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Biochem Winter 2012 > Hemoglobin 1.2 > Flashcards

Hemoglobin 1.2 Flashcards

1
Q

What are the two globin chains in the alpha form?

A

zeta and alpha

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2
Q

What chromosome has gene for alpha globin chains

A

16

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3
Q

What are the genes on the alpha chain

How many alleles responsible for alpha chain?

A

zeta alpha alpha (on each chromosome)

4 total alleles/loci (two from each chromosome)

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4
Q

What globin chains belong to Beta forms

A 
epsilon
G-gamma
G-alpha
delta
Beta
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5
Q

What chromosome has gene for beta chain

A

Chromsome #11

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6
Q

What is the gene cluster that encodes the alpha chain of human Hb

A

zeta, psi-zeta-; psi-alpha2; psi-alpha1; alpha2, alpha1, theta

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7
Q

What is the gene cluster that encodes the beta chain of human Hb

A

G-Gamma, A-gamma, psi beta, delta, beta

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8
Q

How many exons and introns per gene

A

3 exons

2 introns

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9
Q

Hb A1

A

alpha2, beta2

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10
Q

Hb A2

A

Alpha2, delta2

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11
Q

HbF

A

alpha2, gamma2

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12
Q

Hb Gower 1

A

zeta2, epsilon2

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13
Q

Hb Gower 2

A

alpah2, epsilon2

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14
Q

Hb Portland

A

zeta2, gamma2

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15
Q

Which chains are present at britha nd quickly decline up to 6months

A

Zeta and Epsiolon

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16
Q

which globin chain is at its peak at 6 months

A

beta chains

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17
Q

which rises after first tirimester then declines after birth?

A

gamma chain

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18
Q

which chain increses after first tirmester and is steady in adult life

A

alpha

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19
Q

which globin chain appears only after birth and is seen in HbA2

A

delta

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20
Q

which chain decreases at birth? Increases?

A

beta chain increaess

gamma chain decreases

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21
Q

What chromosome is the gene for Mb ?

A

22

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22
Q

How many identities (identical) between BETA and DELTA

A

138

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23
Q

Identities between Beta and Gamma

A

108

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24
Q

Between Beta and Alpha

A

65

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25
Q

What is the location of the proximal HIS in Hb

A

HIS F8

directly binds to HEME

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26
Q

what is location of distal HIS in Hb. What is it’s function?

A

HIS E7

This HIS is displaced by Oxygen when O2 binds to Hb

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27
Q

how many hemes are there/tetramer

A

4

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28
Q

What percent is given to tissues with normal Hb (%) from lungs to tissue

A

66% unloaded

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29
Q

How much oxygen is unloaded from lungs to tissue with myoglobin

A

7%

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30
Q

How much oxygen would beunloaded if there were no cooperativity in Hb

A

38%

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31
Q

Does the PO2 of arterial blood vary with exercise? Does venous blood?

A

Arterial- no

Venous- pO2 willd rop with exercise

21% aoxygen released at reast

45% oxygen released with exercise

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32
Q

How much oxygen unloaded with lowered pH to 7.2

A

77% (shift right)

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33
Q

How much Oxygen released with pH 7.2 and 40 torr CO2

A

88%

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34
Q

what percent shift to right of O2 curve is due to lowered pH (or higher H+)

A

75%

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35
Q

What percent of shift of O2 curve to right due to carbamylation of N-terminal alpha-amino group

A

25%

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36
Q

What percent is due to modification

A

…13% of transported CO2 is carried on Hb

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37
Q

Does H+ bind stronger to oxygenated or deoxygenated Hb. Why? Mechanism

A

Deoxygenated.

Affinity for proton is higher b/c deoxyHb is a weaker acid, has higher pH

0.5 proton taken up upon deoxygeantion

Three gorups are ore negative environment in Deoxy Hb

  1. His 122a
  2. His 146b
  3. alpha amino
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38
Q

What is the net charge of 2,3, BPG?

A

4-5 net negative charge at physio pH

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39
Q

How do you get 2,3,BPG

A

it is a byproduct of glycolysis (no TCA in RBC)

40
Q

How many binding sites of BPG on tetramer

A

one!

