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PHGY 313 > Iron structure and function > Flashcards

Iron structure and function Flashcards

1
Q

What did Robert Boyle demonstrate?

A

Robert Boyle (1627-1691) demonstrated that an animal placed in an airtight chamber could not survive. He concluded that “there is in the air…a vital quintessence”

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2
Q

Who showed that blood contained more oxygen and carbon monoxide that could be explained by simple solution in a pure liquid; (something helps oxygen to be in solution)?

A

Sir Humphrey Davy (1799)

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3
Q

What did Gustav Magnus fo?

A

He demonstrated that arterial blood contained more oxygen and less carbon dioxide than venous blood.

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4
Q

Who first described the term “hemoglobin” and when?

A

In 1862, Felix Hoppe-Scyler

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5
Q

Who separated heme from globin and when?

A

In the second half of the 19th century

Teichman

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6
Q

Who established the structure of heme

A

Kuster (1912)

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7
Q

What is a prosthetic group?

A

heme is the prosthetic group of hemoglobin) – prosthetic group is a nonprotein group forming part of or combined with a protein (not composed of AAs

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8
Q

Who got a novel prize for the synthesis of heme in the lab?

A

Hans Fisher

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9
Q

who presented the first data demonstrating the sigmoid shape of the oxyhemoglobin dissociation curve and when

A

In 1904, Christian Bohr

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10
Q

Who got a nobel prize for doing an X ray analysis of Hgb which resulted in suggesting that a marked structural change accompanies the reaction of Hgb with oxygen?

A

M. F. Perutz

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11
Q

What is hemoglobin?

A
  • Oxygen-binding protein; present in all living organisms
  • Hgb is 90% of a dry RBC
  • Allows for the consumption of ~250ml of oxygen per seconds in a normal adult at rest
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12
Q

How much do tha alpha and beta subunits of heme differ in terms of protein sequence in humans?

A

50%

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13
Q

How do plants and human hgb differ in terms of protein sequence? Do they work in similar ways?

A

80%

But still work in similar ways and have a similar structure

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14
Q

How does the O2 carrying capacity increase with Hgb?

A
  • The solubility coefficient αO2 for human plasma is 0.03ml x liter x mmHg (low). BUT Human Hb binds 1.34 ml of oxygen per gram of protein (70x increase).
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15
Q

Name 2 alternate types of O2-binding proteins and their function/location

A

1) Hemocyanin
a. Copper-based molecule that binds oxygen
b. Present in invertebrates (mollusks)

2) Hemorythrin
a. Iron-based (non-heme)
b. Present in sipunculids and brachiopods
c. Purple: molecule is oxygenated

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16
Q

Which animal doesnt have hemoglobin? Why?

A

Antarctic ice fish
Temperature very low in Antarctic sea; oxygen a lot more soluble in cold temperature. Carries O2 in plasma
Physiological adaptations:
- Big CV system (larger blood vessels; larger hearts; larger cardiac outputs)

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17
Q

What are the advantages of Hgb being in RBCs rather than directly in plasma?

A

Inclusion of Hb in RBCs reduces oncotic pressure and high blood viscosity
RBCs provide a cellular microenvironment where metabolites and other effectors of O2 affinity to Hb can be regulated

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18
Q

Describe Hgb structure

A
  • Vertebrate Hbs are tetrameric molecules with a molecular weight of approximately 64,500 Da;
  • They are composed by two α-like and two β-like chains forming two αβ-pairs;
  • Each subunit contains one O2 binding heme group. Thus, each Hb molecule binds four molecules of O2.

Alpha and beta chains consist of 7 and 8 helical segments, respectively
Each alpha and beta chain binds to a single molecule of heme which lies in a hypo hydrophobic pocket (protects heme iron from oxidation)

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19
Q

Sickle cell anemia is a mutation on which subunit?

A

beta chains

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20
Q

Which type of iron is carried by heme?

A

Ferrous (Fe2+)

Fe3+ gives purple color

21
Q

What is methemoglobin?

