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Biochem Winter 2012 > Hemoglobin 3 11.20.12 > Flashcards

Hemoglobin 3 11.20.12 Flashcards

0
Q

What is the ratio of CO:O2 affinity in Mb and Hb?

A

200:1

Hb combnes 200x more strongly with CO than with Oxygen to form cherry-red compound called CARBONOXYHEMOGLOBIN (Hb + 4CO –> Hb (CO)4)

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1
Q

What causes the Oxyghemoglobin Dissociation curve to shift left?

A

Methemoglobinemia

Carbon Monoxide Intoxication

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2
Q

How does Hb and Mb reduce affinity of CO for the heeme

A

by forcing a less preferred bend mode tof bidning

  1. Bendt mode of binding to CO to heme- distal HIS forces CO to be at an angle to heme plane

Neverless, affinity for CO is still stronger htan O2

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3
Q

What is Methemoblogin (HbM)

A

form of Hb in which iron is in the ferric state. It is different from oxygenated Hb, (oxyhemoblgobin) , in which oxygen is united loosely with ferrous iron. Mb cannot combine with and transport O2

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4
Q

What % of HbM in normal adult?

A

1.7%

Exposure to certain drugs and oxidizing agents can increase the concentration of methemoglobin

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5
Q

What is the cause of Familial Methemoglobinemia?

A

Deficiency in the enzyme methemoglobin reductase , which uses NADH –> NAD+ to go from methebmoblobin to hemoglobin

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6
Q

What happens to individual when methemoglobin exceeds 10% of total Hb,

A

affected individual will have clinically obvious cyanosis

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7
Q

What are the three types of inherited disorders of the hemoglbin?

A

structural variants,

thalassemias,
which are characterized by reduced rate of synthesis of one or more of the globin chains

hereditary persistance of fetal hemoglobin, where fetal hemoglobin synthesis continues beyond the neonatal period

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8
Q

What is genetically determined HbM?

A

it may have a TYR substituted for the PROXIMAL HIS - Fe gets oxidized to ferric form
Prox F8 HIS –> substituted by TYR F8

Also tru for TYR subststitution for DISTAL HIS

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9
Q

What happens wit trace Co in air. How much HbCO? Symptoms

A

Trace
5% HbCO
impaired vision

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10
Q

0.02% CO in air

A

20% HbCO

headach, nausea 
heavy smoker (smoke is not fully combustible, red color to circulation)
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11
Q

0.1% CO in air

A

40-60% HbCO

in garage) Death (RED COLOR

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12
Q

What is normal HbM (%)

A

1.7%

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13
Q

What is cyanosis HbM%

A

10%

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14
Q

What is genetic HbM %

A

15-30%

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15
Q

what leads to headache, weaknes, breathlessness with HbM %

A

> 35%

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16
Q

What %HbM is death

A

~70%

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17
Q

What are the three types of inherited disorders of the hemoglbin?

A

structural variants,
thalassemias, which are characterized by reduced rate of synthesis of one or more of the globin chains
hereditary persistance of fetal hemoglobin, where fetal hemoglobin synthesis continues beyond the neonatal period

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18
Q

How many structural variants of hemoglobin exist?

A

More than 400 structural Hb variants

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19
Q

What are the types of mutations that can result in teh production of essentially normal amounts of aberrant globin chains

A
  1. single base mutation
  2. Elongated globin chain variants
  3. Shortened Globin Chains
  4. Nonhomologous (or unequal) crossing over which produed hybrid globin chains
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20
Q

What causes Single Base Substitutions?

A

most common structural alteration producing hemoglobin variants is the substitution of one amino acid for anotehr.

Most of the amino acid substitutions can be explained by the Change of a SINGLE BASE in a triplet codon.

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22
Q

What causes Elongated Globin Chain Variatns

A

Caused either by single base substitutions in a chain termination codon, frameshift muations, or by mutations that cause failture of cleavage of the initiator methione residue.