41
Q

What conditions lead to elevation of 2,3, BPG (2_

A
  1. Hypoxia (increased elevation)

2. Anemia

42
Q

How is BPG lost in bloo?

A

lost in blood stored in citrate-gucose

43
Q

How is BPG maintained?

A

with inosine via ribose –> pentose shunt –> more BPG

44
Q

How do you get BPG

A

mutatse from 1,3 BPG – >2,3 BPG–> hyrolysis to 3 PG

45
Q

What 3 positively charged groups does BPG interact with on the beta chain

A

Lys 82
His 143
His 2

46
Q

Does HbF have higher or lower affinity for O2 than maternal Hb (HbA)? Why?

A

Fetal red cells have HIGHER oxygena ffinity

b/c HbF:

  1. Binds BPG less strongly than HBA
  2. has higher oxygen affinity with rbc (BPG)

Helsp with transfer of oxygen from maternal to fetal

47
Q

What are regulatros of HbO2 (5) ; all make the curve shift right –> lowers oxygen affinity

A

{H+}
CO2
BPG

Cl-
Temp increase

48
Q

How does the quarternary structure change in oxygenation of Hb

A

alpha1, beta1 shifts 15 degrees, with a translation of 0.8 Anxgroms going form DEOXY (T state) to OXY (R state)

49
Q

How does the quarternary structure change in oxygenation of Hb

A

alpha1, beta1 shifts 15 degrees, with a translation of 0.8 Anxgroms going form DEOXY (T state) to OXY (R state)

50
Q

What is broken during conformational change from deoxy to oxy Hb

A

noncovalent salt bonded (ionic bonds) between alpha nd beta chains are disrupted upon oxygenatino

Lys C5 = H-bonded to beta group of C terminus, asp. FG1

51
Q

What happens to Fe atom on oxygenation?

A

Fe atom moves INTO plane of heme on oxygenation b/c its diameter becomes SMALLER.

His F8 (proximal) is pulled along with Fe2+ and becomes less tilted

52
Q

What are the tetrameric interactions id DeoxyHb(T)

A
  1. all inersubunit salt bridges intact

2. one BPG molecule bound between Beta chains

53
Q

What are tetrameric changes in OXy Hb (R state)

A

sal bridges beween subunits are borken

BPG is expelled

Tertiary and Quarternary structures change

54
Q

Describe Deoxy Hb (T state)

A
  1. Extra bonds form last 2 residues of the beta chain

Fe out of plane toward helix F

Tyr displaces SH groups form pocket between helixes F adn H; forms a bond with Val FG 5

55
Q

What causes shft to right?

A

Increase in red cell 2,3, BPG

56
Q

What causes incrase in red cell 2,3,BPG

A

1.High altitutde adaptation
2. pulmonary hypoxemia
3. cardiac right to left shunt
4. severe anemia, decrese in red cell mass
5. congestive heart failture
6 decompensated hepatic cirrhosis
7. thyrotoxicosis
8. Hyperphosphatemia (ATP alos increased)

57
Q

What causes shift to left

A

Decrease in red cell 2,3 BPG

58
Q

what causes decrease in 2,3, BPG

A 
septic shock
severe acidosis
following transfusions of store blood
Hypophophatemia
panhypopitutitiarism
neonatal respiratory distress syndrome

functonally abnormal Hb variatnts
Methemoglobinemia
CO intoxiation

59
Q

What causes dissociation curve to shift to LEFT

A
  1. Methemoglobinemia

2. Carbon Monoxide Intoxication

60
Q

What is the preferential conformation for CO binding to isolated Iron Porphyrin? What is CO:O2 affinity ratio in this confirmation?

A

Linear mode of binding

CO:O2= 200:1

61
Q

What prevents CO from binding linearly (forces it to bind bent,so affinity not as strong)

A

Distal HIS

62
Q

What protects Hb(Fe2+) from oxidizing to Fe3+?

A

Distal/proximal HIS

63
Q

What type of oxidants oxidize Fe2+ –> Fe3+?

