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CPR 2 > Hemoglobin Structure And Function > Flashcards

Hemoglobin Structure And Function Flashcards

1
Q

What is special about the confirmation of myoglobin and hemoglobin ?

A

The confirmation of myoglobin and a single globin monomer of hemoglobin are practically superimposable

There are many similarities in the primary structure

  • Approximately a fourth (25%) of all residues are identical
  • That means about 75% are different amino acids

The overall fold is same for globin monomers: globin fold

Key amino acid residues are conserved and in the correct place

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2
Q

Describe the globin structure of myoglobin

A

The globin protein monomer is mostly composed of a-helix

A few bends or turns are present

Globin structure is unusual in that it is devoid of B sheet

-Most proteins are a combination of a-helix and B-sheet

Reversible binding of oxygen

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3
Q

What is the significance of Ferrous iron (Fe2+)?

A

Ferrous iron may form 6 coordination bonds

  • four bonds form to the nitrogen atoms in the porphyrin ring
  • One bond links to an amino acid of the globin protein
  • One bond is free to reversibly bind oxygen

Iron ion is buried deep inside the globin protein

 - Helps to ensure that oxygen is released as O2
 - O2 entrance and exit is in a defined path
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4
Q

What is Hemoglobin A?

A

HemeA(HbA) is a pair of identical aB dimers (a2B2 tetramer)

The heme groups are widely spaced

Appreciate that there are extensive interactions between the subunits

  • Hydrophobic
  • Ionic
  • Hydrogen bonds

4 globin monomers means that 4 O2 molecules can be carried on Hb

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5
Q

When is ferric ion present on heme?

A

Methemoglobin (metHb) contains a Fe3+ (ferric ion) in the porphyrin ring

  • Fe2+ (gets oxidized) —> Fe3+
    • Occurs when superoxide (O2^-1) is released instead of dioxyg; molecular oxygen (O2)
  • Ferric ion is the more oxidized version of the iron atom
    • Ferric ion does not bind to O2 when in heme

The remaining 3 O2 sites do not release the oxygen that is bound
-Same argument as for carbon monoxide

Therefore, MetHb does not function as an O2 carrier

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6
Q

What happens if superoxide is released from iron in hemoglobin?

A

If superoxide releases from the iron in hemoglobin, methoglobin is formed

The structure of heme binding pocket of hemoglobin is such that formation of methoglobin is minimized

Normally, methoglobin is formed at a slow rate, it is normally enzymatically reduced back back to the ferrous form

Enzyme deficiency in the pathway for converting metHb(ferric) to Hb (ferrous)

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7
Q

What can be used to form reluctant sand oxidants?

A

Reductant- methylene blue

Oxidant: excessive nitrates

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8
Q

Myoglobin has a higher affinity for oxygen than hemoglobin …

A

The oxygen dissociation curve for myoglobin is hyperbolic.

Hb binds oxygen with cooperatively so it’s dissociation curve is sigmoidal

Binding of one O2 molecule promotes binding of another O2 molecule

This is called cooperative ligand binding

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9
Q

Compare hemoglobin and myoglobin

A

Function: Hb- oxygen transport Mb- oxygen storage

Location: hemoglobin in erythrocytes Mb- muscle tissue

Tissue O2 affinity: hemoglobin- low Mb- high

Lung O2 affinity: Hb: high affinity Mb: none

O2 affinity change with pO2: Hb: yes Mb: no

Allosteric regulation: Hb: yes Mb: no

Quaternary structure: Hb: tetramer Mb: Monomer (n9t quarternary)

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10
Q

What happens when oxygen binds to hemoglobin?m

A

O2 binding to heme leads to a conformational change in hemoglobin leads

Normally the Fe ion is slightly out of plane of the heme ring
(About 0.4A, 0.04nm)
-Teeny tiny but, a big distance for a molecule

The Fe atom (ferrous) moves into the plane of the heme when it is oxygenated.
-Remember, everything is covalently bonded together

Proximal histidine and it’s associated residues are pulled along the iron ion (tugging)
-This is conformational change is transmitted to the other globin monomers in Hb

Provides a mechanism to explain the conformational change associated with oxygen binding
-Explains coorperative oxygen binding

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11
Q

How are the aB dimers held in the hemoglobin?

A

The aB dimers are held together with a stronger interaction then the dimer pairs to each other

A few ionic and hydrogen bonds occur between aB dimer pairs in the deoxygenated state.

Many interactions, primarily hydrophobic, between a and B chains form stable aB dimers.

