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BIOL 2421 - Cellular Biochem > 8. Hemoglobin > Flashcards

8. Hemoglobin Flashcards

1
Q

which protein binds O2 to a heme group for transport in the blood

A

hemoglobin

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2
Q

what is hemoglobin

A

a protein in red blood cells used for oxygen transport

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3
Q

what is oxygen bound to in hemoglobin

A

heme group

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4
Q

how many times bigger is hemoglobin than myoglobin

A

4x bigger

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5
Q

what’s the molecular weight of Hb

A

Mr=64,500

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6
Q

how many polypeptides make up Hb

A

4 (it’s a tretramer)

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7
Q

T or F: each of the 4 polypeptides in Hb have a heme prosthetic group

A

true

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8
Q

describe the types of polypeptides that make up Hb

A

two chains are alpha type, two are beta

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9
Q

T or F: the two subunit types of Hb (alpha and beta) look very different in their tertiary structure

A

false; they look very similar

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10
Q

what naming system do we use for the Hb helices

A

the same naming system as Mb

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11
Q

why do we use the same naming system for Hb and Mb

A

the Hb monomers are very similar to Mb in tertiary structure

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12
Q

T or F: the primary structures of Hb and Mb are very similar

A

false; only 27 of 150 positions are the same

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13
Q

does Hb have distal and proximal His like Mb does

A

yes

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14
Q

in the quaternary structure of Hb, which subunits have strong interactions

A

the unlike subunits (alpha with beta)

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15
Q

give an example how the unlike subunits of Hb have strong interactions between them

A

alpha1beta1 interface has 30 interacting residues

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16
Q

T or F: it’s easy to separate the a1 monomer and the b1 monomer in Hb

A

false! they are the unlike subunits and have strong interactions

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17
Q

T or F: it’s easy to separate a1b1 dimer from the a2b2 dimer of Hb

A

true; mild reagents can be used

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18
Q

what are the interactions between the unlike subunits of Hb

A

salt bridges, hydrogen bonds, etc

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19
Q

how many conformations does Hb have

A

2

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20
Q

what are the conformations of Hb

A

T (tense) and R (relaxed)

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21
Q

which conformation of Hb has a hollow center

A

T

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22
Q

which conformation of Hb has a filled in center

A

R

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23
Q

T or F: oxygen will bind to heme when Hb is in either conformation

A

true

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24
Q

which conformation of Hb has a significantly higher affinity for O2

A

R

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25
Q

describe what occurs when O2 binds to Hb in the T state

A

O2 binding in the T state triggers a conformational change of that subunit to the R state

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26
Q

which state is most predominant form for oxyhemoglobin

A

R

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27
Q

which state is most predominant form for deoxyhemoglobin

A

T

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28
Q

in which conformation is the heme porphyrin ring slightly puckered

A

T

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29
Q

what is the outcome of the heme ring being puckered in the T state

A

the heme iron protrudes a bit towards the proximal his (His F8)

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30
Q

what happens to the heme ring when O2 binds to the puckered ring in the T state

A

binding of O2 causes the heme to be more planar, and this shifts the proximal his, the entire F helix, and the relative position of the entire subunit (domino effect of movement= conformational change of T to R)

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31
Q

how does binding of the O2 to the puckered T state change the subunit interactions

A

the a1b1 and a2b2 dimers rotate 15 degrees with respect to one another (dimers themselves are relatively unchanged), and we’re now in the R conformation

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32
Q

T or F: Mb and Hb have very similar ligand binding curves

A

false; they’re significantly different

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33
Q

why would the ligand binding curves of Mb and Hb be different

A

because one is more suited for O2 storage, and the other for O2 transport

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34
Q

describe ligand affinity and Kd for Mb

A

high ligand affinity with a low Kd (very steep curve right at the beginning)

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35
Q

describe the implications of Mb having a high ligand affinity and low Kd

A

it’s very good at keeping O2 bound to the heme and only releases O2 under very low pO2 conditions

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36
Q

why would Mb make a poor transport molecule

A

low Kd=high affinity for O2, so it wouldn’t want to let it go when it’s time to release it

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37
Q

what is the shape of the Hb ligand curve

A

sigmoidal (S shape kinda)

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38
Q

what does it mean when a curve is sigmoidal (in regards of ligand affinity)

A

the binding of one ligand increases the likelihood of a ligand binding to another occupied site

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39
Q

what does the sigmoidal curve represent

A

represents a hybrid curve as the protein transitions from an initial low affinity state to a high affinity state as more O2 is bound

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40
Q

for Hb, what conformation is the low affinity state and which is the high affinity state

A

low affinity state: T

high affinity state: R

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41
Q

which part of the body would have low pO2

A

tissues

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42
Q

which part of the body would have high pO2

A

lungs

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43
Q

why can’t Mb produce a sigmoidal curve (2 reasons)

A

it’s a monomer with only one binding site, and each molecule of O2 binds independently

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44
Q

define positive cooperative binding of a ligand

A

the O2 affinity of Hb increases as each O2 binds to each subsequent subunit

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45
Q

describe the process of cooperativity

A

O2 weakly binds with deoxyhemoglobin subunit 1 in the T state. Change of subunit 1 from T to R. A change in the subunit interface between subunit 1 and other subunits. O2 has a higher affinity to bind to subunit 2

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46
Q

is cooperativity direct or indirect

A

indirect

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47
Q

why is cooperativity indirect and not direct

A

it all happens through conformational changes in quaternary structure and interactions between subunits, because heme groups are too far away from each other for direct interactions

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48
Q

where in the body are Mb and Hb both fully saturated

A

in the lungs

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49
Q

in the tissues, which of Mb and Hb have a lower O2 affinity

A

Hb has a much lower O2 affinity than Mb in the tissues

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50
Q

because Hb has a lower affinity for O2 in tissues, what does Hb do in tissues?

