Hemoglobin and Hemoglobinopathies Flashcards Preview

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Flashcards in Hemoglobin and Hemoglobinopathies Deck (115):
1

Is like a little computer, sensing the gasses around it, the pH around it, and the other ligands in the area. Then it computes wether or not it needs to release or bind oxygen

Hemoglobin

2

Goes through a breathing motion. As it breathes, it binds an oxygen molecule. Then when it reaches it's destination, it exhales its oxygen and inhales CO2

Hemoglobin

3

Per fluorocarbons make liquids at room temperature with very high solubility for gasses such as oxygen. When blood is replaced with this liquid, a rat can breathe in water or in air. This is called

Liquid ventillation

4

A non amino acid type group

Cofactor

5

Acts as a dissolver of oxygen

Heme

6

Heme needs to be in blood because by itself, heme is oxidized forming a

u-bridged heme compound with a hyrdrophobic layer on the top and bottom, which will cause them to aggregate out of solution

7

Two ferrous (2+) hemes can form a bridged complex with oxygen, producing

Non-functional oxidized heme

8

What do we call reduced Fe 2+ hemoglobin?

Ferrohemoglobin (an oxygen carrier)

9

What do we call oxidized Fe 3+ hemoglobin?

Methemoglobin (nonfunctional)

10

Hemoglobin is only functional in the

Ferrous state (2+)

11

What is a synthetic way to make heme and keep it from forming bridged heme aggregates?

-developed for artificial blood substitutes

Picket-fence heme

12

In the cell, our hemoglobin is not the picket-fence type. So how do we protect heme from being oxidized?

Heme is surrounded by the hemoglobin protein, which prevents oxidation and u-bridge formation

13

Heme is the O2 binding molecule common to

Myoglobin and Hemoglobin

14

Once sequestered inside a hydrophobic pocket created by the folded globin polypeptide, heme encounters a protective environment that minimizes

The oxidation of Fe 2+ to Fe 3+

15

Mutations that lead to anemia do so by weakening the proteins binding to heme, thus making it more likely that

Iron is oxidized, creating nonfunctional methemoglobin

16

The O2 binding of myoglobin is not optimal for

O2 transport

17

Which binds oxygen more tightly, myoglobin or hemoglobin?

Myoglobin

18

Enables hemoglobin to deliver oxygen over a range that best suits our needs

Hemoglobins complex structure

19

The partial pressure of oxygen, where protein sites are half saturated

P50

20

Oxygenated and deoxygenated blood are different colors because

They absorb at different wavelengths

21

Measures the absorption of 660nm and 940nm wavelengths in the arteries

Pulse oximetry

22

If we take ratios of the extinction coefficients at 660nm and 940 nm, what does it mean if the ratio is less than one?

We have more oxygenated blood than deoxygenated blood

23

A single-chain globular protein of 153 amino acids.

-made up of all alpha helices

Myoglobin

24

Myoglobin is located in the

Cytosol of muscle cells

25

Binds oxygen that has been released by Hb in the tissue capillaries and has subsequently diffused across cellular membranes

Myoglobin

26

Controls the gasses which can and can not bind heme

-Prevents CO from binding

The E-helix Histidine

27

What holds myoglobin together?

The hydrophobic effect from the 60 hydrophobic residues

28

How many circulating globins are there?

1 (hemoglobin)

29

How many non-circulating globins are there?

3 (myoglobin, neuroglobin, cytoglobin)

30

Hemoglobin is essentially four myoglobin subunits coming together. These four subunits interact with eachother and change the

P50

31

A different globin gene encodes

the alpha and beta subunits

32

The primary sequence of hemoglobin and myoglobin is actually

Much different (but their structures are almost identical)

33

What holds hemoglobin together?

Intermolecular salt bridges (ex: btw Asp and Lys)

34

Why are the intermolecular salt bridges that hold hemoglobin together good?

1.) They don't compete with the hydrophobic interactions in the core
2.) They allow for flexibility

35

The amount of oxygen bound to hemoglobin by the time it reaches the tissues is

Low

36

Allows us to sequester more oxygen within the blood

Hemoglobin

37

Takes more partial pressure of oxygen to 50% saturate

Hemoglobin

38

Ligand binding causes structural rearrangement that
orients enzyme in its active conformation and makes it
easier for next substrates to bind. This describes

Cooperative binding

39

Also utilized in protein folding. Once the fold starts, it becomes a chain reaction of folding

Cooperativity

40

When you look at oxygen binding, we are essentially moving from a low affinity state to a high affinity state.
Hemoglobin is in a low affinity state, then the first oxygen binds and

The affinity increases and keeps increasing with each successive oxygen that binds

