Hematology-1/08/08 Heme & Hemoglobin: Synthesis, Structure & Function

Front 1

Which steps of protoporphyrin synthesis occur in the mitochondria?

Back 1

the initial step and the final three steps

Front 2

How many reactions are involved in heme synthesis?

Back 2

eight rxns

Front 3

Where does 85% of heme synthesis occur?

Back 3

In the erythropoietic marrow, the rest mostly happens in the liver

Front 4

What is the first step for heme synthesis? Where does it occur? What inhibits the enzyme in nonerythroid tissue?

Back 4

Succinyl CoA (from Kreb cycle) + glycine condense to form delta-ALA. Occurs in the mitochondria (Succinyl CoA formed in mito, and enzyme located there). Heme inhibits the enzyme delta-ALA synthetase.

Front 5

What is the second step of heme synthesis?

Back 5

Two delta-ALA condyse to form porphobilinogen (PBG). Enzyme is delta-ALA dehydratase. Occurs in the cytoplasm.

Front 6

What is the third step of heme synthesis?

Back 6

Four porphobilinogens (PBGs) linked by porphobilinogen deaminase to form linear hydroxymethylbilane. cytoplasmic.

Front 7

What is the fourth step of heme synthesis?

Back 7

linear tetrapurole (hydroxymethylbilane) cyclizes into uroporphyrinogen III. cytoplasmic.

Front 8

After the fourth step of heme synthesis, what are the last several steps of heme synthesis?

Back 8

alter the functional groups of the porphyrin skeleton. last step is incorporation of ferrous iron in to the protoporphyrin to form heme.

Front 9

What is the last compound that is formed in the cytoplasm for heme synthesis?

Back 9

coproporphyrinogen III. This enters the mitochondria for the last three steps.

Front 10

What is the last enzyme of heme synthesis and where is it located?

Back 10

ferrochelatase (heme synthetase). reaction occurs in the mitochondria.

Front 11

When monoblasts contain low levels of heme due to low levels of iron what is the level of protoporphyrin?

Back 11

Because heme is low, the neg. feedback of delta-ALA synthetase is not active. This leads to a high level of protoporphyrin. This is caused by iron deficient anemia.

Front 12

What delivers iron to erythrocytes? What oxidation state is the iron in? How many irons are transfered? What happens to the compound after iron delivery?

Back 12

Transferrin transports two irons in the ferric state (3+). After delivery the transferrin is recycled.

Front 13

How is heme synthesis regulated in nonerythroid tissues?

Back 13

Heme suppresses ALA-S1 (synthetase). This is the rate limiting step. ALA-S1 is also known as the house keeping isoform of ALA-S.

Front 14

How is heme synthesis regulated in erythroid tissues? What else does it have to help regulate synthesis?

Back 14

ALA-S2 has iron response element (IRE). Heme inhibits the cellular acquisition of iron from transferrin. Proteins bind to the IRE based on iron availability thus controlling the ALA-S2 translation and ALA formation.

Front 15

What are the porphoryias?

Back 15

Metabolic disease characterized by (usually genetic) deficiencies of specific enzymes needed for heme synthesis.

Front 16

How are the porphyrias divided?

Back 16

hepatic and erythropoietic

Front 17

Explain the mechanism of congenital erythropoietic porphyria. Which enzyme is missing, where is it, what compound builds up? What happens to RBCs, what is the clinical manifestations? What is therapy?

Back 17

Missing uroporphyrinogen III cosynthetase (step 4 of heme synthesis). It is erythropoietic, and uroporphyrinogen I builds up. RBC prematurely destroyed (anemic) and urine is red (from uroporphyrin I). light sensitive, teeth fluorescent. treat with hematin (form of heme) or blood transfusions.

Front 18

Explain the mechanism of acute intermitent porphyria. Which enzyme is depressed? What is the effects of this depression? What are the clinical manifestations? What is the treatment?

Back 18

In the liver, the porphobilinogen deaminase (step 3) is depressed. This causes a compensatory increase in delta-ALA synthetase. There is an increase in delta-ALA synthetase and porphilinogen (seen in liver and urine). Clinically seen as intermittent abdominal pain and neurological disturbances. Treat with hematin (form of heme).

Front 19

What are the two tasks of hemoglobin?

Back 19

Delivery of O2 from lungs to tissue. Removal of CO2 from tissue to lungs.
NOTE: it also acts as buffer for H2CO3

Front 20

What is the P50 for hemoglobin?

Back 20

The partial pressure of oxygen where there is 50% saturation of the heme with O2.

Front 21

When the iron of heme is oxidized to 3+, hemoglobin is called what?

Back 21

methemoglobin.

Front 22

What fills the six coordination sites of iron in oxy hemoglobin?

Back 22

four nitrogens from the porphyrin ring, a nitrogen from the proximal histidine, and O2.

Front 23

How many chains and hemes are in hemoglobin? What is the shape of the binding curve? What effect of this curve?

Back 23

Four chains each with a heme which enables a sigmoid binding curve. This allows for better release of O2 at the tissue than Mb.

Front 24

What are thre modifying agents on hemoglobins sigmoid curve?

Back 24

Bohr effect, CO2 effect, 2,3-diphosphoglyceric acid (DPG).

Front 25

Many forms of hemoglobin exist. How are these Hb ID?

Back 25

ID with electrophoresis.

Front 26

What is HbA1c

Back 26

It is the glucosylated form of of HbA. Glucose is added to the N-terminal of the beta chains. In diabetics this form can be 6-17% (normal is up to 3%).

Front 27

What are the three normal hemoglobins?

Back 27

HbA (alpha2beta2), HbA2 (alpha2delta2), HbF fetal (alpha2gamma2)

Front 28

What is the structure of HbS?

Back 28

Sickle cell hemoglobin has a chain at the sixth aa of the beta chain from Glu to Val. alpha2betaS2

Front 29

What is Hb Barts and where is it seen?

Back 29

HbBart is gamma4. It is seen in alpha thalassemia.

Front 30

What is the progression of hemoglobin in fetal development?

Back 30

Hb Grower present in embryo (alpha2epsilon2), HbF (alpha2gamma2), in adults this changes to mostly HbA (alpha2beta2)

Front 31

What is the difference in hemoglobin between the oxy and deoxy form?

Back 31

In the deoxy form the porphyrin is bowed and the structure is the taught form. In the oxy form the O2 pulls the ring into a linear structure and pulls the proximal histadine creating a more relaxed structure. As a result the subsequent binding of O2 is easier.

Front 32

What is the Bohr effect?

Back 32

O2 affinity of Hb is pH dependent. There is a release of O2 at the tissues which have a lower pH. Binding of protons facilitates the release of O2. This helps O2 be delivered to where it is needed.

Front 33

How does 2,3-diphosphoglyceric acid (DPG) change the oxygen affinity curve of hemoglobin?

Back 33

DPG right shifts the oxygen curve. DPG binds to the deoxy form of Hb and binds to HbF. This allows fetal blood to have a higher O2 affinity.