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BMS-I > Hemoglobin > Flashcards

Hemoglobin Flashcards

1
Q

Why do we need transporters of O2?

A

Dissolved O2 in plasma is not enough for respiration.

O2 demands of tissue (350ml o2/min) > o2 supply (15ml02/min)

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2
Q

What is heme??

A

A non-protein cofactor (prosthetic group)

Molecule that binds O2 and keeps it in solution

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3
Q

What is liquid ventilation?

A

Replacing air/blood with perfluorocarbons (it is possible)

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4
Q

What are some other names for heme?

A

Heme, Hemin, Protoporphyrin IX

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5
Q

How is heme usually bound to proteins?

A

Thru histidine bond

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6
Q

What happens if hemes dimerize? What is the process called?

A

Hemes will get oxidized and literally rust.
Process is called (u-oxo) bridge.
Very hard to reduce this oxidized dead end product. (Creates a hydrophobic face on top and bottom)

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7
Q

In what oxidation states can hemes be in?

A

Reduced (2+) ->ferrous = ferrohemoglobin (02 carrier)
Oxidized (3+) -> ferric = methemoglobin (non functional)

2 ferrous hemes (2+) can form a bridged complex with oxygen and become nonfunctional oxidized heme. These will aggregate and crystalize.

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8
Q

What kind of artificial porphyrins are being produced?

A

Ones with large t-butyl groups increase steric hindrance. May be solution for artificial blood supply.

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9
Q

What protects heme from auto-oxidation?

A

Proteins. Heme is sequestred inside a hydrophobic pocket.
If the protein has a mutation where the pocket may become more hydrophilic (polar) then this means heme may not bind as tightly and then protein may become non-funcitonal (i.e. Methemoglobin)

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10
Q

What does the myoglobin O2 binding curve look like? Why is this not ideal for O2 transport?

A

AsympTotic (Hyperbolic). myoglobin holds on very tightly to its 02.

Hemoglobin is sigmoidal

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11
Q

What is the p50? Kd? How do these relate to partial pressures?

A

Partial pressure = amount of gas in a solution. At higher p02 we have more o2 in that solution.
P50- amount of pressure in which 1/2 protein is bound to that particular gas
Kd- [ligand] in which half the amount is bound to enzyme.

(In torr atmospheric pressure is 750. We know 20 atmosphere is 02. So top p02 of o2 is somewhere around 120-130, which is the p02 we see in the lungs.

P50 for myoglobin is very low
P50 for hemoglobin is around 26

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12
Q

What is structure of myoglobin?

A 
All alpha helices. 
Single globular chain of 153 AA
Contains heme in center
Located in cytosol of muscle cells
About 60 hydrophobic residues hold myoglobin together.
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13
Q

What is the only sigmoidal binding curve in the globin family of proteins?

A

Hemoglobin.

Myoglobin/neuroglobin/cytoglobin all have hyperbolic binding curves

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14
Q

What is structure of hemoglobin?

A

Tetramer, composed of 2alpha and 2 beta subunits.
Total of 4 hemes (each subunit has one)

Myoglobin and hemoglobin have very different structures esp. The histidine sequences.

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15
Q

What holds the hemoglobin tetramer together?

A

Salt bridges. Electrostatic.
These do not compete with the hydrophobic core.
We need alpha chains moving and shifting relative to one another.
I.e. Arg 141(+) with Asp126(-)
Cysteine127(+) with Asp126(-)

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16
Q

What are differences in Myoglobin and Hemoglobin?

A 
Function
Location
Amount of 02 bound at p02 in lungs. 
Amount 02 bound at p02 in tissues
Quaternary structure
Binding curve
Number of heme groups.
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17
Q

What is cooperativity in heme binding o2?

A

Coop. Is a type of allosteric activity.

1st binding of 02 molecule has a very low affinity and subsequent ones will have an easier time activating.

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18
Q

What is the explanation for Hemoglobin’s sigmoidal curve; as opposed to the curves for myoglobin etc?