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23
Q

What causes shortened Globin Chains

A

These variants involve deletion of one or more intact codons

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24
Q

What are nonhomologous (or unequal) crossing over

A

they are produced by hybrid globin chains

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25
Q

What type of structural mutations can result in molecular pathologies

A
  1. Altered exterior –> sickle cell anemia
  2. Altered active site
  3. Altered secondary and/or tertiary structure
  4. Altered quaternary structure
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26
Q

What is HbS and what causes sickle cell anemia

A

Hemoglobin S, a mutant form of Hb A in which a Glu is substituted by a Valine at position 6 of the beta chain ( replaces a polar maino acid with a non-polar one) produces sickle cell anemia

This substitution from polar to non-polar reduces the solubility tof the DEOXYGENATED HbS, but has little effect on the solubility of oxygenated HbS

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27
Q

Is solubility of deoxygenated HbS affected by Glu–>Val? Is solubitliy of oxygenated Hb S affected?

A

Deoxygenated is LESS soluble

Little effect on solubitlyt of oxygenated HbS

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28
Q

Explain the pathway of the “sickling crisis”

A

HbS aggregating/crystallizing in the capillaries where oxygen tension is lower –> this distorts RBC, increases blood viscosity causing increased stasis –> followed by further hypoxia

Vascular occlusion may occur iwth serious effects on organ funciton ,including the heart. Hypoxia, poor cicularion and hemolysis FEED BACK to lower oxygen concnetrations furtehr increasing extent of socklign and prolonging and intensifying teh criis

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29
Q

What happens if there is Vascular Hypoxia

A

Sudden ORGANOMEGALY - massive RBC sequestration in liver and spleen

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30
Q

What is the result of Perivascular Hypoxia

A

Vascular Occlusion

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31
Q

What is the intravascular Hypoxia

A

Hemolysis and severe anemia

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32
Q

What does Hypoxia in vascular, perivascular, and intravascluarl lead to?

A

HEART FAILURE

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33
Q

What is the genetic defect of Sickle cell disease (codon)

A

DNA base substitution: CTC –> CAC

mutant mRNA codon: GAG –> GUG

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34
Q

What is the molecular defect of sickle cell disease

A

Abnormal beta globain: Glu –> Val at position 6

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35
Q

What is the biochemical defect of sickle cell anemia

A

Anbormal HbS

altered isoelectric and solubility characterisitcs

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36
Q

What is the Pathophysiological defect of sickle cell

A

Sickling of Red Cell:

Increased Red Blood Cell Destruction

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37
Q

What are the clinical defects

A

Pleotropic manifestation

Anemia
jaundice
ischemia
joint and abdominal pain, 
renal failure
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38
Q

How many afro-americans are heterozygous for hte HbAS, sickle cell trait

A

7-10%

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39
Q

How Many Afro-Americans are homozygous for HbSS, SCD

A

0.4%; 50,000-72,000 afflicted

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40
Q

How does HbAS protect from Malaria (Plasmodium falciparum) ?

A

inefected HbAS cells –> knobs, sticks to endothelial cells, sickle and CLEAR. !!!
Immunoregulatory mechanism

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41
Q

What is the treatment of Sickle Cell Anemia

A

Hydroxyurea (urea solubilizes protein)
5-azactidine (increases HbF, gamma chain)

Bone Marrow Transplant

Gene Therapy (experimental)

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42
Q

What is BC11A

A

inhibits HbF Silencing protein

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43
Q

What is an example of molecular pathology form Altered Active Site

A

Defective subunit cannot bind oxygen b/c of a structureal change near the heme that directly affects oxygen binding

When either proximal or distal His is replaced by TRYOSINE, the heme is stabilized in the FERRIC form and cannot bind oxygen

Sucha mutatng Hemoglobin is called Hemolgobin M

44
Q

What is Hemoglobin M? What causes it?

A

Hemoglobin M is a mutatng hemoglboin caused by replacement of either proximal or distal HIS by Tyrosine. The heme is stabilized in the FERRIC form, which cannot bind oxygen.

