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BMS1. Hemoglobin (NANDA) > Hemoglobin (Part 1) > Flashcards

Hemoglobin (Part 1) Flashcards

1
Q

Heme (General Information):

A
  • a prosthetic group (non-protein molecule required for biologic activity of some enzymes)
  • tightly, but not covalently bonded to hemoglobin or myoglobin (does not dissociate)
  • iron-containing molecule
  • a functional oygen carrier
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2
Q

Heme synonyms:

A
  • heme
  • hemin
  • protoporphyrin IX
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3
Q

Heme is bound to a hemoglobin molecule via:

A
  • a histidine residue
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4
Q

Heme structure:

A
  • protoporphyrin ring ligated to an iron (in center)
  • iron binds to four nitrogens of the protoporphyrin ring, a histidine sidechain on the bottom, and an oxygen on top
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5
Q

Iron attaches to the protoporphyrin ring of heme via:

A
  • 4 nitrogen bonds
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6
Q

Hb and Mb themselves are protected from degradation by:

A
  • sequestration in red blood cells (Hb) and muscle (Mb).
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7
Q

Myoglobin (Mb) Structure and Location:

A
  • monomeric protein (single polypeptide chain) with one heme group.
  • found in muscle only
  • binds oxygen tightly until an oxygen-depleted state induces its release for metabolic oxidation
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8
Q

Mb amino acid make-up and secondary structure:

A
  • 153 amino acids in 8 alpha-helical segments connected by beta-bends.
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9
Q

The purpose of the heme group and surrounding polypeptide chain in Mb is:

A
  • to keep ferrous iron from being oxidized to the ferric state (which would prevent it from binding oxygen).
  • Mb does this by providing a hydrophobic pocket to bind heme, while allowing a channel for oxygen access.
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10
Q

Mb secondary structure is dominated by:

A
  • alpha-helice segments (8)
  • hydrophobic core
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11
Q

Only the ____ form of heme is capable of reversibly binding oxygen.

A
  • ferrous (+2)
  • reduced
  • “ferrohemoglobin”
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12
Q

The form of heme/hemoglobin not capable of reversibly binding oxygen is:

A
  • ferric (+3)
  • oxidized
  • methemoglobin
  • non-functional
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13
Q

CO forms a particularly strong bond with:

A
  • ferrous iron in hemoglobin
  • favored 200-fold over oxygen.
  • In the presence of CO, oxygen is displaced and hemoglobin can no longer function as an oxygen carrier.
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14
Q

Function of polypeptide chain (Hb or Mb) surrounding a heme group:

A
  1. prevents aggregating
  2. prevents rust (going from ferric to ferrous - oxidizing)
  3. destabilize CO bonding to heme/active site
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15
Q

Are heme groups hydrophobic or hydrophilic?

A

hydrophobic

  • reason for aggregating in solution when not bound to protective protein such as Hb or Mb
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16
Q

How does Hb and Mb destabilize CO binding to heme?

A
  • second histidine (E7) coming from the E-helix forces CO into a bent conformation which is energetically unfavorable.
  • shifts the equilibrium between O and CO binding from a 25,000 fold affinity difference to a 200 fold difference.
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17
Q

Hemoglobin (Hb) Structure:

A
  • tetrameric protein (four polypeptide chains)
    • two alpha-globins
    • two beta-globins
  • four heme groups
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18
Q

Hb location and general function:

A
  • high concentration in red blood cells
  • transports oxygen from the lungs throughout the body/tissues
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19
Q

How are the four subunits of Hb held together?

A
  • series of ion pairs (salt bridges)
    • between oppositely charged amino acids on adjacent domains
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20
Q

Despite low amino acid sequence similarity between Hb and Mb, the two show:

A
  • remarkably similar tertiary structure
  • residues that surround the heme binding site are well conserved in the primary sequence
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21
Q

Most of the intramolecular interactions between the four different subunits of Hb are between:

A
  • alpha and beta chains
  • NOT between alpha-alpha or beta-beta
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22
Q

In a fully oxygenated Hb, between what residues do the salt bridges form on the alpha-helices?

