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Biochemistry 1 > Hemoglobinopathies I and II (L7,8) > Flashcards

Hemoglobinopathies I and II (L7,8) Flashcards

1
Q

What does Myoglobin (Mb) consist of?

A

A single polypeptide chain and a single heme prosthetic group.

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2
Q

Describe the heme prosthetic group.

A

It is a planar structure w/ a hydrophobic and phydrophillic edge.

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3
Q

What are the 2 oxidation states of the Heme iron and which one binds oxygen?

A

Ferrous state (+2): BINDS oxygen

Ferric state (+3): Doesn’t bind oxygen

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4
Q

How many helical segments does each globin polypetide chain have?

What % of the globin chain is alpha helix?

A

8 (A thru H);

75%

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5
Q

Describe the core and the exterior of each globin chain.

A

Interior core consists of NONPOLAR AA’s EXCEPT for 2 Histadines.

Exposed surface has both polar AND nonpolar AA’s.

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6
Q

Where is the Heme found in the globin chain?

A

The hydrophobic pocket formed by the polypetide chain.

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7
Q

Why isn’t Heme oxidized by oxygen?

A

The hydrophobic pocket inhibits oxidation of heme by oxygen.

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8
Q

Where does oxygen bind to on Fe?

A

The sixth coordination position of Fe.

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9
Q

Which are the proximal and distal His and where are they located?

A

His F8 is proximal His, bound to heme at fifth coordination position.

His E7 is distal His, close to sixth coordination position.

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10
Q

What are the affinity ratios of CO to O2 for Free Heme and Hemoglobin?

What is the main cause of this discrepancy?

A

Affinity for CO is 25,000 fold greater than for O2 in FREE HEME.

Affinity for CO is 250 fold greater than for O2 in HEMOGLOBIN.

His E7 causes steric hindrance decreasing affinity of Heme for CO.

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11
Q

Who crystallized Hb? How long did it take him?

A

Max Perutz. Took 20 years.

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12
Q

Describe the structure of Hb.

What does it transport?

A

A tetramer that has 2 alpha chains and 2 beta chains whose tertiary structures conform to the globulin fold. Each subunit has a bound heme prosthetic group.

It transports CO2, H+, and O2.

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13
Q

What are the 2 quaternary structures of Hb?

A

Oxy Hb and deoxy Hb.

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14
Q

Which are the Hb tetramers found during fetal and adult stages?

A

Fetal: alpha2epsilon2 (Hb F)

Adult: alpha2beta2 (Hb A), alpha2,delta2 (Hb A2)

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15
Q

Why does Hb bind oxygen with positive cooperativity?

What does this allow Hb to do?

A

B/c Oxygen is a HOMOTROPIC ALLOSTERIC EFFECTOR.

This allows Hb to transport O2 from lungs to peripheral tissue.

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16
Q

What are the O2 dissociation curves for Mb and Hb like?

A

Mb: hyperbolic (characteristic of a single O2 binding site), binding of O2 to one Mb doesn’t affect binding to another.

Hb: Sigmoidal (characteristic of cooperative binding).

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17
Q

Cooperativity can be described as a conversion of the protein from ____ state to ____ state.

A

Low/tensed (T) state

High/relaxed (R) state

18
Q

What are the 4 structural changes that occur upon oxygen binding to Hb?

A
  1. O tugs on Heme Fe, pulling it toward plane of heme
  2. Helix positions change due to intrasubunit helix interactions, altering 3o structure
  3. Subunit ionic bonds are broken to alter 4o structure
  4. alpha-beta subunit interfaces are changed
19
Q

Name 3 heterotropic allosteric effectors that decrease Hb’s affinity for O2.

A
  1. 2,3-bisphosphoglycerate (BPG)
  2. Protons (H+)
  3. CO2
20
Q

Where is BPG made and how do its levels fluctuate from day-to-day?

A

BPG is made in RBCs, is present at high concentrations, and BPG levels DON’T fluctuate much day-to-day.

21
Q

Where does 2,3-bisphosphoglycerate (BPG) bind?

A

To the central cavity in Hb and links beta subunits by ionic bonds.

22
Q

How does BPG affect Fetal Hb (HbF)?

