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biochem > Chapter 7: Hemoglobin and Myoglobin pt.2 > Flashcards

Chapter 7: Hemoglobin and Myoglobin pt.2 Flashcards

1
Q

protein family

A

group of evolutionary related proteins

-share a common ancestor and have similar 3D structures, functions, have significant sequence similarity

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2
Q

Myoglobin (Mb)

A

-monomer
-have 8 alpha-helices (A-H)-both
*onlynhave 24/141 AA identical to Hb
*Mb is very similar to 3D structure of beta subunit of hemoglobin

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3
Q

Hemoglobin (Hb)

A

-tetramer of 4 Mb like subunits
-have 8 alpha-helices (A-H)-both

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4
Q

Yo2 curves for Myoglobin (Mb)

A

-hyperbola curve: no cooperativity

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5
Q

Yo2 curves for hemoglobin (Hb)

A

-sigmoidal curve: cooperativity

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6
Q

cooperativity/ allosteric effect

A

-allostery= the other site
-binding at one site affects binding at others
-allosterism req with protein with >1 subunit
-S curve indicates cooperativity (=allosterism)

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7
Q

Homotropic allosteric interaction

A

effector and ligand regulated by the effector are the same molecule
*part of equation

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8
Q

Heterotropic allosteric interaction

A

effector and ligand are different molecule
*effector is not in rxn

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9
Q

Activator

A

shifts equilibrium towards R-state
=positive allosteric interaction

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10
Q

inhibitor

A

shifts equilibrium towards T-state
=negative allosteric interaction

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11
Q

Heterotropic inhibitors for hemoglobin

A

-BPG
-H+
-Co2
-Cl-

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12
Q

homotropic effector for hemoglobin

A

O2

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13
Q

The Bohr effect Summary

A

-increasing [CO2], increasing H+, decreasing pH, increasing temp. = releases O2 from Hb
*curve shifts to the right
*low affinity for O2

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14
Q

what does the curve, temp, CO2, and pH look like when there is a high affinity for O2

A

-pH increases
-CO2 decreases
-temperature decreases

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15
Q

Where on T-state do the Bohr protons bind?

A

on the N-terminal and His 146-beta (amide)

  • H-bonds and ion pairs in the T-state are not present in the R-State
  • T to R transition changes the pka’s of these groups causing them to release their coordinated H+
    *N-term needs to be protonated to be an ion pair
    *surroundings can effect pka of WA/WB of groups

Hb (t-state)+ O2 = Hb(r-state)O2 + H+
*H+ (bohr protons) released when Hb binds O2

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16
Q

N-terminal amino groups are responsible for how much of the bohr effect?

A

20%-30%

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17
Q

His 146 beta accounts for how much of the Bohr effect (has a NH group)

A

40%

18
Q

Bohr effect CO2: the carbonate rxn

A

-CO2 can react to form carbamates with the N-terminal amino groups of blood proteins
*CO2 reacts with the R-state Hb to create a T-State HB with carbonate
*Carbonate only in T-state

19
Q

Bohr effect CO2: CO2 transport

A

H2O+CO2<–>H2CO3<–>HCO3- + H+

-when there is more CO2 then H+ released increases so pH in blood decreases
*means that Hb is dumping off oxygen
*favors deoxy-Hb (t-state) = CAPILLARIES

-when there is less CO2 then H+ in blood decreases which means the pH is blood increases
* means that Hb is binding oxygen
*favors Oxy-Hb (r-state) = LUNGS

20
Q

D-2,3-bisphosphoglycerate (2,3-BPG) basic summary

A

-also known as BPG, 2,3-diphosphoglycerate, 2,3-DPG

  • MOST ABUNDANT organic phosphate in blood
    -occurs in red blood cells as a HETEROTROPHIC INHIBITOR

-inhibits oxygen from binding
-curve goes towards x-axis

21
Q

2,3-BPG: where does it bind and what it does?