A
  • Arg 141 (+) and Asp 126 (-)
  • Carboxy-terminus 141 (-) and Lys 127 (+)
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23
Q

Mb general function:

A
  • storage molecule, acting as a reserve supply of oxygen
  • in muscle
  • has higher oxygen affinity than Hb so that blood flow does not deplete these stores through regular circulation
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24
Q

Partial pressure of oxygen is directly related to:

A
  • concentration.
  • higher the concentration, greater its partial pressure.
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25
Q

P50 is a term used to describe:

A
  • oxygen pressure at which Hb or Mb is 50% saturated.
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26
Q

P50 of Hb:

A

26 torr

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27
Q

P50 of Mb:

A

1 torr

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28
Q

The oxygen binding curve for Mb is:

A
  • hyperbolic
    • suggests a simple equilibrium between oxygenated and deoxygenated states (i.e. no cooperativity)
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29
Q

The higher the P50 =

A
  • the lower the oxygen affinity
30
Q

The oxygen binding curve for Hb is:

A
  • sigmoidal (S-shaped)
  • indicates allosteric interactions
    • subunits in the tetramer cooperate (interact) during the binding event.
31
Q

As oxygen molecules bind to hemoglobin:

A
  • the affinity for oxygen increases
  • due to cooperativity of the subgroups
  • reason why most Hb molecules are either found with no oxygen (deoxyHb) or with all four oxygens (oxyHb)
32
Q

Why is histidine critical in the structure of Hb and Mb?

A
  • one histidine holds heme in place
  • another histidine protects us from CO poisoning
    • through making the CO-heme bond sterically/energetically unfavorable
33
Q

Myoglobin is held together via:

A

hydrophobic forces

34
Q

Hemoglobin is held together via:

A

four salt bridges

35
Q

Hill coefficient (n):

A
  • tells you extent of cooperativity of subunits.
    • 1 = no cooperativity
    • 4 = perfect cooperativity
    • 2.8 = somewhere in between (the Hill coefficient of hemoglobin). Not perfect cooperativity, but pretty good. Leads to sigmoidal curve.
36
Q

Hill coefficient of Mb:

A

1 (no cooperativity)

leads to hyperbolic curve

37
Q

Hill coefficient of Hb:

A

2.8 (moderate cooperativity)

leads to sigmoidal curve

38
Q

As the Hill Coefficient (n) increases, what happens to the binding curve?

A

it becomes more sigmoidal (due to increasing cooperativity)

39
Q

Allostery allows Hb to:

A
  • bind and release more oxygen over physiological oxygen concentrations.
40
Q

Allostery =

A
  • action at a distance
  • binding at one site affects the activity of an enzyme (or a transport protein) at another site.
41
Q

After the first oxygen binds to Hb, the change in conformation is about:

A
  • ½ angstrom
    • very subtle change that causes the cooperativity
42
Q

The two forms of Hb:

A
  • T-form (taut)
  • R-form (relaxed)
43
Q

T-form of Hb:

A
  • tense/taut (closed fist)
  • deoxygenated
  • low affinity for oxygen
44
Q

R-form of Hb:

A
  • relaxed (open hand)
  • oxygenated
  • high oxygen affinity
45
Q

In a solution of Hb, what is in equilibrium with one another?

A

T-form and R-form

46
Q

What form of Hb has more salt-bridges: T-form or R-form?

A

T-form

this is why it is more tense/taut than the R-form

47
Q

Difference between T-form and R-form of Hb:

A
  • T-form: iron and heme ring different planes
    • forces heme into unfavorable state for oxygen binding
  • R-form: iron and heme same plane
    • oxygen binding favorable
48
Q

Overall model for allosteric regulation of oxygen binding in Hb:

A
  1. No oxygen bound: all four subunits in T-form (low affinity)
  2. One oxygen bound: induces strain in the T-form, forces other subunits to take up the R-form, oxygen affinity is increased.
49
Q

Physiological factors affecting Hb oxygen affinity:

A
  1. pH (Bohr Effect)
  2. BPG
  3. CO2
50
Q

Bohr Effect:

A
  • lower pH, lower Hb oxygen affinity
  • lowering the pH stabilizes the T-form of Hb
51
Q

As you acidify the blood, you:

A
  • push Hb back into the T-state, forcing oxygen out of Hb and lower the affinity of oxygen.
    • dumps more oxygen to the tissues
52
Q

Bohr Effect mechanism:

A
  • As Hb changes conformation from T-state to R-state, some protons are ejected into solution, increasing the acidity of the solution.
  • Asp94-beta and His146-beta are responsible for this (become protonated and deprotonated)
53
Q

T-form of Hb and Bohr Effect:

A
  • Asp94beta and His146beta are right next to each other and the histidine wants to have a higher pKa and hold on to a proton.
  • Push oxygen off Hb, push on protons
54
Q

R-form of Hb and Bohr Effect:

A
  • Asp94beta and His146beta are far from each other and the histidine wants to have a lower pKa and lose a proton.
  • Push oxygen on Hb, push off protons.
55
Q

What two amino acids in Hb drive the Bohr Effect?

A
  • Asp94-beta
  • His146-beta
  • lowering the pH stabilizes the T-form
56
Q

The two effects of CO2 on Hb:

A
  1. CO2 dissolves in blood, in equilibrium with carbonic acid, acidifies blood
    • stabilizes T-form
    • Bohr Effect - lowers Hb oxygen affinity
  2. CO2 forms carbamates with N-terminus of the Hb beta chain at valine
    • stabilizes T-form
    • how CO2 is transported out of the body
57
Q

Increasing the acidity of the blood has what effect on Hb?

A
  • stabilizes the T-state
  • more oxygen is let go in tissues since oxygen affinity is now lower
  • raises the P50 of hemoglobin
58
Q

BPG is a normal constituent of red blood cells. Its synthesis may be upregulated in situations where:

A
  • greater oxygen delivery to tissue is needed
  • BPG decreases Hb affinity for oxygen (Hb delivers more oxygen to tissue)
    • stabilizes the T-state
59
Q

BPG is generated as a product of:

A

glycolysis

60
Q

BPG only binds to what state of Hb?

A
  • T-form
  • stabilizes the T-form, lowers Hb oxygen affinity, delivers more oxygen to tissue
61
Q

BPG binding site in deoxyHb is where?

A
  • the pore between the four chains.
  • Interacting sidechains include:
    • His 143-beta
    • His 2-beta
    • Lys 82-beta
    • beta-chain amino terminus.
62
Q

Nitric oxide is an allosteric regulator of:

A
  • bloodflow
  • vasodilator, increases blood flow to certain tissues, thereby increasing oxygen delivery
63
Q

Nitric Oxide binding to Hb:

A
  • binds to a cysteine on oxyHb (in lungs)
  • released in deoxyHb (in tissues)
64
Q

Hb T-form stabilized by:

A
  1. low pH (Bohr Effect)
  2. BPG
  3. CO2
65
Q

Hb R-form stabilized via:

A
  1. high pH
  2. NO
  3. oxygen
66
Q

Does myoglobin experience any allosteric regulation?

A

No. It has no cooperativity.

Allostery needs cooperativity.

67
Q

Methemoglobin:

A
  • when iron atom of the heme group is in the ferric (3+) charge state.
  • cannot bind oxygen
  • mutations in cytochrome b5 or cytochrome b5 reductase can lead to increases in metHb
  • very high affinity for cyanide
68
Q

What can methemoglobin be used as a treatment for?

A
  • cyanide poisoining
  • metHb has very high affinity for cyanide poisoining
69
Q

Methemoglobinemia (excess metHb accumulation) can be caused by:

A
  • mutations in cytochrome b5 or cyt b5 reductase
  • mutations in the hydrophobic pocket of Hb
  • exposure to oxidizing agents
70
Q

Methemoglbin aka:

A
  • ferrihemoglobin
  • when the heme iron is in the ferric state (3+)
    • cannot bind oxygen
    • high affinity for cyanide

BMS1. Hemoglobin (NANDA) (4 decks)

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