A

it will pass some of its O2 to Mb for effective diffusion to tissues and storage

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51
Q

T or F: Hb fraction saturation (Y axis) stays relatively the same when Hb reaches the tissues from the lungs

A

false; it is really sensitive over that range

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52
Q

why is Hb sensitive when it reaches the tissues

A

tissues have different pO2 levels depending on their activity, so when Hb reaches a really active tissue it will release much more O2 for us

53
Q

what is the equation for ligand association when there are multiple binding sites

A

P + nL = PLn

54
Q

what is the Hill equation

A

log(y/1-y)=nlog[L]-logKd

55
Q

what would a hill plot have on the x axis

A

log[L]

56
Q

what would a hill plot have on the y axis

A

log(y/1-y)

57
Q

what would the slope be on a hill plot

A

nH

58
Q

what values will nH have

A

between 1 and 4

59
Q

what would it mean if nH was 1

A

no cooperativity. The four subunits do not communicate or influence each other

60
Q

what would it mean if nH was 4

A

full cooperativity. the four subunits fully cooperate (all protein binding sites bind ligand simultaneously)

61
Q

what would it mean if nH was between 1 and 4

A

partial cooperativity. The subunits influence each other and promote more O2 binding, but Hb can exist as partially saturated

62
Q

what would it mean if nH was less than 1

A

negative cooperativity

63
Q

since we’re dealing with pO2 and not [O2], what is the new hill equation

A

log(y/1-y)=nlog[pO2]-log(P50)

64
Q

what is the fraction saturation for a hill plot

A

0 on the y axis (you get this when you plug 0.5 into the left of the hill equation)

65
Q

T or F: on a hill plot, when you use 0 on the y axis to find fraction saturation, the x axis represents Kd

A

false, it represents log of Kd

66
Q

what are the two models that describe the transition from T to R

A

concerted model and sequential model

67
Q

what happens in the concerted model of T –> R

A

all subunits transition from T to R simultaneously. When one subunit goes, they all go

68
Q

describe the process of the concerted model

A

O2 binding can happen in either conformation, but the successive binding makes the transition from T to R more likely. At each level of O2 loading, an equilibrium exists between T and R states. The equilibrium shifts favoring T when no O2 is bound to favoring R when O2 is bound to all subunits

69
Q

what happens in the sequential model of T –> R

A

individual subunits can change one at a time from T to R

70
Q

describe the process of the sequential model

A

the conformational change of T to R in one subunit as O2 binds makes both a similar conformational change in an adjacent subunit and O2 binding in an adjacent subunit more likely

71
Q

between the two models of T to R, which one does Hb more closely follow

A

both! neither model in its pure form fully accounts for the behavior of Hb

72
Q

describe how Hb follows both models of T to R

A

kind of concerted: the tetramer with 3 O2 bound is almost always fully in the R state. The binding affinity of the final empty subunit has increased over 20x from plain deoxyhemoglobin

its kind of sequential because the tetramer with 1 O2 bound is almost always still fully in the T state, but still has a higher affinity for O2 compared to plain deoxyhemoglobin

73
Q

what makes Hb an allosteric protein

A

the binding affinity of O2 to a Hb subunit can be affected by the binding of a ligand to another subunit

74
Q

when discussing allostery, the ligand binding elsewhere is referred to as a ___

A

modulator

75
Q

what is a modulator

A

a term for a ligand binding elsewhere to affect the affinity of O2 to a subunit

76
Q

T or F: a modulator can be an activator or an inhibitor

A

true

77
Q

define homotropic allostery

A

when the normal ligand and the modulator are the same chemical

78
Q

define heterotopic allostery

A

when the normal ligand and the modulator are different chemicals

79
Q

in regards to modulators, what is the term for O2 in relation to Hb

A

a homotropic activator

80
Q

other than O2, what can Hb carry

A

H+ and CO2 (products of cell respiration)