41

A measure of the degree of cooperativity

-represented by n in the saturation equation

Hill coefficient

42

Hemoglobins high degree of cooperativity enables it to

Pick up more oxygen in the lungs and deliver more oxygen in the body

43

Favors the T-state

Deoxy-Hb

44

Favors the R-state

Oxy-Hb

45

The binding of oxygen to a hemoglobin subunit in the T-state triggers a change in conformation to the

R state

46

When the entire protein undergoes the T to R transition, the αβ subunit pairs slide past eachother and rotate, which

Narrows the pocket between the β subunits

47

Change little in the transition from the T state to the R state

The structures of the individual α and β subunits

48

A protein that exhibits changes in ligand (or substrate) affinity under the influence of small molecule

Allosteric Protein

49

Bind to proteins at sites that are spatially distinct from the active sites and, through long-range conformational change, alter the affinity of the active site for the substrate

Allosteric Effectors

50

Often multi-subunit proteins

Allosteric proteins

51

May either increase an enzymes affinity for substrate or decrease an enzymes affinity for substrate

Allosteric effector

52

What are the two major conformation of hemoglobin?

T and R states

53

Although oxygen binds to hemoglobin in either state, it has a significantly higher affinity for hemoglobin in the

R state

54

More stable when oxygen is absent experimentally and is thus the predominant conformation of deoxyhemoglobin

T state

55

What makes the T-state more tense than the R state?

The T state has an increased number of salt bridges

56

Describes how hydrogen ions and carbon dioxide effect the affinity of oxygen in hemoglobin

Bohr Effect

57

What is the effect on hemoglobin of lowering pH?

When hemoglobin binds oxygen, it releases hydrogen ions. However, at lower pH, there are more hydrogen ions in solution, which prevents hemoglobin from binding oxygen as well. Thus the affinity of hemoglobin for oxygen is lower in acidic pH

58

What is the effect on hemoglobin of increases pH?

Higher pH increases the affinity of hemoglobin for oxygen. It will bind oxygen more tightly

59

What effect do high levels of carbon dioxide have on hemoglobins affinity for oxygen?

High levels of CO2 result in the formation of carbonic acid, which decreases pH, thereby decreasing Hb's affinity for oxygen

60

What effect do low levels of carbon dioxide have on hemoglobins affinity for oxygen?

Low levels of CO2 increase Hb's affinity for oxygen

61

What serves as the pH sensor on Hb?

Asp 94 and His 146 on the β chains far from heme binding sites

62

Why is the T state favored at lower pH?

His 146β gets protonated and becomes positively charged, resulting in salt bridge formation with Asp 94β. This interaction stabilizes the T state

63

Why is the R state favored at higher pH?

Histidine 146β is deprotonated, breaking the salt bridge with Asp 94β, thus relaxing the protein and stabilizing the R state

64

In the lungs, Hb releases a proton as it binds O2, the proton reacts with bicarbonate, reforming carbonic acid. This results in

CO2 liberation and water formation

65

Some CO2 is transported directly with Hb by forming

Carbamates with amine groups on the N-terminus

66

When hemoglobin goes from the R state to the T state, two free amines are exposed. The amines can bind CO2, forming a carbonate. This stabilizes the

T state

67

Promotes the excretion of bicarbonate in the kidneys

Diamox (acetazolamide)

68

How can we use Diamox (acetazolamide) to treat altitude sickness, which is caused by a decrease in oxygenation of the bodies tissues at high altitudes.

When bicarbonate is excreted in the kidneys, blood pH drops. This drop in blood pH decreases the affinity of hemoglobin for oxygen, which improves Hb's ability to deliver oxygen to the body

69

Binds to the R state of Hb directly on the heme iron, as well as a thiol-nitrosyl bond on Cys 93β

Nitric oxide

70

Release of Nitric oxide upon deoxygenation of Hb allows NO to?

Bind vascular endothelium receptors, triggering vasodilation and increased blood flow to hypoxic tissues

71

A normal product of glycolysis in erythrocytes that is critical to the release of oxygen from hemoglobin

2,3-BPG

72

Binding of 2,3-Biphosphoglycerate (2,3-BPG) to Hb does what?

Stabilizes the T state and reduces affinity for oxygen

73

Without 2,3-BPG, hemoglobin acts just like

Myoglobin

74

What affect does acidification of blood have on myoglobin?

None

75

How does 2,3-BPG stabilize the T-state and reduce hemoglobins affinity for oxygen?

Forms a network of salt bridges between the two β subunits

76

What three things stabilize the T-state?

-decreases Hb's affinity for oxygen?