A

Cooperativity. (High affinity state; low affinity state; transitions from low-to-high affinity state)

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19
Q

What is the saturation equation for determining sat in myoglobin? Hemoglobin?

A

myoglobin: Y(saturation) = (p02/(p02+p50)
hemoglobin: [hb(o2)4/ (Hb(o2)4)+ [hb]

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20
Q

What is the Hill coefficient for Hgb?

A

2.8

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21
Q

What is difference between uncooperative Hgb and natural Hgb?

A

Hill coeff.
Look at binding curve. It is all about the change in saturation when traveling prior to lungs and then in the lungs.
Natural change in sat is 66%
Uncooperative change in sat is 36%

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22
Q

What oxygenation state is the “t” state of Hb? “R”?

A 
T= deoxy
R= oxy

Overall the structure of the protein doesn’t change much, but the alpha/beta subunits slide past each other and narrow the pockets between the beta subunits.

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23
Q

Can oxygen bind to Hb in the ‘t’ state?

A

Yes, but it has much lower affinity.

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24
Q

What does oxygen binding to Hb do (in far of the t/r states?

A

Stabilizes the R state

25
Q

What is the predominant form of Hb in the absence of 02?

A

T state (deoxyHb)

26
Q

Describe the Bohr effect:

A

Acidification of blood significantly lowers the affinity of Hb for 02

The lower the pH of the blood (more acidic), the affinity of 02 becomes weaker.
C02 dissolves -> HC03 + H+ -> leads to carbonic acid

Happens at Asp84, His146 on B chain (away from heme binding sites)

27
Q

How does the Bohr effect work?

A

T state is favored at a lower pH
Salt bridge betwn His146B and Asp94B. Ionic interaction

I.e. In R state, H+ can be given off?

28
Q

How does CO2 influence Hgb (2 mechanisms)?

A
  1. Release of C02 into blood lowers pH
    C02 + H20 -> H2C03 (carbonic acid) -> H+ + HC03
    In the lungs Hgb releases an H+
  2. Some c02 is transported directly with Hgb by forming carbamates with amine grps on protein (N-terminus/lysine/arginines
    Carbamates stabilize deoxy state (t)
29
Q

How does Acetazolamide work? (Clinical correlation)

A

MOA: promotes excretion of bicarbonate in the kidneys. Bicarbonate is the conjugate base to carbonic acid. This acidifies the blood

Acid increases the t state affinity of hb which influences more 02 to be released to tissues.

According to professor this will help total deliverY of 02 to tissues.

30
Q

Why is NO (nitric oxide) pathway important in Hgb?

A

NO binds R state of Hb directly on heme iron, as well as thiol-nitrosyl bond on Cys 93B.

Release of NO upon deoxygenation of Hb allows NO to vascular endothelium receptors, triggering vasodilation, and increased blood flow to hypoxic tissue.

31
Q

What is the 2,3, BPG binding phenomenon? Where does 2,3 BPG come from?

A

2,3 BGP normal product of glycolysis in erythrocytes
Essential for release of O2 from Hb at Po2 values found in tissues
2,3 BPG stabilizes t form and reduces affinity for 02.

(Stripped HbA w/o any bpg kind of looks hyperbolic.

32
Q

How does 2,3 BPG bind?

A

Cationic nest . Favors t state.

33
Q

Review of allosteric modifiers in oxygen binding:

A

T state: low pH (acid), 2,3 BPG, C02

R state: high pH (alkalosis), oxygen (allostery), NO

34
Q

What is the predominant form of Hgb in the fetus? At birth? Adults?

A

Fetal: Fetal Hgb
@birth: HbF, production of HbA ramps up
Adults: HbA, also has HbF (2%), HbA2 (2-5%, 2alphas+2deltas), HbA1C (3-9%, glycosylated Hb)

35
Q

What is embryonic Hb?

A

2 alpha and 2 sigma chains

36
Q

How many copies of the alpha chain to healthy individuals possess in their genes? Beta?

A

Alpha- 4 (Chromosome 16)
Beta- 2 (Chromosome 11)

Beta has similar forms that can be replaced to produce other types of Hb. Like gamma and delta.

