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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
P50 is a term used to describe:
* oxygen pressure at which Hb or Mb is 50% saturated.
26
P50 of Hb:
26 torr
27
P50 of Mb:
1 torr
28
The oxygen binding curve for Mb is:
* hyperbolic * suggests a simple equilibrium between oxygenated and deoxygenated states (i.e. no cooperativity)
29
The higher the P50 =
* the lower the oxygen affinity
30
The oxygen binding curve for Hb is:
* sigmoidal (S-shaped) * indicates allosteric interactions * subunits in the tetramer cooperate (interact) during the binding event.
31
As oxygen molecules bind to hemoglobin:
* 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
Why is histidine critical in the structure of Hb and Mb?
* one histidine holds heme in place * another histidine protects us from CO poisoning * through making the CO-heme bond sterically/energetically unfavorable
33
Myoglobin is held together via:
hydrophobic forces
34
Hemoglobin is held together via:
four salt bridges
35
Hill coefficient (n):
* 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
Hill coefficient of Mb:
1 (no cooperativity) leads to hyperbolic curve
37
Hill coefficient of Hb:
2.8 (moderate cooperativity) leads to sigmoidal curve
38
As the Hill Coefficient (n) increases, what happens to the binding curve?
it becomes more sigmoidal (due to increasing cooperativity)
39
Allostery allows Hb to:
* bind and release more oxygen over physiological oxygen concentrations.
40
Allostery =
* action at a distance * binding at one site affects the activity of an enzyme (or a transport protein) at another site.
41
After the first oxygen binds to Hb, the change in conformation is about:
* ½ angstrom * very subtle change that causes the cooperativity
42
The two forms of Hb:
* T-form (taut) * R-form (relaxed)
43
T-form of Hb:
* tense/taut (closed fist) * deoxygenated * low affinity for oxygen
44
R-form of Hb:
* relaxed (open hand) * oxygenated * high oxygen affinity
45
In a solution of Hb, what is in equilibrium with one another?
T-form and R-form
46
What form of Hb has more salt-bridges: T-form or R-form?
T-form this is why it is more tense/taut than the R-form
47
Difference between T-form and R-form of Hb:
* 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
Overall model for allosteric regulation of oxygen binding in Hb:
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
Physiological factors affecting Hb oxygen affinity:
1. pH (Bohr Effect) 2. BPG 3. CO2
50
Bohr Effect:
* lower pH, lower Hb oxygen affinity * lowering the pH stabilizes the T-form of Hb
51
As you acidify the blood, you:
* 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
Bohr Effect mechanism:
* 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
T-form of Hb and Bohr Effect:
* 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
R-form of Hb and Bohr Effect:
* 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
What two amino acids in Hb drive the Bohr Effect?
* Asp94-beta * His146-beta * lowering the pH stabilizes the T-form
56
The two effects of CO2 on Hb:
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
Increasing the acidity of the blood has what effect on Hb?
* stabilizes the T-state * more oxygen is let go in tissues since oxygen affinity is now lower * raises the P50 of hemoglobin
58
BPG is a normal constituent of red blood cells. Its synthesis may be upregulated in situations where:
* greater oxygen delivery to tissue is needed * BPG decreases Hb affinity for oxygen (Hb delivers more oxygen to tissue) * stabilizes the T-state
59
BPG is generated as a product of:
glycolysis
60
BPG only binds to what state of Hb?
* T-form * stabilizes the T-form, lowers Hb oxygen affinity, delivers more oxygen to tissue
61
BPG binding site in deoxyHb is where?
* the pore between the four chains. * Interacting sidechains include: * His 143-beta * His 2-beta * Lys 82-beta * beta-chain amino terminus.
62
Nitric oxide is an allosteric regulator of:
* bloodflow * vasodilator, increases blood flow to certain tissues, thereby increasing oxygen delivery
63
Nitric Oxide binding to Hb:
* binds to a cysteine on oxyHb (in lungs) * released in deoxyHb (in tissues)
64
Hb T-form stabilized by:
1. low pH (Bohr Effect) 2. BPG 3. CO2
65
Hb R-form stabilized via:
1. high pH 2. NO 3. oxygen
66
Does myoglobin experience any allosteric regulation?
No. It has no cooperativity. Allostery needs cooperativity.
67
Methemoglobin:
* 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
What can methemoglobin be used as a treatment for?
* cyanide poisoining * metHb has very high affinity for cyanide poisoining
69
Methemoglobinemia (excess metHb accumulation) can be caused by:
* mutations in cytochrome b5 or cyt b5 reductase * mutations in the hydrophobic pocket of Hb * exposure to oxidizing agents
70
Methemoglbin aka:
* 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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