A

Hgb with ferric iron, which cannot bind O2

22
Q

Name other molecules that contain iron in the body

A

myoglobin, cytochromes, catalases, heme peroxidase, and endothelial nitric oxide synthase

23
Q

Does the valence (2+) of iron change upon O2 binding and unbinding?

A

no

24
Q

How does structure of Hgb change upon O2 binding?

A

During oxygenation, the molecules shift from the T (tense) to the R (relaxed) structure that represent distinct spatial arrangements of the alpha and beta subunits and distances between the iron atoms;
The oxygen affinity of Hb in the oxygenated R state is higher than that of hemoglobin in the deoxygenated T state;

25
Q

What is AA that stabilizes iron in Hgb?

A

the distal Histidine residue.

26
Q

What is cooperativity?

A

Vertebrate Hbs show cooperativity, that is, an increase in the O2 affinity of the remain subunits when one or more subunits have become oxygenated;
- This causes the sigmoidal shape of the oxygen dissociation curve (ODC) of Hb.

27
Q

Compare Hgb to myoglobin’s affinity to oxygen

A

Myoglobin curve has more of a hyperbolic shape; more affinity to oxygen. In most cases, when myoglobin binds oxygen, it rarely releases it.

28
Q

what is bohr effect?

A

a decrease in the amount of oxygen associated with hemoglobin and other respiratory compounds in response to a lowered blood pH resulting from an increased concentration of carbon dioxide in the blood.

There is a decreased pH in tissues compared to the lungs
Low pH: got to release the oxygen
Increase in pH (lungs) –> need to bind oxygen

29
Q

Which enzyme catalyzes the change from 2CO2 + 2H20 –> 2H2CO3 (carbonic acid)

A

Carbonic anhydrase

30
Q

What is haldane effect?

A

O2 displaces Co2 from Hgb

31
Q

Explain the cycle of CO2 in the body

A

CO2 made in tissues, is released and eventually reaches RBCs (Hgb) – carbonic anhydrase forms carbonic acid from water and CO2.
Carbonic acid is dissociated to protons and bicarbonates. Hgb binds 2H+ to buffer. Then at lungs the 2 H+ and 2 HCO3- are exchanged for 4 O2 molecules
Carbon anhydrase takes remaining carbonic acid and changes it to 2CO2 and 2H2O – CO2 is exhaled

32
Q

Is Hgb carrying Co2 back to the lungs?

A

CO2 is not ACTUALLY carried by hgb but in the solution in RBCs
About 15% of CO2 binds Hgb
DeoxyHb has a higher affinity and binds more CO2 than HbO2 at a given pH, which favors the removal of CO2 from CO2 producing tissues.

33
Q

What are the major allosteric effectors that modulate Hb-O2 affinity in vivo ?

A

organic phosphates, H+ and CO2, and Cl- and lactate ions

34
Q

What is the affinity of Hgb to o2 in the absence of the allosteric effectors?

A
  • In absence of these chemical cofactors Hb exhibits a high intrinsic O2 affinity
35
Q

How do the allosteric effectors work?

A
  • In absence of these chemical cofactors Hb exhibits a high intrinsic O2 affinity;
  • The reduction of the affinity is achieved by the interaction with the heterotrophic allosteric effectors;
  • These effectors commonly bind more strongly to deoxyHb than to oxygenated form to stabilize T-state through the formation of additional salt bridges (concentration in RBC changes).
36
Q

What is 2,3-BPG and what is its function

A

Very important allosteric effector
- DPG [2,3-bisphosphoglycerate (2,3-BPG)] is found in RBCs of mammals and a few species of other vertebrates;
- 2,3-BPG decreases the HbO2 affinity of human Hb dramatically compared to the effects of other allosteric ligands.
1 x 2,3-BPG per Hgb molecule (stands in middle)

37
Q

Name 2 other molecules that play a similar role to 2,3-BPG but in other organisms

A

IHP (inositol hexaphosphate) and ATP
(IHP = in birds; ATP = in amphibians)
ATP doesn’t bind Hgb in humans because scavenged by magnesium

38
Q

How is 2,3-DPG made?