37
Q

How are Hb genes arranged on chromosomes?

A

In the order of their expression during development

38
Q

What does the HbF binding curve look like compared to HbA?

A

HbF has 2 alpha and 2 gamma chains.
It has a higher affinity for 02 (smaller p50).

02 flows from maternal oxyHb to fetal deoxy Hb via placenta

39
Q

How does 2,3 BPG affect HbF?

A

Remember that 2,3 BPG in HbA favors the T state.

But HbF has a lower affinity for 2,3 BPG than does HbA.

This is b/c His 143B in HbA is a Ser in hbF. This positive charge found in HbA (that sticks with neg BPG) is neutral in HbF.

40
Q

What is the affinity for carbon monoxide (CO) to bind Hb compared to O2?

A

250X greater.

41
Q

What are symptoms of CO poisoning? How do we treat?

A

Produces cherry red discoloration of skin and organs.

Tx: 100% o2 or hyperbaric 02.

42
Q

Why is the histidine component of the E helix so important when it comes to O2 binding vs (CO)?

A

Histidine stabilizes 02 binding and destabilizes CO binding.
Any other AA (described experimentally) would favor CO binding and displace 02.

43
Q

Is HbA1c produced enzymatically?

A

Glycation (glycosylation) of Hb is non-enzymatic. Described as a chemical modification.

Hb + glucose Schiff base –> HbA1c (spontaneously thru Amadori rxn)

Molecular mechanism of DM

44
Q

What are some signs and symptoms of Sickle Cell disease?

A

Severe anemia. Painful joints, kidney and spleen damage, frequent hospitalizations.

45
Q

People who have sickle cell trait are usually asymptomatic…where could these pts potentially experience symptoms?

A

Renal Medulla -> 02 tensions are low enough to induce sickling (very deoxygenated state) and renal damage. (Renal papillary necrosis)

46
Q

What options are available to treat SS anemia?

A

Rxtx: butyrate/ hydroxyurea.

Potential new gene therapy : CRISPR-Cas9. Targets gamma chain promoters.

47
Q

Why is HbS protectant against malaria.

A

Free heme is toxic to lifecycle of parasite. Likes to sequester heme into crystalline form hemozoin. (Hemozoin disruption is target of many anti-malarials)

48
Q

What are alpha chain aggregates called in beta thalessemias?

A

Heinz bodies

49
Q

Is there a cure for Beta thalessemia?

A

Potentially bone-marrow transplants.

50
Q

What is methemoglobinemia?

A

Higher than normal (bind to cyanide, producing cyanohemoglobin. Keeps cyanide from binding with cytochrome c oxidase needed for cellular respiration.

HbM (Hb Hyde Park) -> his92betaTyr muttion effects cty-b5-reductase interactions.

51
Q

What is the only connection between two alpha chains in fully oxygenated Hb?

A

Asp 126 - Arg 141

Lys 127 - Corboxy 141

52
Q

How do structural changes (t-R) affect o2 binding in Hb?

A

T form - Fe2+ out of plane of geme ring towards the proximal histidine. Heme is in an unfavorable state

R-state = Fe2+ is in place with ring, making 02 binding more favorable

53
Q

How does Bohr effect play a role in the structual compnenets of Hb?

A

PkA His 146: T: 8.0 ; R: 7.1

His in t-state is protonated, where as His in R state is losing a hydrogen.

54
Q

Does oxy-Hgb bind any BPG? Where does BPG bind?

A

No oxy hb does not bind BPG

BPG binds at t-state (Positively charged residues/amino terminal of Bchain)

55
Q

Where does NO bind?

A

Cys93 on Beta chain in oxy state.
Released in deoxy state

NO potent vasodilator, increases blood flow

56
Q

Does myoglobin undergo and allosteric modifications?

A

No

57
Q

Why can’t methemoglobin coordinate o2 binding?

A

Binds with water instead

58
Q

What causes methemoglobinemia?

A

Deficiency in cypB5

59
Q

What residues are involved in the Bohr effect?

A

His146&Asp94 on beta chain

BMS-I (17 decks)

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