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MCP Unit 3 > Hemoglobin > Flashcards

Hemoglobin Flashcards

1
Q

life needs oxygen

A
  • most living organisms need oxygen to carry out basic metabolic functions-used for electron transport chain
  • rate of o2 transport in tissues is inversely proportional to the square of the distance it must diffuse-makes diffusion rate too slow to support life thru tissue thicker than 1 mm
  • evolution of larger organisms required to acquisition of oxygen carriers and circulatory systems-b/c o2 not soluble in water
  • Hg is predominant-10 mM Hb monomer binds 10 mM o2 (compared to less than 1/4 mM in air sat water)
  • Mg is intracellular o2 transport and storage protein
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2
Q

oxygen transport-the big picture

A
  • Hg just one step
  • need o2 for oxidative phosphorylation
  • ultimate destination is mito-cytochrome oxidase, Km <1 torr, which means it will run at full speed for any oxygen concentration above a few torr (2.5-5 in myocytes)
  • o2 from atm (760 torr) is energetically downhill, need to speed it up
  • Hb carries o2 from alveoli (100 torr) to tissues (20 torr)
  • steepest gradient b/n red cell in cap and surface of myocyte-20 to 5 torr in 2 um or less
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3
Q

myoglobin folding

A
  • helical protein with 8 helices and a heme
  • heme binds 02
  • 153 aa
  • similar to subunits of Hb, only 18% identical in primary sequence
  • globular shape, 44x44x25 angstroms
  • intracellular transport and temporary storage of oxygen needed for aerobic metabolism
  • highly abundant in muscle cells
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4
Q

Quaternary Structure of hemoglobin

A
  • tetrameric protein with a2b2 (dimer of ab protomers, ab dimer is protomer)
  • globular shape 64x55x50 angstroms
  • each a and b subunit is bound non-covalently to a prosthetic heme group
  • Hb molecule has 4 hemes that hold 4 o2 molecules (8 o atoms)
  • B units toward front in diagram
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5
Q

ApoHb

A

empty Hb tetramer consisting of a1b1 a2b2 subunits

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6
Q

holoHb

A
  • Hb

- ApoHb + 4 hemes

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7
Q

assembly of hemoglobin

A
  • assembles first into ab heterodimers=protomers
  • two of the protomers come together to form the tetramer
  • association is loose and flexible
  • rapid eq b/n dimers and tetramer (favors tetramer)
  • two different ways of associating: T and R
  • T has lower affinity for o2, R has higher
  • basis for coopertivity resulting in sigmoid binding curve
  • protomers rotate 15 degrees b/n T and R
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8
Q

heme

A
  • porphyrin ring
  • Fe-protoporphyrin IX, porphyrin with side chains
  • heterocyclic ring systan, tetrapyrrole-4 pyrrole rings linked by bridging carbons
  • nitrogens of each pyrrole face inwards to the center, creating a metal chelating site where Fe binds
  • 4 methyl, 2 vinyl, 2 propionate substituent groups
  • Fe likes hexacoordinate, in heme 4 ligands are provided by 4 N of the porphyrin ring (equitorial). the 5th and 6th ligand would be in front of and behind heme plane (axial).
  • heme proteins will bind by providing aa which act as the axial ligands
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9
Q

deoxy Hb

A
  • Hb with no oxygen
  • the iron is 5 coordinate with 5 N, 4 from pyrroles and other from proximal His
  • electronic state Fe (II)-ferrous
  • distal His in space behind
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10
Q

o2 binding

A
  • o2 binds the heme iron closer to the distal His
  • Fe is hexa-coordinate-5 N and 1 O2
  • o2 binds to distal His too
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11
Q

o2 binding 2

A
  • dramatic consequences for the properties of Hb
  • deoxyHb is dark red while oxyHb is bright red
  • small molecules like CO, NO, h2S bind heme with higher affinity-poison
  • ferrous to ferric- makes methemoglobin or metmyoglobin-brown red- doesnt bind o2
  • see slide-o2 can bind without affecting oxidation state
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12
Q

clarification

A
  • oxidation is redox state-ferrous or ferric
  • oxygenation is whether or not oxygen is present
  • coordination state refers to number of atoms bound to Fe- 5 or 6 depending on o2 binding
  • oxidation of Fe in oxyHb is complicated, may be some resonance to ferric and a superoxide
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13
Q

oxygen dissociation curves

A
  • o2 is 20 torr in venous blood
  • 100 torr in arterial blood
  • 158 in atm
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14
Q