A

Sulfonamide

64
Q

What is required to convert MetHb 3+ –> Fe2+

A

MetHb Reductase

65
Q

what is missing in Familial Mehemoglobinemia? What is the mutation

A

MeHb Reductase

Tyr substituted for the proximal his- iron gets oxidiezed to ferric form

Also true for try subsittution for distal His (E7)

66
Q

What is presentation of trace CO in air

A

5% HbCO

Impaired vision

67
Q

0.02% of CO in air

A

20% HbCO

headache, nausea

68
Q

0.1 CO in air

A

40-60% HbCO

death (red color

69
Q

What is normal % HmM

A

1.7%

70
Q

Cyanosis due to HbM

A

10%

71
Q

Genetic HbM

A

15-30%

72
Q

headeache, weakness, breathlessness due to HbM

A

> 35%

73
Q

Death due to HbM

A

70%

74
Q

How many babies are born with SCD annually in Afical and will die befor age of 5 fromanemia and infection?

A

200,000

75
Q

How many Afro-Americans are heterozygous % for HbAS sickcle cell trait

A

7-10%

76
Q

How many are homozygous -afflicate for HbSS , SCD

A

0.4% 50-72,000

77
Q

What is the mutation that causes Deoxy HbS to be insoluble and sickle?

A

There is a Glu–> Val @ Beta 6

from (-) –> (0) so now H-phobic patches/interactions of Val with Ph–> Polymerization

78
Q

What does the electrophoresis show for HbS vs HbA

A

HbA travels further up towards + charge (b/c GLu is negative)

while HbS is lower and does not travel as far on the gel

79
Q

What does the PEPTIDE MAP of HbA and HbS show?

A

that there is a difference in one spo of the peptide –> you can sequence this to find position where mutation occured!

2D chroatogorpahy/eletorphoresis

80
Q

Why is there pain the in periphery with SCD

A

HbS –> sickled cells polymerize and are less flexible, they can’t squeeze through

Esp in spleen

81
Q

What are the treatments for SCD

A

hyroxyurea, 5-azactydine (increases HbF)

BM transplant

Gene therapy

Inhibition of HbF silencing protein (BC11A)–HbF will help create more HbF

82
Q

What is B^0

A

2 Beta alleles missing

Cooley Anemia B
Thalassemia Major

83
Q

What is B+

A

1 allele missing

clinical effect seen later

84
Q

What is HPFH1

A

Hereditary Persistant Fetal Hemoglobinemia

Delete Beta alleles

Affets Gamma gene upstream –> turns on Gamma gene–> get HbF!! inc affinity of O2 –> can funciton b/c there is similar allosteric features

Gamma has lower affinity for BPG in RBC

85
Q

What causess Lepore

A

No A2 (no delta)

86
Q

what are non-deletion forms of Beta thalassemia mutations

A

usually single base changes in, or upsream of beta gene

87
Q

What are deletion forms?

A

different sizes; B0, HPFH, multiple, hybride

88
Q

HbH

A

B4- acts like monomer

89
Q

Hb Bart’s (Hyrops Fetalis)

A

Gamma4-

90
Q

What form of Fe usually comes from food

A

Fe3+, low pH, ascrobic acid in stomach

91
Q

What form of iorn is needed to pass through membranes

A

Ferrous form Fe2+

92
Q

what does Ferroxoxidase do?

A

oxidize Fe2+ –> 3+ in plasma ,so iron can bind to Transferrin

93
Q

What is the role of Transferrin

A

to transport Fe3+ to tissuess when low in Fe , needed for Hb

94
Q

What can Iron overload lead to? What is the mutation?

A

hereditary hemochromatosis (primary = genetic)

H41D mutation in HFE, alpha-MHC-I, related preotine that binds trasferrin receptor

95
Q

What is seconardy Hemochromatosis

A

usually caused by transfusions

undiagnosed, untreated iron overlaod, regardless of its orgin lead to diabetes, arthritis, depression, impotetece, liver-gall bladder disease, complete liver failure, hear attack and cancer

96
Q

what is wrong with too much iron?

A

Causes hemosiderin to form and ferric ion promotes oxidation of other cellular constituents

Inc Fe –> Lipid peroxidation

inc apoferritin syntehsis

increases lysosome lability leads to release of acid hyrolases

damage cells

inc fe upteake by paranchymal cells

Biochem Winter 2012 (10 decks)

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