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MCBG > 8.3.16 Lecture > Flashcards

8.3.16 Lecture Flashcards

1
Q

What are the four major differences between myoglobin and hemoglobin?

A
  1. Location: Skeletal muscle (Mb) vs. Red blood cells (Hb) 2. Job: Oxygen storage for contraction (Mb) vs. Oxygen transport from lungs to tissues (Hb) 3. Structure: Monomer (Mb) vs. Tetramer (Hb) 4. Prosthetic group(s): 1 Heme-Fe2+ (Mb) vs. 4 Heme-Fe2+ (Hb)
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2
Q

What is a prosthetic group?

A

A prosthetic group is a nonpolypeptide moiety that forms a functional part of a protein.

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3
Q

Describe the secondary structure of myoglobin.

A
  • All helical (8 helices, A-H)
  • 153 amino acids
  • Oxygen-binding heme group non-covalently bound to a pocket in the protein.
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4
Q

Mb and Hb are ___% identical and ___% similar.

A

26; 59

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5
Q

What are two differences between the secondary structures of Mb and Hb?

A
  1. Hb N-terminus is longer and C-terminus is shorter 2. Hb has more hydrophobic residues on the surface to make contact with the three other subunits.
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6
Q

Describe the secondary structure of hemoglobin.

A

Hemoglobin is composed of 2 alpha chains and 2 beta chains. Alpha1Beta1 and Alpha2Beta2 each act as a dimer. These two dimers form the tetramer.

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7
Q

What are the two types of hemoglobinopathies (hereditary disorders)?

A
  1. Structural variants (altered amino acid sequence) 2. Thalassemias (decreased abundance of one or more globin chains)
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8
Q

Describe the pathology of sickle cell disease (HbS).

A

Oxygenated blood appears normal; deoxygenated blood assumes the sickle cell shape. These block capillaries, preventing blood flow to the tissues, which results in local ischemia and a painful sickling crisis. The RBCs also have weak membranes, which can break (hemolysis), leading to a decrease in RBC and to anemia.

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9
Q

What is the mutation in HbS? How does this change the structure?

A

Glu6Val; this amino acid is found on the surface of beta chains and the mutation changes it from a hydrophilic amino acid to a hydrophobic one. Val binds to a normal hydrophobic patch in Hb, leading to aggregation, polymerization, and ultimately deformation.

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10
Q

What type of genetic disease is HbS?

A

Autosomal recessive

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11
Q

If you are heterozygous for HbS, you have the sickle cell ___. If you are homozygous for HbS, you have the sickle cell ___.

A

Trait; disease

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12
Q

There is a geographically higher frequency of sickle cell trait in…

A

…areas where malaria is common; those with the trait are resistant to malaria.

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13
Q

Describe the structure of heme.

A
  • Planar porphyrin structure
  • Ferrous (Fe2+) ion in the middle
  • N from pyrrole groups make coordinate covalent bonds with Fe2+
  • One edge of heme has hydrophobic groups; the other has hydrophilic proprionic acid groups
  • Fe2+ binds oxygen
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14
Q

What happens if the ferrous ion is oxidized?

A

It is changed to Fe3+ (ferric ion), which cannot bind oxygen. This is known as methemoglobin.

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15
Q

Where is the heme binding site found?

A

Between the E and F helices

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16
Q

What mutation occurs in Hb Hammersmith? How does this affect Hb?

A

Phe42Ser; Ser is smaller and hydrophilic, which causes the heme to slip out of the pocket. Hb becomes unstable, aggregates, and precipitates. It does not polymerize.

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17
Q

Describe the process of oxygen binding to heme.

A
  1. F8His (proximal His) makes a 5th covalent bond with Fe2+. 2. O2 makes 6th bond to Fe2+ 3. E7His (distal His) hydrogen bonds with the oxygen
18
Q

What are the two conformations of heme?

A
  1. Deoxygenated (found in the tissues): T-conformation 2. Oxygenated (found in the lungs): R-conformation
19
Q

Which conformation of heme has a greater oxygen affinity?