P50

A

pressure at which binding is half maximal

-pressure value at which 50% of maximal o2 load released

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15
Q

Mb

A
  • hyperbolic curve

- P50 2.6- much higher affinity than Hb- makes sense, want Hb to give it up then

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16
Q

Hb

A
  • sigmoidal curve, coopertivity b/n o2 binding sites

- P5- 26- lower affinity than Mb at lower concentrations- want that

17
Q

coopertivity

A
  • convolution of 2 molecular states
  • high affinity of R state is high hyperbolic
  • low affinity of T state is low hyperbolic
  • curve mimics T and R and connects the middle
  • o2 drives T-R conversion- one o2 binds means more likely to go to R and more will bind
  • at high concentration, curve is closer to R-saturated; high affinity
  • at low concentration- curve is closer to T- low affinity
18
Q

hemoglobin in vivo

A
  • allosteric interaction
  • binding of o2 to one site increases affinity for other binding sites on same protein
  • effectors can decrease affinity for o2
  • results from quaternary structure, which is in eq b/n T and R
  • stripped purified Hb has a higher affinity for o2 than whole Hb
  • effectors can be pos or neg
  • positive effector is o2-stabilize R state
  • neg is BPG (decreases affinity), CO2, H+, Cl- (inc affinity in lungs (R) and decrease in tissues)-stabilize T state
  • T in muscles-releases o2
  • R in lungs, gains o2
19
Q

allostery

A
  • effect of something happening at another site on the active site
  • other site can be another active site in a multimeric protein or it can be a completely different type of site, binding the same or another molecule as in allosteric regulation of PFK by ATP
20
Q

coopertivity

A
  • type of allostery in which what is happening at one site promotes the same thing happening at another identical site like Hb
  • requires having multiple sets of the same kind, generally a property of multimeric proteins
21
Q

positive effectors

A
  • stabilize R state

- shift dissociation curve to left-increase affinity

22
Q

negative effectors

A
  • stabilize T state

- shift curve to right-decrease affinity

23
Q

BPG

A

-present in whole blood
-decreased affinity for o2 by binding to heme and stabilizing T state (deoxyHB) (binds weakly to oxyHb)
-shifts curve to right
-leads to more release of o2 in respiring tissues
P50 is 3 torr without BPG- wouldn’t ever let go of o2, even in venous blood
-arterial blood po2 is 100 torr- Hb is 95% saturated
-venous blood po2 is 43 torr-Gb is 43% saturated
-Hb with BPG is an efficient o2 carrier and unloads 52% of o2 in capillaries

24
Q

BPG binding

A
  • binds at tetramer interface and interacts with several lysines, histidines, and N termini
  • stabilizes T state
25
Q

changing BPG [ ]

A
  • acclimation to high altitude have altered BPG levels
  • shifts curve to right even more (more BPG)-more o2 unloading because P50 is 31(takes longer to get to half sat)- lower affinity means more release of o2
  • change in tissues is greater than in lungs
26
Q

Bohr Effect

A
  • oxygenation of Hb makes it a stronger acid
  • lungs have lower CO2, higher pH-lower H-Hb has higher affinity for o2, stabilizes R state
  • tissues have higher CO2, lower pH-higher H-lower affinity for o2. stabilizes T state
  • look at slide for reaction-low H in solution drives reaction towards more H in environment and o2 onto Hb (tissues go other way)
  • in RBCs, carbonic anhydrase speeds reaction up
27
Q

CO2 regulates other ways

A
  • combines reversibly with N terminal aa of blood proteins to form carbamates
  • leads to decreasing affinity in tissues, more o2 out
  • CO2 stabilizes T state (binds more readily with deoxy Hb)
28
Q

fetal hemoglobin

A
  • a2gamma
  • gamma has higher affinity than beta
  • P50 is 15
  • deoxyHbF has lower affinity for BPG, more R state at lower o2 [ ]
29
Q

HbA2

A

-3% of Hb in RBCs has 2 alpha chains and 2 delta chains

30
Q

variants

A
  • there are almost 900 naturally occurring variants of Hb known, >90% from a single aa substitution in one of the globin polypeptide chains
  • ~300,000 ppl with serious disorders born every year
  • ~5% of worlds pop have an inherited variant Hb
31
Q

changes in surface residues

A
  • mutations are usually innocuous except sickle cell
  • Glu to Val=HbS
  • leads to aggregation of B dimers due to hydrophobic binding, only one of the 2 Val6B contacts neighbor
  • hemolytic anemia
  • heteros protected from malaria, RBCs shorter lifetime
32
Q

changes in internally located residues

A
  • destabilize Hb structure and or alter its o2 binding dunction
  • hemolytic anemia
33
Q

changes in stabilizing methemoglobin

A
  • usually near o2 binding site, favor heme oxidation
  • can’t bind oxygen
  • methemoglobinemia
  • promotes conformational change and stabilizes R state, don’t release oxygen in tissue
  • bluish skin
34
Q

linus pauling

A

-coined the term molecular disease

35
Q

HbC

A
  • subunit a2b2
  • glu to lys
  • doesn’t polymerize
  • protects against malaria
36
Q

HbH

A
  • b4
  • binds o2 very tightly and non coopertively
  • inefficient o2 delivery in tissues
37
Q

HbBarts

A
  • gamma4

- high affinity non coopertive binding to o2, poor o2 delivery

38
Q

detect forms of Hb

A

-native gel electrophoresis

MCP Unit 3 (8 decks)

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