Heme Synthesis & Hemoglobin

Question 1

What are the 3 main functions of heme?

Answer 1

transport of O2
electron transport
oxidation-reduction reactions (cyps)

Question 2

Where is heme produced?

Answer 2

bone marrow-hemoglobin
liver-cyps
all other cells EXCEPT mature erythrocytes

Question 3

What is a porphyrin?

Answer 3

cyclic tetrapyrroles capable of chelating to various metals to form essential prosthetitic groups for various biological molecules

Question 4

What is heme?

Answer 4

Ferroprotoporphyrin IX

Question 5

Does heme contain Fe3+ or Fe2+?

Answer 5

Fe2+

Question 6

Where is ALAS localized to?

Answer 6

inner mitochondiral membrane

Question 7

What is ALAS dependent on as a cofactor?

Answer 7

PLP (pyridoxal phosphate)

Question 8

What are the 2 isoforms of ALAS? Location?

Answer 8

1-liver

2-erythroid/reticulocyte

Question 9

Which isoform of ALAS undergoes feedback inhibition?

Answer 9

ALAS1-feedback inhibition by heme (at translational and transcriptional levels & mitochondrial import)
ALAS2-NOT regulated by feedback inhibition

Question 10

How can lead poisoning affect the ALAD reaction?

Answer 10

Pb2+ can displace Zn2+ and eliminate catalytic activity, this leads to increased ALA in urine

Question 11

What does lead poisoning mimic?

Answer 11

Acute porphyrias

Question 12

What affects does ALA have on the brain?

Answer 12

it is toxic, causes the neurological effects of lead poisoning, Pb2+ may also directly affect nervous system

Question 13

What does UROS do?

Answer 13

step 3 pt 2

converts uroporphyinogen III to the right isomer

Question 14

What does ALAS do?

Answer 14

step 1

condenses glycine and succinyl Co-A to yield ALA

Question 15

What does ALAD do?

Answer 15

step 2

condenses 2 molecules of ALA to form one molecule of PBG

Question 16

What does PBGD do?

Answer 16

step 3 pt 1

form a linear tetrapyrrole

Question 17

What does UROD do?

Answer 17

step 4

decarboxylates acetate side chains to methyl group

Question 18

What does CPO do?

Answer 18

step 5

converts propionic acid side chains to vinyl groups

Question 19

What does PPO do?

Answer 19

step 6

converts rpotoporphyrinogen IX to protoporphyrin IX

Question 20

What does ferrochelatase do?

Answer 20

enhance the rate of Fe2+ into protoporphyrin IX insertion

Question 21

What can inhibit ferrochelatase?

Answer 21

lead (increase protoporphyrin in urine)

iron deficiency

Question 22

What is porphyria?

Answer 22

defect in heme biosynthesis

inherited or acquired

Question 23

Inheritance of porphyria?

Answer 23

Al are AD except congential erythropoietic prophyria (AR)

Question 24

What is the most common porphyria?

Answer 24

Porphyria cutanea tarda (PCT)

Question 25

Most common acute porphyria?

Answer 25

Acute Intermittant Porphyria (AIP)

Question 26

Most common erythropoietic porphyria?

Answer 26

``` Erythropoietic protoporphyria (EEP) most common porphyria in childhood ```

Question 27

What are symptoms of porphyrias with early defects?

Answer 27

accumulation of ALA, neurologic dysfunction

Question 28

What are symptoms of porphyras with late defects?

Answer 28

sunlight induced cutaneous lesions, due to accumulation of cyclic tetrapyrroles, generare ROS

Question 29

Acute porphyria symptoms? causes?

Answer 29

periodic acute attacks abdominal pain, neuro defects, psych, red urine casuses: drugs, environment, diet

Question 30

chronic porphyria symptoms?

Answer 30

dermatologic disease that may or may not include liver and nervous system

Question 31

What enzyme do RBCs contain that is needed for CO2 transport?

Answer 31

Carbonic anhdrase, RBCs carry bicarb

Question 32

Hemoglobin vs myoglobin

Answer 32

hemoglobin: tetramer, signmoidal cooperative binding of O2 myoglobin: monomer in muscle, stores O2, normal binding curve/hyperbolic

Question 33

What is methemoglobin?

Answer 33

Ferric form of hemoglobin

Question 34

R vs T state

Answer 34

R: relaxed, high affinity for O2 T: taut, low affinity for O2

Question 35

What effect does CO have on hemoglobin?

Answer 35

much higher affinity than O2 | causes all four subunits to lock in R conformation, limiting O2 release

Question 36

What allosteric regulators can reduce Hb affinity for O2?

Answer 36

H+, CO2, 2,3 DPG | if O2 is high equilibirium is driven to the right and these will dissociate as Hb binds O2

Question 37

What are H+ and CO2 classified as in regards to their effect on hemoglobin?

Answer 37

heterotropic negative allosteric effectors

Question 38

What is O2 classified as in regards to it's effect on hemoglobin?

Answer 38

positive homotropic allosteric effector (basis for O2 binding cooperativity)

Question 39

How does 2,3 DPG work?

Answer 39

binds a site in central caity between the beta subunits, stabilizes T state, w/o Hb would have binding curve like myoglobin

Question 40

What can cause an increase of 2,3 DPG?

Answer 40

high altitude, anemia, smoking

Question 41

What affect does temperature have on O2 affinity?

Answer 41

incrased temperature, decreased O2 affinity (useful for O2 unloading w/fever)

Question 42

Where are alpha globin genes located? how many?

Answer 42

chrom 16 | 4 total, 2/chrom

Question 43

Where are beta globin genes located? how many?

Answer 43

chrom 11 | 2 total, 1/chrom

Question 44

What are HbA, HbA2 & HbF, respectively?

Answer 44

a2B2, a2d2, a2g2

Question 45

What is the mutation in sickle cell anemia? what does this cause?

Answer 45

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

Question 46

What is HbS?

Answer 46

2 normal alpha chains, 2 sickle adult beta chains

Question 47

What 3 variables does polymer formation depend on?

Answer 47

1. degree of deoxygenation 2. intracellular hemoglobin concentration 3. relative amount of HbF present

Question 48

Beta Thalassemia

Answer 48

major: severe transfusion dependent anemia two Affected alleles minor: heterozygote have a mild asymptomatic microcytic anemia

Question 49

alpha thalassemia

Answer 49

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