The disease has only been seen in heterozygous form since homozygosity would be lethal.

Recognition of HbM is important in newborns wince accomapnying cyanosis may be mistakingly identified as a manifestation of congenital heart disease.

45
Q

What kind of disease can be caused by alterend secondary and/or tertiary structure? How?

A

Congenital Heinz Body Hemolytic Anemia

amino acid substitutions can prevent the polypeptide chain from assumign its normal 3D conformation . The rusling hemoglobin is usually unstanble

Degree of severity depends on degree of instability of aparticular hemoglobin

loss a single salt bridge or H bond can tip equilibirum far enought toward unfolded form to denaure protien in vivo and cause idsease

46
Q

What is an altered Quaternary Strucutre

A

Mutations at subunit interfaces can lead to loss of allosteric properties.
Such substituions raise the oxygen affinity of the moleul.e Less frequently the oxygen affinity is lowered.

47
Q

What are the Thalassemia Syndromes?

A

group of inherited disorders in which teh production of a single type of globin chain is either diminished or absent

48
Q

What is alpha thalassemia

A

means that the alpha chain is decreased or missing

49
Q

What is beta thalassemia

A

means that the beta chain is decreased or absent

refers to heterogenous grup of conditions charcterized by QUANTITATIVE deficiency in BETA GLOBIN production relative to alpha glovein synthesis in erythroid cells

50
Q

Wha ti sthe beta thalassemia diseroder of homozygous individuals called

A

it is generally severe and is called THALASSEMIA MAJOR or COOLEY’s ANEMIA

51
Q

What is it called when no HbA is found?

A

condition is termed Beta O thalassemia (all beta is absent)

52
Q

What some HbA is found it is called

A

Beta + (beta is depleted)

53
Q

What is the presentiaton of patient with beta thalasemia at birth?

When does anemia ensue?

A

pat appears normal at birth b/c HbF comprises majority of hemoglobin at time.

Anemia ensues during 6 months as shift is made from HbF to HbA

Pts generally become dependent on transfusion to maintain a hemoglobin level compatible with life

54
Q

What are the different forms that cause molecular basis of beta thalassemias

A

Nondeletion forms

Deletion forms

55
Q

What are nondeletion forms that cause beta thalassemia

A

simple
involve SINGLE BASE SUBSTITUTION or SMALL DELETION or INSERTIONS within or immediately upstream of beta globin gene.

These changes ultimately affet genral aspects of gene functional transcription, RNA processing, and RNA translation

56
Q

How do nondeletion forms affect gene???

A

affects gene fnctinoal transcription

RNA processing,

RNA translation

57
Q

What are DELETIon forms that cause beta thalassemia

A

Deletions of differnt sizes involve beta glboin gene cluster tha produce different syndroms

Beta 0 thalassemia

Hereditary Persistance of Fetal Hemoglobin (HPFH)

detla-beta thalassemia

gamma-delta-beta-thalassemias

and hemoglobins due to HYBRID GENES (Lepore, Kenya)

58
Q

What are hemoglobins due to hybrid genes of beta thalassemia?

A

Lepora, Kenya

59
Q

Describe the anemia of severeity of delta beta thalassemia and HPFH

A

syntehsis of both delta and beta globin does not occur at all and only hemoglobin synthesized is HbF

anemia is delba beta is mild an

anemia in HPFH is absent

difference in clinical severity between beta thalassemisas is due to differences in levels of compensation by HbF

60
Q

Homozygotes for beta thalassemia, level of HbF produciton is greater than normal, but insufficient to compensate for decreased or absent syntehsis of HbA

In delta beta thalassemia, HbF produciton is sufficiently increasee so that only a mild anemia results
in HPFH, compensation by HbF is complete

A

yep

61
Q

What is the molecular basis of alpha thalassemia

A

alpha chain synthesis is diminished or absent

Since all tehnormal human hemoglobins otther than two of the embryonic hemoglobins contians alpha chians, the alpha thalassemisas lead to decreased productino of HbA, A2, and HbF.

