to accumulation of cyclic tetrapyrroles, generare ROS
Acute porphyria symptoms? causes?
periodic acute attacks
abdominal pain, neuro defects, psych, red urine
casuses: drugs, environment, diet
chronic porphyria symptoms?
dermatologic disease that may or may not include liver and nervous system
What enzyme do RBCs contain that is needed for CO2 transport?
Carbonic anhdrase, RBCs carry bicarb
Hemoglobin vs myoglobin
hemoglobin: tetramer, signmoidal cooperative binding of O2
myoglobin: monomer in muscle, stores O2, normal binding curve/hyperbolic
What is methemoglobin?
Ferric form of hemoglobin
R vs T state
R: relaxed, high affinity for O2
T: taut, low affinity for O2
What effect does CO have on hemoglobin?
much higher affinity than O2
causes all four subunits to lock in R conformation, limiting O2 release
What allosteric regulators can reduce Hb affinity for O2?
H+, CO2, 2,3 DPG
if O2 is high equilibirium is driven to the right and these will dissociate as Hb binds O2
What are H+ and CO2 classified as in regards to their effect on hemoglobin?
heterotropic negative allosteric effectors
What is O2 classified as in regards to it’s effect on hemoglobin?
positive homotropic allosteric effector (basis for O2 binding cooperativity)
How does 2,3 DPG work?
binds a site in central caity between the beta subunits, stabilizes T state, w/o Hb would have binding curve like myoglobin
What can cause an increase of 2,3 DPG?
high altitude, anemia, smoking
What affect does temperature have on O2 affinity?
incrased temperature, decreased O2 affinity (useful for O2 unloading w/fever)
Where are alpha globin genes located? how many?
chrom 16
4 total, 2/chrom
Where are beta globin genes located? how many?
chrom 11
2 total, 1/chrom
What are HbA, HbA2 & HbF, respectively?
a2B2, a2d2, a2g2
What is the mutation in sickle cell anemia? what does this cause?
Valine substituted for glutamic acid at AA6
valine causes sticky patch on deoxyHb, leads to polymerizatoin into long chains, causes sickle shape, decreased deformability and problems in microcirculation
What is HbS?
2 normal alpha chains, 2 sickle adult beta chains
What 3 variables does polymer formation depend on?
- degree of deoxygenation
- intracellular hemoglobin concentration
- relative amount of HbF present
Beta Thalassemia
major: severe transfusion dependent anemia
two Affected alleles
minor: heterozygote have a mild asymptomatic microcytic anemia
alpha thalassemia
caused by mutations that result in reduced or absent synthesis of alpha globin chains
unpaired beta chains are more soluble than unpaired alpha chains, thus effects less severe than in beta thalassemias