1.) Low pH
2.) 2,3, BPG
3.) High levels of CO2

77

What three things stabilize the R-state?

-Increases Hb's affinity for oxygen

1.) High pH
2.) Oxygen (allostery)
3.) Nitric oxide

78

The varying Hb's are arranged on chromosomes in the order of

Their expression during development

79

Instead of being composed of 2α and 2β subunits, fetal hemoglobin is composed of

2α and 2ƴ subunits

80

Has a lower affinity for 2,3-BPG

-Has a higher affinity for oxygen

Fetal Hb

81

There are two very important Histidine's in Hb. The distal histidine binds the Fe 2+. What does the other (known as the E helix) do?

Sits on the top side of the Fe 2+ and destabilizes CO binding while at the same time stabilizes oxygen binding

82

A colorless, odorless gas responsible for more than half of annual poisoning deaths worldwide

Carbon Monoxide (CO)

83

How much greater of an affinity does CO have for Hb than oxygen?

250 times

84

Produces cherry red discoloration of the skin and organs

-treated with 100% or hyperbaric oxygen

CO poisoning

85

Glucose can be added to the N-terminal of the beta chains of Hb, resulting in

Glycation of Hb by glucose to HbA1c

86

Glycation of Hb by glucose to HbA1c is a relatively irreversible reaction which affects the binding of

2,3-BPG

87

Representative of glucose over 6-8 weeks, making them a good indicator of diabetes risk or the efficacy of current treatment

HbA1c levels

88

Affects the electrophoretic mobility of Hb

Glycosylation

89

When Hb sickles it can cause red blood cells to rupture, which can result in

Blockages and Ischemia

90

In people with Sickle Cell Anemia, Red blood cells are more

Fragile than normal

91

An autozomal recessive (AR) disorder that is a homozygous condition

Sickle Cell Anemia

92

You can be heterozygous for sickle cell and not have full blown sickle cell anemia. This is called having the

Sickle Cell Trait

93

Usually asymptomatic, except in the renal medulla where oxygen tensions are low enough to induce sickling and renal damage

Sickle cell trait

94

Butyrate and hydroxyurea stimulate the production of HbF, why might this be an effective treatment to alleviate the presentation of sickle cell?

HbF brings in healthy beta chains in the form of Y chains

95

What are two other methods to treat sickle cell?

1.) Bone marrow stem cell transplant
2.) Gene therapy

96

Individuals heterozygous for sickle cell are protected against the most lethal forms of

Malaria

97

Part of the life cycle of the malaria parasite plasmodium is spent reproducing in red blood cells, however, free Hb is toxic to plasmodium so it sequesters Hb into a crystalline form called

Hemozoin

98

Many anti-malarials disrupt

Hemozoin formation

99

Infection of RBCs by plasmodium triggers sickling, recruiting phagocytes that then clear the infected cells in

HbS

100

A Glu 6 Lys mutation that causes intracellular crystallization of Hb and cation leak, resulting in dehydration

Hemozoin (HbC)

101

Genetic disorders of Hb synthesis

Thalassemias

102

What are the three main causes of Thalassemias?

1.) Hb gene is missing
2.) Gene is present, but expression is impaired
3.) mRNA is produced, but it encodes disfunctional Hb

103

Thalassemias caused by impaired expression of the Hb gene are due to

Modifications to gene promoter region

104

What causes the Thalassemias where the mRNA is produced but it encodes grossly disfunctional Hb?

Introduction of an early stop codon

105

In β-thalassemias, α-chains aggregate into

Heinz bodies

106

The β4 tetramers form (HbH) which has reduced
solubility and lacks allosteric regulation found in HbA

α-thalassemias

107

What are the four types of α-thalassemias

1.) Silent carrier
2.) Trait
3.) Disease
4.) Hydrops fetalis (death occur because no alpha chains)

108

β-thalassemias have higher levels of

HbF or HbA2

109

α-thalassemias have higher levels of

Hb Barts: y4, or HbH

110

The nonfunctional oxidized version of hemoglobin

-often manifests in cyanosis (blue lips, extremities)

Methemoglobin

111

Higher than noirmal (> 1%) levels of oxidized hemoglobin

Methemoglobinemia

112

Methemoglobinemia can be induced by certain

Antibiotics

113

Effects interactions with cytochrome-b5-reductase and can lead to methemoglobinemia

HbM (Hb Hyde Park) mutations

114

Can be used to treat cyanide poisoning by oxidizing Hb, which readily binds cyanide, producing cyanohemoglobin.

Amyl Nitrate

115

The production of cyanohemoglobin keeps HCN from binding

-Critical for respiration

Cytochrome C oxidase

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