Alpha-glboin haplotype may be written alpha-alpha representing the alpha1a and alpha2 respectively

A normal indiviual has genotype alpha-alpha/ alpha-alha

62
Q

How many genes are responsible for alpha chain?

A

four!

63
Q

What is alpha-thalassemia due to deletions? why is it more complex than beta thalassemia?

A

the most common molecular defects underlying alpha-thalassemia involve the delatino of one or more alpha-globin genes

since tehre are 4 alpha gene loci, the deltion pattern is more graded ad complex than with beta thalassemia

further comlicating the piccture is the prsence of the beta-like polypeptide, gamma chain, and teh ability of the beta or gamma chains by themselves to tetramize, although without allosteric or Hill properties (alpha chian does not tetramize tby themselves)

64
Q

Do beta, gamma, or alpha chains tetramize by itself?

A

beta-yes

gamma-yes

alpha -no

65
Q

What are non-deletion forms of alpha-thalasemia?

A

non-deletion forms are caused by the same type of mutations whih cause the no-deletion forms of beta-thalassemia.

However, unlike with Beta-thalassemia, these types ofmutatins are a relatively rare cause of alpha-thalasssemia

66
Q

How many functional alpha genes does normal phenotype have?

A

4

67
Q

how many Hb Bart’s at birth for normal phenotype?

A

0

68
Q

what is %HbH/Inclusions for normal phenotyrpe

A

0/none

69
Q

What is HbH

A

beta-4

still forms tetramer, but NOT regualted alone! no allosteric! not good

70
Q

What is Hb Bart’s?

A

Consists of four gamma chains . It is moderately insoluble, and therefore accumulates in the red blood cells. It has an extremely high affinity for oxygen, resulting in almost no oxygen delivery to the tissues. It is produced in the disease alpha-thalassemia and in the most severe of cases, it is the only form of haemoglobin in circulation. In this situation, a fetus will develop hydrops fetalis and normally die before or shortly after birth, unless intrauterine blood transfusion is performed.Gamma-4

all 4 alleles gone (B4) ?

71
Q

Descibe alpha-Thalassemia minor (mild)

A

3 functional alpha genes

0-2 Hb Bart’s at birth

0/rare % HbH/Inclusion

72
Q

Describe alpha- thalassemia minor (sever)

A

2 functinoal genes

2-8 Hb Bart’s at birth

0/some % HbH/Inclusions

73
Q

Describe HbH disease

A

1 fucntional alpha gene

10-40- Hb Bart’s at birth%

0/Some %HbH/Inclusions

74
Q

Hb Bart’s Hydrops Fetalis

A

0 functional alpha genes

~80 Hb Bart’s at birth %

present/present % HbH/INclusions

75
Q

What are some pathophysiological features of Beta Thalassemia

A

overall reduction in Hb synthesis

destruction of RBC precursor cells

Ineffective erythropoiesis

Destruction of mature RBCs

Hypoxia, anemia

76
Q

What is the total iron in the body?

A

3.5 grams

77
Q

How much iron does a male require to replace iron losses?

A

1 mg/day

78
Q

How much Fe lost inurine

A

0.1 mg

79
Q

How much Fe lost by skin desquamation and sweat

A

0.1 mg

80
Q

how much iron lost by shedding of intestinal mucosa and biliary excretion

A

0.3 mg

81
Q

How much Fe lost due to normal GI bleeding of 1 ml/day?

A

05 mg/day

82
Q

Where is iron primarly abosrbed in our body?

A

from teh duodenum and proximal jejunum.