81
Q

where does Hb carry H+ and CO2

A

from the tissues to the lungs and kidneys

82
Q

T or F: CO2 is not very soluble in blood

A

true

83
Q

since CO2 is not soluble in blood, how does it travel in the blood

A

travels as bicarbonate

84
Q

what is the reaction to make bicarbonate

A

CO2 + H2O –> H+ + HCO3-

85
Q

what enzyme catalyzes bicarbonate formation

A

carbonic anhydrase

86
Q

where is the enzyme carbonic anhydrase located

A

red blood cells

87
Q

why is carbonic anhydrase located in the blood

A

it catalyzes bicarbonate formation so CO2 has a way to travel through the blood

88
Q

what is the result of changes in H+ (and pH) and CO2 concentrations

A

changes can greatly influence the ability of Hb to bind O2

89
Q

where on Hb does O2 bind

A

to the heme iron

90
Q

where on Hb does H+ bind

A

can bind to any amino acid R groups that are positively charged (basic)

91
Q

where on Hb does CO2 bind

A

binds to the amino group at the N-terminus of each polypeptide as carbamate adducts

92
Q

T or F: CO2 binding to Hb produces more H+

A

true

93
Q

why does CO2 binding to Hb cause more H+ to form

A

when CO2 attaches to the amino group at the N-term of each polypeptide, it forms a carbamate adduct, which releases H+ from the amino group

94
Q

what does the bohr effect describe

A

the effect of pH and CO2 concentration on the binding and release of O2 by Hb

95
Q

what is the relationship between H+/CO2 binding and O2 binding

A

they’re inversely related

96
Q

describe Hb’s affinity for O2 when we have low pH (high H+) and high CO2

A

low affinity for O2 (O2 is released into tissues)

97
Q

describe Hb’s affinity for O2 when we have high pH (low H+) and low CO2

A

high affinity for O2 (O2 binds to Hb for transport to tissues)

98
Q

name a major site for H+ binding

A

His 146 aka His HC3

99
Q

what is His146 aka His HC3

A

it’s in the linker of helix H between H and it’s C terminus

100
Q

what happens when H+ protonates His HC3

A

His HC3 forms one of the ion pairs (to Asp FG1) across subunits to help stabilize the T state

101
Q

what is the result of His HC3 being protonated and forming one of the ion pairs across subunits

A

pKa rises, so it’s very unlikely for it to be deprotonated

102
Q

since the T state is very stabilized (due to His HC3 protonation), what is the R state like

A

in the R state, His HC3 ion pair cannot form

103
Q

in regards to His HC3, what happens as H+ concentration rises

A

protonation of His HC3 promotes the release of oxygen by favoring a transition to the T state

104
Q

what is 2,3BPG (not the name but the role)

A

it’s a heterotrophic modulator of mammalian Hb

105
Q

where is BPG

A

erythrocytes

106
Q

what does BPG do

A

it raises the P50 of Hb

107
Q

what is the relationship between O2 binding and BPG binding

A

inverse relationship

108
Q

what is the formula for BPG formation

A

HbBPG + O2 -> HbO2 + BPG

109
Q

where on Hb does BPG bind

A

binds the central cavity of the Hb tetramer between the two beta subunits

110
Q

what type of charges does BPG have

A

negative

111
Q

what type of charges does the binding pocket of Hb have (this is where BPG binds)

A

positive

112
Q

which state is stabilized when BPG is bound

A

T

113
Q

which state is stabilized when BPG is unbound

A

R

114
Q

describe Hb saturation when BPG is absent

A

Hb is nearly saturated

115
Q

what would happen is BPG was not present in blood

A

Hb would not release O2 within body tissues

116
Q

T or F: BPG plays a big role in what happens when you move from sea level to higher altitudes

A

true

117
Q

how would high altitude affect your O2 delivery

A

limited O2 in the lungs to pick up –> won’t have Hb leave lungs 100% saturated with O2

118
Q

what happens to BPG levels when we move to higher altitudes

A

red blood cells produce more BPG

119
Q

how does the increase in BPG affect the curve

A

more BPG=lower O2 affinity (sounds bad), but it causes fraction saturation to be lower. While overall affinity is lower, your drop off rate has increased (which is good)

120
Q

what are the isoforms of embryo Hb

A

ζ2ε2, ζ2γ2, or α2 ε2 (aka no beta)

121
Q

what is the isoform for fetus Hb

A

α2γ2 (no beta)

122
Q

describe the P50 for embryo and fetus Hb

A

embryo Hb: low P50

fetus Hb: intermediate P50

123
Q

why is it important that embryo and fetus Hb have low and intermediate P50

A

fetal Hb will have a higher affinity for O2 than adult Hb

124
Q

what type of mutation produces sickle cell anemia

A

single amino acid change

125
Q

what amino acid change occurs to produce sickle cell anemia

A

glutamine to valine (E to V)

126
Q

where does the amino acid change occur to produce sickle cell anemia

A

at position 6 in the two beta chains

127
Q

what is the result of the amino acid change to produce sickle cell anemia

A

negative aa to hydrophobic aa: creates sticky hydrophobic contact point on the outer surface of the molecule, so in the deoxygenated form the molecules stick together and form aggregates

128
Q

what are some symptoms of sickle cell

A

weakness, dizziness, shortness of breath, heart murmurs, low erythrocyte count, blocked capillaries

129
Q

what happens if you’re heterozygous for the sickle cell allele

A

you have a mild condition called sickle cell trait (only 1% of erythrocytes are sickle shaped)

BIOL 2421 - Cellular Biochem (21 decks)

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