Some ionic and hydrogen bonds between aB dimers are broken in the oxygenated states

As Hb binds oxygen, it’s oxygen affinity increases

Later, when we discuss CO poisoning, you will see that:
The terms oxy-Hb and R-state are NOT synonymous
The terms deoxyHb & T-state are synonymous

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12
Q

Explain the postage stamp metaphor

A

Two perforated edges must be torn to remove the first stamp.
-First, O2 binds with the lowest affinity

Successive stamp removal is easier as more stamps are removed
-Medium affinity O2 binding

By the end,the last stamp is free without tearing any edges
-Last O2 binds with the highest affinity

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13
Q

How does 2,3 BPG promote formation of taut formation

A

A single molecule of 2,3 BPG binds to a positively charged cavity formed by the B-chains of deoxyhemoglobin

-2,3. BPG is negatively charged
   Phosphate groups (PO4^3-)
   Carboxylate groups (COO-)

-2,3 BPG allows the formation of additional salt bridges between the aB/aB dimers

This creates a driving force for Hb to assume the deoxyHb structure (taut form)
-Promotes unloading O2 in the tissues

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14
Q

How does 2,3 BPG decreases Hb oxygen affinity?

A

Higher levels of 2,3 BPG promote oxygen release to the tissues

Decreases the affinity of Hb for oxygen

2,3 BPG is a negative allosteric effector

Promotes release of oxygen from hemoglobin

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15
Q

How can glycolysis effect oxygen affinity?

A

Partial deficiencies in glycolysis may affect the oxygen binding affinity of hemoglobin

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16
Q

Give the differences between Hexokinase and pyruvate kinase deficiencies

A

Hexokinase deficiency-

  • reduced 2,3 BPG levels
  • left shift on binding curve
  • increased O2 affinity

Pyruvate kinase deficiency

  • Elevated 2,3 BPG levels
  • Right shift on binding curve
  • Decreased O2 affinity
17
Q

What is the Bohr effect?

A

As pH decreases, Hb O2 affinity decreases

This is the Bohr effect

Logic:

  • Aerobic tissues form CO2 as they produce ATP
  • Dissolved CO2 can become an acid when it reacts with H2O
  • Anaerobic tissue also produce organic acids

CO2 and H+ ions signal a need for more O2

H+ and CO2 have no effects on O2 binding to myoglobin

18
Q

At reduced pH …

A

Reduced pH/more H ions there will be more charges on Hb, and this allows formation of more interactions, & increased stabilization of the taut state

19
Q

What is the function of carbonic anhydrase?

A

Carbonic anhydrase promotes formation of carbonic acid from CO2

H+ ions protonate Hb, forms positive charges
Allows formation of additional salt bridges
Stabilizes the taut form of Hb, promotes O2 delivery to tissues

CO2 may react with the amino terminus of one of the globin-chains—> carbanino. Hemoglobin. Allows formation of additional salt bridges, and also the release of H+ ions (so lower pH, and contribution to Bohr effect)

20
Q

Give the physiology of hemoglobin in the lungs

A

In the lungs, CO2 and H+ leave Hb, which promote the release of 2,3-BPG, as O2 binds

The high O2 atmospheric pressure in the lungs is sufficient to overcome the T-state, so O2 may bind to Hb (in lungs). This forces out the 2,3 BPG, H+ ions are released (H+ associates with HCO3^- to form carbonic acid which decomposes to form CO2).

Also, CO2 bound to the N-terminal end of some globulin subunits may be released

21
Q

Explain the physiology of hemoglobin in tissues

A

In tissues, CO2 and H+ ions bind to Hb, which promote the binding of 2,3-BPG, and the delivery of O2.

H+ ions, CO2 and 2,3-BPG enhance oxygen delivery by decreasing O2 affinity in response to the decreased oxygen tension in the tissues. The T state is favored in the presence of H+ ions, CO2 and 2,3-BPG

22
Q

How does Hb interact with CO2 and protons?

A

Hemoglobin mops up most of the protons generated during CO2 transport (volatile acid)

CO2 is transported in blood as

  1. HCO3^-
  2. Carbamino Hb
  3. Dissolved CO2

Hb is responsible for a significant proportion of acid buffering during CO2 transport

23
Q

What is the significance of free heme?

A

Free heme will bind to CO 25,000x more tightly than to O2

Proffered bond angles for bonding of O2 and CO to the iron (ferrous) of heme

  • The distal histidine forces CO to bond in a strained manner, thus weakens the interaction.
  • CO binds to hemoglobin about 200x stronger than oxygen
  • CO binding to Hb is stronger than O2 binding, but it is reversible

Angles for bonding of oxygen and carbon monoxide ti the heme iron of myoglobin. The distal E7 histidine hinders bonding of CO at the preferred (180 degree angle) angle to the plane of the heme ring

24
Q

How does anemia effect hemoglobin?