A

RBC have enzyme called diphosphoglycerate mutase (DPGM) which starts a reaction from the glycolytic pathway and generates 2,3-DPG
–> Rapoport-Lübering shunt
Increased pH = increased synthesis of 2,3-DPG

39
Q

Why does fetal Hgb have higher affinity to O2 than regulat Hgb?

A
  • The residue H21 of the γ subunit of fetal Hb (HbF) is Ser rather than His. Since Ser cannot form salt bridge, 2,3-BPG binds more weakly to HbF than HbA. As a result, HbF has a higher affinity for O2 than HbA and this facilitates the transfer of O2 from mother to fetus;
40
Q

How does 2,3-BPG play a role in adaptation to high altitude and hypoxia?

A

Elevated 2,3-BPG (in response to hypoxia) lowers the affinity of HbA for O2 which enhances release of O2 to the tissues.

41
Q

What is nitric oxide (NO)’s main function?

A

It is best known by its function as endothelial-derived relaxing factor

42
Q

Where is NO formed?

A

Nitric oxide (NO) is formed in a variety of cell types

43
Q

Describe the importance of Hgb in NO action

A
  • The action of NO released from cells is modulated by the presence of RBCs where it binds to hemoglobin;
  • Hemoglobin has been suggested as a regulator of NO bioavailability when the NO:Hb ratio is low, that is, at nanomolar concentrations of NO;
  • In the relatively hypoxic venous blood, Hb is in the T state configuration and NO diffusing into the red cells is taken up rapidly by heme
    Hgb might use NO to vasodilate tissues and facilitate passageway
44
Q

What is methemoglobin?

A

Methemoglobin (MetHb) is a derivate of Hb in which the iron of the heme group is oxidized from Fe+2 to Fe+3

  • MetHb is no longer capable of reversible binding O2 and it is ineffective carrier of O2;
  • Steady state level of MetHb is less than or equal to 1% of total Hb;
  • MetHb forms continuously because Hb auto-oxidation; must be reduced actively by normal RBC metabolism.
45
Q

Describe methemoglobinemia and its 2 types

A

blood disorder in which an abnormal amount of methemoglobin is produced
2 types:
1) Acquired or toxic
a. Drug induced (nitrites, sulfonamides, aniline dyes, etc)
2) Hereditary
a. HbM: abnormal globin: HisF8 (involved in Fe binding) is replaced by tyrosine; this stabilizes the Fe+3 form
b. Cytochrome b5 deficiency (cyto b5 normally reduces iron from Fe3+ to 2+)
c. NADH-Cytochrome b5 reductase (b5R) deficiency (Blue Fugates) (which reduces cyto b5 so it can reduce Fe2+)
d. Phenotype of “blue” color of skin

46
Q

What is carboxyhemoglobin

A

Cigarette smoking
Carboxyhemoglobin (COHb) is a stable complex of carbon monoxide that forms in red blood cells when carbon monoxide is inhaled. COHb should be measured if carbon monoxide or methylene chloride poisoning is suspected. COHb is also useful in monitoring the treatment of carbon monoxide poisoning

47
Q

Name the proportion of each type of Hgb in normal human adults

A

hemoglobin A accounts for approximately 97% of the protein molecules, hemoglobin A2 for 2% and hemoglobin F or fetal hemoglobin for 1%;

48
Q

What is Hgb A2? HbF?

A

a hgb molecule that has 2x alpha and 2x delta globin chains

HbF is fetab Hgb and has 2 x alpha and 2x Agamma chains

49
Q

Name multiple types of hemoglobinopathies

A

sickle cell disease, thalassemias and other important variants such as HbC, Hb DPunkab , Hb E, Hb Lepore, and HbOArab .

PHGY 313 (10 decks)

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