83
Q

How much % iron ingested in our food is actually aosrbed

A

10%

84
Q

What are the two types of absorbable iron in food

A

Heme iron found in meats, poultry, and finsh

non-heme iron prsent in foods sch as vegetables, fruit, legumes, nuts, breads, cereals

85
Q

How is heme iron taken up

A

easily absorbe by mucosal cells and the iron is split form porphyring ring in the mucosal cytoplasm

86
Q

How is non-heme iron taken up

A

as free iron and/or in protein-bound form

87
Q

What subastanes in diet increase absorption of Fe

A

ascrobic acid or amino acids from meats

88
Q

waht subtances decrease absorption of non-heme iron

A

phytates form bran

tannates in tea

polyphenosl in vegetable,s calcium salts,

phosphoprotein in egg yolk

factor in soy proetin

antacids

89
Q

What is transferrin?

A

Serum Fe3+ transport protein

major protein in serum involve in the transport of iron

beta-1- glycoportien synthesized in teh liver, and consisting of a single polypeptirde chain with two iron-bidning sites

Iron must be in ferric steae tobe boudn by transferrin

90
Q

What is the transferrin recetpor

A

a glycoprtein that mediates internatlizatino of transferrin

Both transferrin and transferrin R can be reuitlied for the transport and cellular uptake of iron.

91
Q

What is ferritin?

A

Cellular Fe 3+ storage

primary and most readily avaialble irone storage protein in teh body

Ferritin is a protein that may contain as much as 23% iron by weight

Fe is prsent as micelles or colloidal particles, composed of a feric hydroxide-ferric phosphate complex, bound rather firmaly t the protein

It can be freed from iron without denaturing the protein, and this protein, apoferritien, is made up of 24 subunits with a MW of 44 kDa each

IN normal sujcets most of the Fe reserve is prsen in liver, Bm and sk muslces

92
Q

what kind of complex is ferritinaand Fe

A

ferric hydorxide-ferric phosphate complex , boundrather fimraly to protein

93
Q

How many subunits is apoferritin made up of?

A

24 subunits with a MW of 44kDa each

94
Q

Wher eis most of the iron reserve presen in?

A

liver, BM, and sk muscles

95
Q

what is correlatin of ferritn to Iron

A

1 ug of ferritin/L = 8 mg storage iron

96
Q

What is Hemosdierrin

A

Denatured, insoluble, Ferritin

insoluble compoutn which is formed by denaturation of ferritin with ass. loss of apoferritin and micellalr aggregation; consequently hemosiderin contains a larger perecentatge of iron than its precursor

Hemosiderin aggregates into particles large enoguth to be seen microscopically

97
Q

Whwer eis 95% of ferritin sotred?

A

in hepatovytes

98
Q

where is hemosiderin stored?

A

in Kupffer cels.

iron sotred in either form may remain sequestered for prolonged peridos of time, or ay be returned almost immediately to a mroe active metabolic role.

99
Q

How much iron does an average male store?

A

1000 mg storage iron

100
Q

how much does menstruatoring female adult sore?

A

300 mg, since she requires about 1.7 mg/day

She has a dietary intake of 10-12 mg daily

101
Q

what are the three facotrs that determien amt of iron absorbed

A

Quantitiy of iron in the diet

Composition of teh diet

Behavior of the mucosa of the duodenum and upper jejunum

102
Q

when there is iron deficiency, the amount of …..increses

A

the amt of tranfer increases

103
Q

when there is iron overload..teh amount …..is curtailed subtantially

A

amount transferred

104
Q

what happens when little iron is reuqired by host

A

large amt of apoferritin is syntehsized trap iron within mucosal cell and prevent transfer to capillary bed

as cells turn over within one week, contnets are extruded into intestinal lumen without absorption ocurring.

105
Q

what happens when there is iron deficiencty

A

no apoferritin is synthesized

so as not to compete vs the transfer of iron to tranferrin in teh plasma

106
Q

what is Ferrochelatase

A

enzyme that catalyzes insertion of ferrous iron into porphyrin

107
Q

What causes Elongated Chain Variants?

A

Caused by either single base substitutions in a chain termination codon
frameshift mutations,
or my mutations that cause failure of cleavage of the initiator methione residue

Biochem Winter 2012 (10 decks)

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