A

HbF binds BPG w/ lower afinity than adult Hb (HbA). Thus BPG allows transfer of O2 from maternal HbA to HbF.

23
Q

How does HbF have weaker BPG affinity?

A

Ser 143 in gamma globin weakens BPG binding b/c it can’t form electrostatic interaction seen w/ His 143 in beta globin.

24
Q

What is the equation of Hb w/ respect to oxygen and protons?

What does this mean about high proton concentrations?

A

Hb + 4O2 ⇔ Hb(O2)4 + 2H+

High proton concentrations will DECREASE Hb affinity for Oxygen.

25
Q

pH in lungs is ___ than in peripheral tissues. What does this mean?

A

Greater.

This means Hb has a higher affinity for Oxygen in lungs and lower affinity for oxygen in the peripheral tissues, which helps for oxygen to be unloaded there.

26
Q

How does CO2 affect Hb affinity for Oxygen?

A

It decreases it b/c more CO2 become carbonic acid by carbonic anhydrase which then become bicarbonate with a proton. More CO2 means more H+ WHICH DECREASES THE PH IN ACTIVE TISSUES which means Hb affinity for O2 decreases.

27
Q

Protonation of which side chain allows formation of salt bridges that stabilize the T deoxy form of Hb?

A

His 146.

28
Q

Besides lowering the pH in peripheral tissues, how else does CO2 decrease Hb affinity for Oxygen?

A

CO2 carbamylates N-terminal amino groups of Val of the Hb subunits, which stabilize the T form.

29
Q

What are the levels like for pO2, pCO2, and H+ in the lungs and peripheral tissues?

A

Lungs: high pO2, low pCO2, low H+ (high pH)

Tissues: low pO2, high pCO2, high H+ (low pH)

30
Q

What are the 2 general classifications of hemoglobinopathies and what do they mean?

A
  1. Thalassemias: decreased expression of globin chains
  2. Structural hemoglobin variants: mutated globin chains due to point mutations, deletions, and frame shift, or nonsense mutations in the globin chains.
31
Q

Alpha thalassemia is associated w/ deletion of ___ of the ___ alpha globin chains.

The alpha globin gene cluster is on chromosome ___. There are ___ genes on each copy of this chromosome.

A

one or more; 4

16; 2

32
Q

What are the different deletion/clinical manifestations for alpha thalassemia?

A

Deletion of __ chains; clinical manifestation

1; no clinical manifestation

2; mild symptoms

3; (called Hb H) severe manifestation

4; hydrops fatalis (lethal)

33
Q

Alpha-thalassemia leads to low levels of alpha chains. What does this cause?

A

Excess beta-chains that form tetramers called Hb Barts. This leads to severe anoxia b/c Hb Barts have a high affinity for oxygen so they don’t release oxygen in the peripheral tissues.

34
Q

Structural Hb variants are predominantly the result of:

A

missense mutations that change a single important AA.

35
Q

What is the most common Hb abnormality in the US?

What are the major symptoms?

A

Sickle cell anemia.

Anemia, Jaundice, Cardiac hypertrophy, Kidney damage

Mneumonic: Awful Jokes Can Kill

36
Q

% of sickled RBCs is increased by:

A

Exertion.

37
Q

How present is sickle cell train hetero/homozygous in African Americans

A

Heterozygous trait is present in 8% of African Americans

Homozygous disease occurs in 1/600 African Americans and is higher in African countries.

38
Q

Why will HbS polymerize at low O2 concentrations?

Polymerization induces what?

A

B/c it has low solubility. It will polymerize and form fibrous precipitates at low pO2 that induce sickled shape RBCs.

39
Q

Hbs is less ___ charged than HbA

A

negatively

40
Q

How does deoxyHbS promote polymerization?

A

It exposes complimentary hydrophobic sticky spots

41
Q

What are the 3 major negative effectors of Hb?

A
  1. 2,3-Bisphophoglycerate (BPG)
  2. Acidosis (more protons)
  3. CO2
42
Q

What is myoglobin used for with respect to oxygen?

Where is it located?

A

It is an intracellular storage site for oxygen. Oxymyoglobin releases Oxygen when oxygen is otherwise low in the cell.

It is found in heart and skeletal muscle.

Biochemistry 1 (18 decks)

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