A

A person who has an anemia condition which reduces his Hb by 50% may still be alive

A person who has 50% of his Hb oxygen binding sites occupied by CO is near death (if not dead already)

Carboxyhemoglobin has a characteristic cherry red appearance —

25
Q

What is the function of carboxyhemoglobin ?

A

Maintains a high oxygen affinity

CO poisoning:

  • objective- remove the toxic CO
  • Use 100% oxygen
  • Sometimes under elevated pressure

Elevated oxygen pressure also has risks

26
Q

When do different hemoglobin chains appear and disappear?

A

The alpha-chain is the same in all Hb’s (after embryo)

The y-chain disappears soon after birth (HbF)

The delta chain is found in low amounts in adults (HbA2)

26
Q

When do different hemoglobin chains appear and disappear?

A

The alpha-chain is the same in all Hb’s (after embryo)

The y-chain disappears soon after birth (HbF)

The delta chain is found in low amounts in adults (HbA2)

27
Q

What are the quartenary structures of Hb?

A

Fetus- HbF-a2Y2-1% of total adult Hb

Adult- HbA-a2B2- 90% of total adult hemoglobin

Adult- HbA-a2delta2- 2% of total adult hemoglobin

Adult- HbA1-c- a2B2-glycated - 5% of total adult hemoglobin

28
Q

How does fetal hemoglobin react with 2,3-BPG?

A

Fetal hemoglobin binds to 2,3-BPG less tightly, so it has slightly higher O2 affinity

Some adults express a2y2 at high levels

Persistence of fetal Hb

  • Benign condition
  • If able to induce, may be a “cure” for the disease B-thalassemia and for sickle cell disease
29
Q

Where is the glycosylation point of HbAc1?

A
  • The N-terminus of B-globin may be glycated
    • Glycosylation is non-enzymatic, spontaneous reaction
    • (Hb—> non-enzymatic—> HbA1c)
    • Glycosylation is enzymatic, and regulated by the body

HbA1c formation has no effect on the function of Hb
-Glycation of other biological molecules might explain some of the other aspects of the diabetic sequelae

HbA1c levels may be useful to monitor blood glucose levels over the previous three months

30
Q

What are the causes and effects of hemoglobin S?

A

Position 6 on B-chains, Glu is replaced by Val

Hydrophobic interaction between Hb leads to aggregation

  • Deoxygenated HbS polymerizes into filaments altering cellular shape
  • Sickle erythrocytes are more rigid, they may block blood flow
  • Blocked blood flow causes tissue hypoxia/anoxia which leads to tissue damage (infarction, microinfarct)
31
Q

What is the cause of HbS?

A

HbS is caused by a single base pair mutation

  • This is unusual, most single base pair changes in DNA do not cause disease
  • Changing glutamate for valine causes a very drastic change in the surface properties of this protein
  • This mutation does not alter the oxygen carrying properties of hemoglobin
32
Q

Explain the pathology of HbS

A
  1. A point mutation in the DNA codes for structurally altered HbS
  2. In the deoxygenated state, HbSpolymerizes into long, rope like fibers
  3. Intracellular fibers of HbS distort the erythrocyte
  4. Rigid erythrocytes occlude blood flow in the capillaries
  5. Microinfarcts produce tissue anoxia, resulting in severe pain
33
Q

What is the phenotypic effect of a single amino acid substitution on surface of hemoglobin A?

A

Generally harmless-HbS is an exception

34
Q

What is the phenotypic effect of substitutions in the vicinity of the heam group, e.g. replacement of proximal or distal His with Tyr?

A

Tend to impair oxygen binding e.g. iron trapped in its ferric state in His- Tyr replacements

35
Q

What is the phenotypic effect of amino acid substitution in interior of hemoglobin A?

A

Often distort the 3-dimensional structure and produce unstable molecules

36
Q

What are the phenotypic effects of substitutions in subunit interfaces

A

Usually affects oxygen binding and interfere with allosteric properties

37
Q

What are the phenotypic effects of thalassemias?

A

Defective production of either a or B chains

Abnormal aggregates of a and B chains with impaired oxygen binding properties

38
Q

What are the phenotypic effects of HBA1c formed by nonenzymatic reaction of glucose with N-termini of B-glucose “?

A

Harmless but levels of Hemoglobin A1c are useful indicators of regulation obbblood glucose levels in diabetics

CPR 2 (32 decks)

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