A

-binds to the central cavity of T-state and stabilizes it and “fine tunes” Hb’s O2 binding capability
*can’t bind the R-state
*causes HB to release O2

-gives Hb a P50 of 26 torr
*without it it only has 12 torr

22
Q

2,3-BPG and altitude

A

-body increases BPG production in higher altitudes
-restores 37% release of O2

23
Q

Allosteric effector: Cl-

A

-heterotrophic effector
- Cl- floods into RBCs to neutralize the electrostatic potential
-Cl- binds to deoxy Hb
*causes O2 to be released (t State)

24
Q

why are Hb’s and Mb’s called honorary enzymes

A

they bind O2 like how a enzyme binds a substrate

25
Q

Hill equation

A

YO2= pO2/P50+pO2

Ys=[S]^n/Kd+[S]^n
*S=ligand/substrate
*E=enzyme/protein
*n=number of S molecules bound

26
Q

HIll plot

A

-slope of the line shows the degree of cooperativity
-nH is experimentally determined
-nH< n actual usually
-nH= n actual when all ligand binds simultaneously

27
Q

1.n=1
2.n>1
3.n<1

A
  1. non-cooperative
  2. positive coop
  3. negative coop
28
Q

hemoglobin cooperativity

A

about 3

-when the first O2 binds, the rest bind and when 1 is released the rest are released

29
Q

Monod, Wyman, Changeux

A

-MWC MODEL: model for allosteric proteins

  • equilibrium btwn T and R states
    -ligand can bind to T or R state conformation
    -all subunits have to be in the SAME STATE
    -in ABSENCE of ligand, equilibrium favors T state
    -Ligand binding shifts equilibrium toward R state

-Limitation: only models positive cooperativity

30
Q

Koshland-Nemethy-Filmer

A

-found the Sequential (induced fit) model for allosteric protein
-KNF model

-subunits can exists in R or T conformations but can also change conformation independently on binding of a ligand
-PRESENCE of R-site induces increased affinity in adjacent sites

-complete T –> R transition is a sequential process
*accounts for both positive and negative cooperativity

31
Q

Perutz mech for HB allostery

A

look at slide 16 for mech

-basically once one oxygen binds it shifts from t-state to r-state and then all the other subunits get bonded to oxygen

32
Q

Mutation on hemoglobin
(methemoglobin and cyanosis)

A
  • when mutations occur in germ line they are passed to offspring
    *inheritable or genetic diseases

-sickle cell anemia

-stabilizes Methemoglobin: eliminates O2 binding
-cyanosis: blood is blue to chocolate brown

33
Q

Pathologic Mutation in Hb specific (Boston, Black mouth, and Hb Hammersmith)

A

-Boston: His E7–>Tyr
*type of Methemoglobin

-Black Mouth: HisF8–>Tyr

-Hb Hammersmith: Phe–>Ser
*loses heme so it doesn’t bind oxygen

34
Q

Pathologic mutation at surface of HB

A

-HbE: Glu 26 on beta chains –>Lys
*not harmful

-HbS: Glu 6 on beta chains –>Val
*sickle cell anemia
*causes precipitation

*both have same O2 binding ability
*have 4 hemes
*iron in Fe2+ state
*have same active site

35
Q

sickle cell anemia

A

-autosomal recessive genetic disorder
-can get pain crises
-10% african americans are heterozygous for this trait

36
Q

Hbs pathology (valine): causes sickle cell anemia

A

-E–>V in beta chain decreases surface charge making HbS more hydrophobic
-ONLY in T-state (deoxy Hbs) does Val fit into a hydrophobic pocket of beta chain
-causes long linear polymers (fibers) to form

37
Q

Hbs pathology in capillaries

A

HbS loses O2–>deoxy HbS starts to polymerize which causes the blood to sickle
*sickled RBCs block capillaries and blood flow

38
Q

Benefit of HbS gene

A

people who have are heterozygous for HbS gene have a higher survival rate from malaria
*25% African Americans

39
Q

difference btwn adult Hb and Fetal Hb

A

-normal adult Hb (HbA) = alpha2beta2
-Fetal Hb (HbF)= alpha2gamma2
*gamma is a separate gene product made by the fetus

40
Q

O2 delivery to fetus

A
  • in presence of 2,3 BPG, HbF has a higher affinity for O2 than HbA
    *allows transfer of O2 from the mother (less tightly bound) to the baby (more tightly bonded)

-so HbF has a lower affinity for 2,3 BPG than HbA and thus it is less affected by it

*gamma chains have Ser instead of His143(+) so they have less affinity for (-) phosphates on 2,3 BPG

biochem (13 decks)

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