A

R (150-300x greater than T)

20
Q

As the concentration of oxygen increases, oxygen begins to bind to hemoglobin. Conformational changes occur in one subunit and these are transmitted to the others. The oxygen affinity increases. What is this called?

A

Positive cooperativity

21
Q

Describe the mechanism of positive cooperativity in hemoglobin.

A
  1. In the T-conformation, Fe2+ is slightly out of the plane of heme. 2. Oxygen binds to Fe2+, bringing it more into the plane. The proximal histidine also moves, as it is attached to oxygen. 3. The F helix changes conformation, which changes the FG corner. 4. The FG corner interacts with the C helix of a neighboring subunit through non-covalent interactions. 5. The C helix moves toward the R-conformation.
22
Q

Interactions between hemoglobin subunits occur primarily between ___ and ___.

A

Alpha1Beta2 and Alpha2Beta1

23
Q

What is Hb Kempsey?

A

Hemoglobinopathy caused by Asp99Asn, which is found at the FG corner/Alpha1Beta2 interface. This mutation locks hemoglobin in a high oxygen-affinity structure (R). It cannot release oxygen.

24
Q

What is oxygen saturation?

A

The percent or fraction of Mb or Hb that has oxygen bound.

25
Q

What is pO2?

A

The concentration of oxygen given as a partial pressure (torr).

26
Q

What is p50?

A

The pO2 where 50% of Mb or Hb has oxygen bound.

27
Q

Between Mb and Hb, which has a higher oxygen affinity?

A

Mb

28
Q

Draw the Oxygen Binding Curves for Mb and Hb.

A
29
Q

Cooperativity can be measured by the ___ of oxygen needed to go from 10% to 90% saturation.

A

Fold-change

30
Q

Smaller fold-change indicates ___ cooperativity.

A

Higher

31
Q

What is the Hill coefficient?

A

1 = no cooperativity

<1 = negative cooperativity

>1 = positive cooperativity

32
Q

How does pH affect hemoglobin/oxygen binding?

A

When T binds oxygen to become R, ~1-2 H+ are released. As the number of hydrogen ions increases, the pH decreases (becomes more acidic), shifting the reaction to the left. This increases oxygen release. The oxygen-binding curve shifts to the right.

Hb + 4O2 <> Hb(O2)4 + nH+

33
Q

In the tissues, metabolizing cells produce ___ and ___ acids, decreasing the pH. What does this do?

A

Lactic; carbonic; enhances O2 release by decreasing the pH, increasing p50.

34
Q

Where is BPG made? Describe its structure.

A

Made in RBC, has 2 phosphates and 5 negative charges.

35
Q

BPG increases under ___ conditions.

A

Hypoxic (anemia, high altitude, etc.)

36
Q

How does BPG bind to Hb?

A

BPG fits into the positively charged Beta1Beta2 interface of the T conformation (due to its 5 negative charges), stabilizing the conformation. It does not bind to oxygenated Hb.

37
Q

How does BPG affect hemoglobin/oxygen?

A

As BPG increases, the reactions shifts to the left, increasing the amount of Hb in the T conformation. This increases p50 and increases oxygen release to the tissues.

38
Q

What are some of the different types of globin genes and their chains?

A
  1. HbA (alpha and beta chains): adult Hb
  2. HbGower1/HbGower2/HbPortland (zeta, eta, and gamma chains): Embryonic Hb
  3. HbF (alpha and gamma chains); fetal Hb
39
Q

How is HbF different than HbA?

A

HbF has a high oxygen affinity and pulls oxygen from the mother’s deoxygenated HbA.

40
Q

___ chains are made early in development and continue to develop through adulthood. ___ chains are made at a low level prior to birth, and increase after birth. ___ chains are high in the fetus and decrease post-birth.

A

Alpha; beta; gamma

41
Q

What is a thalassemia?

A

An imbalance of alpha and beta globin subunits; carrier resistant to malaria

42
Q

What are the two major types of thalassemia?

A

Alpha-thalassemia: mostly alpha-globin gene deletion

Beta-thalassemia: mostly single base pair mutations, leading to decreased or defective mRNA.

MCBG (28 decks)

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