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Flashcards in Heme and Hemoglobin Deck (21):
1

Which steps in the heme synthesis pathway are located in the mitochondria?

1st step and last 3 steps

2

What is needed in the first step of heme synthesis, for succinyl co-A and glycine to come together in a condensation reaction?

Vit B6

3

What occurs in the second step of heme synthesis?

two delta-ALA condense to form porphobilonogen (pyrrole ring). Catalyzed by delta-ALA dehydratase

4

What is the third step in heme synthesis?

four porphobilonogen molecules are linked to form hydroxymethylbilane, a linear terapyrrole compound. Catalyzed by porphobilonogen deaminase.

5

How is heme synthesis regulated in non erythroid tissues?

First step of synthesis is rate limiting step, catalyzed by isoform ALA-S1. Heme has negative feedback on ALA-S1.

6

How is Iron delivered to erythroid precursor cells?

Via transferrin, which has 2 receptors for ferric iron Fe3+. Binds to RBC precursor and is internalized via receptor mediated endocytosis. The pH is lowered and iron is released from transferrin as Fe2+. Transferrin is recycled out.

7

What is the last step in heme synthesis?

Addition of Fe2+ to protoporphyrin IX via ferrochelatase

8

How is heme synthesis regulated in erythroid tissues?

Fe availability controls translation of ALA-S2 synthesis. IRE contained on ALA-S2 mRNA
iron deficiency: IRE binds to IRE-BP and inhibits translation
excess iron: Fe-S clusters bine IRP and blocks binding to IRE. Translation occurs.
IRE=iron response elements
IRP=iron regulatory proteins

9

Describe congenital erythropoietic porphyria.

-deficiency in uroporphyrinogen III cosynthetase (acts on hydroxymethylbilane)
clinical features: red urine due to excretion of uroporphyrin I, light sensitive skin, fluorescent teeth, anemia.

10

Describe acute intermittent porphyria

deficient porphobilinogen deaminase, compensatory increase in delta-ALA synthetase (step before hydroxymethylbilane)
liver: increase in delta ALA and porphobilinogen, lots in urine too
clinical: intermittent abdominal pain, neurologic disturbances
90% asymptomatic
contraindications: barbituates stimulate ALA synthetase and exacerbates condn

11

What are some general properties of Hb?

1. Hb changes structure going from oxy(relaxed) to deoxy (taut) forms
2. Cooperativity of O2 binding: heme-heme interaction
3. Control mechanisms alter O2 affinity
4. O2 binding and transport of Fe2+ (oxidized Fe3+ won't bind O2)

12

In O2 saturation curves, a curve shift to the right indicates?

decreased affinity for oxygen. Hb more readily releases O2 to the tissues at lower partial pressure

13

What is HbA1c and how does that measure glucose levels?

It is a glucosylated form of Hb where glucose is attached to the NH2 end of both beta chains.
In diabetes patients, levels of HbA1c increases to 6-17% compared to normal 3%

14

Where if Fe2+ bound to heme?

Ligand bonds to proximal his F8 of globin chain, 5th coordination site. O2 bound to 6th coordination site

15

How is heme bound to globin?

It is not covalently bound. It sits in a hydrophobic pocket between the F and E helices

16

What are the differences in expression of globin genes during stages of development?

adult: alpha2 beta2 HbA
newborn: alpha 2 gamma2
embryo: alpha 2 episilon2 Hb Gower

17

What conformational changes occur with the binding of O2? Why is this important?

O2 binding changes Hb conformation (does not happen with monomeric Mb)
Without O2 bound, Fe is out of heme plane
O2 binding pulls the Fe into the heme pocket
Fe pulls the proximal His (F8) ligand along with it
Thus, the F helix moves when O2 binds
Total movement of Fe is ~0.29Å
This minimal change has a dramatic effect on Hb
conformation in each chain (tertiary conformation
change) and then in the whole Hb molecule (quaternary conformation change after 2nd or 3rd O2 binds): this explains heme-heme interaction or cooperativity of O2binding

18

What is the Bohr effect?

Binding of protons to Hb at the tissue level facilitates release of O2. Lower pH causes right shift in O2 saturation curve, which means higher P50 (lower affinity for oxygen), O2 is given up at greater ease.
Mechanism: protonation-->positive charges in several amino acids that create salt bridges that stabilize deoxy form. As venous blood returns to lungs, opposite effect occurs. curve shifts left.

19

What is P50?

The partial pressure of oxygen in which hemoglobin is 50% saturated?

20

How does 2,3-DPG affect oxygen binding?

DPG binds to deoxy Hb between two beta chains to + charged AAs, interferes with binding of Co2. Stabilizes that deoxy form. Causes curve to shift to right
-This is important in Hb F which cannot bind DPG and so has higher affinity for oxygen and so fetal Hb can bind O2 tighter than maternal Hb

21

How does CO2 bind to hemoglobin?

-CO2 binds more to deoxy than to oxy Hb
-binds to alpha amino groups more than beta
-forms salt bridges with + charged groups to stabilize deoxy form
-10-15% transported as CO2, rest as bicarbonate