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Cellular Anatomy > Hemoglobin > Flashcards

Hemoglobin Flashcards

1
Q

What is hemoglobin’s structure?

A
  • 4 polypeptides called globins

- 4 heme prosthetic groups

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2
Q

Mutation of Sickle Cell Disease

A

Mutation in the Beta globin chain

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3
Q

What is the therapy for sickle cell disease?

A

Increase the number of F cells which express HbF and has a higher affinity for oxygen than HbA

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4
Q

When is Gamma globin expressed?

A

After 6 months of age

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5
Q

Hb is slowly non-enzymatically…

A

glycated (measurement of diabetes - hemoglobin A1C)

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6
Q

What is Heme’s structure

A

Consists of protoporphyrin IX (tetrapoyrole ring) + ferrous iron (Fe2+) in the center

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7
Q

When heme is not associated with a protein it is called?

A

Pro-oxidant

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8
Q

The bonds of hemoglobin and heme are ___ and ___.

A

Proximal histidine (Fe 2+ of heme and histidine interaction in the F helix)

Distal histidine (histidine in the E helix - helps stabilize the interaction)

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9
Q

What is oxidized hemoglobin called?

A

Methemoglobin (Fe3+) and cannot bind oxygen

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10
Q

What is distal histidine’s role?

A

To prevent the oxidation of Fe2+ to Fe3+ and reduce Hb ability to CO. To stabilize the interaction of heme to hemoglobin.

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11
Q

When Fe livers are high the liver produces…

A

Hepcidin - inhibits transport of Fe from the mucosal cell by degrading ferriportin

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12
Q

Transferrin (binds only Fe3+)

A

Transfer of iron from mucosal cell to capillary bed

Carries Fe in blood, delivers to cells by reception-mediated endocytosis

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13
Q

Transfer of iron out of mucosal cell is regulated by

A

Ferriportin (coupled with ferroxidase, hephaestin or ceruloplasmin) to form Fe3+

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14
Q

Hepcidin is synthesized by

A

IL-6 which contributes to anemia of chronic disease

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15
Q

Hemochromastosis

A

abnormal increase in iron absorption (Iron overload)–> decrease in hepcidin

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16
Q

TIBC

A

Transferrin Iron Binding Capacity –> increases in Fe deficient states

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17
Q

Ferritin

A

Storage of iron

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18
Q

Hemosiderin

A

aggregates of degraded ferritin (and iron) in lysosomes that are increased in iron overload

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19
Q

Ferritin translation

A

Regulated by IRE (iron response element) in the 5’ UTR

-When iron levels are low translation is inhibited

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20
Q

Transferrin Receptor

A

IRE in 3’ UTR

  • High levels of iron, mRNA is degraded
  • Low levels of iron, IRE bound by IRE-BP and mRNA is stabilized and translated
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21
Q

Transferrin and Ferritin Correlation

A

High iron = increase in ferritin (storage) decrease in transferrin

Low iron = decrease in ferritin and increase in transferrin via IRE-BP to IRE

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22
Q

DMT1

A

Divalent Metal Transporter 1 - receptor of iron that other divalent metals compete for

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23
Q

Ferrireductase

A

Reduction of Fe3+ to Fe2+

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24
Q

Heme Synthesis

A

First step is the rate limiting step and occurs in the mitochondria, last three steps occur in the mitochondria

The intermediate steps occur in the cytosol

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25
Q

ALA Synthase

A
  • Rate limiting step
  • 8 molecules of glycine
  • 1 molecule of succinyl coA
  • creates ALA (d-aminolevulinic acid )
  • inhibited by heme
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26
Q

ALA Dehydrastase Reaction

A
  • second step
  • occurs in the cytosol
  • inhibited by lead
  • forms PBG - porphobilinogen
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27
Q

Ferrochetalase

A
  • Final Reaction
  • in mitochondria
  • inhibited by lead
  • Catalyzed Fe 2+ into protoporphyrin IX
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28
Q

Regulation of Heme Synthesis

A
  • By rate limiting step ALA synthetase
  • Inhibited by heme
  • Induced by Fe in red blood cells
  • Glucose inhibits
  • Steroids increase synthesis
  • Cytochrome P450 increase ALA synthetase
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29
Q

ALA Synthase Isoform 1 (ALAS1)

A

ALAS1 - in the liver, and other tissues

Regulated by heme (negative feedback)

  • Inhibits transcription
  • Increases mRNA degradation
  • Blocks post-translational translocation of ALAS1 to the mitochondria
  • Short-half life
  • Induced by steroid hormones
  • Inhibited by glucose
  • Activity increased by certain drugs
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30
Q

ALA Synthaste Isoform 2 (ALAS2)

A

ALAS2 - in the erythroid

  • Makes heme for hemoglobin(85% daily heme)
  • Response to heme levels is more leisurely

Regulated in response to Iron levels

  • IRE in 5’UTR translation
  • When Iron levels are low translation is inhibited
  • Heme regulates synthesis indirectly by regulating Fe from the transport protein transferritin

-Long half life

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31
Q

Heme Synthesis Coordination

A

Erythroprotein induces translation of ALAS2 and alpha and beta globins

Heme increases transription of globins and stabilizes the mRNAs to be translated

  • If heme levels are low a kinase is activated that phosphorylates eiF-2-GDP and inhibits translation and globin chains
  • If heme levels are high, kinase is inhibited and translation is allowed
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32
Q

Defects in Heme Synthesis

A
  • Lead poisoning

- Porphyrias

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33
Q

Lead Poisoning

A

Inhibits ALA dehydrastase
Inhibits Ferrochetalase
Anemia because decreased Hb
Competes with Calcium and causes calcium disruption in homeostatis

Symptoms are age and dose related

34
Q

Porphyria

A
  • Genetic defect in heme synthesis
  • Symptoms due to accumulation of toxic intermediates
  • Depletion of essential cofactors, substrates
  • Dominantly inherited
-Precipitating factors:
Drugs metabolized by Cytochrome P450
Alcohol
Fasting/Severe dieting
Hormones 
Stress
35
Q

Treatment of porphyria

A

Hematin (stable derivative of heme)
Carb rich diet
Withdrawal of any precipitating diet

36
Q

Porphyria cutanea Tarda

A 
Most common porphyria
Dominant
In patients with alcoholism 
No neurological symptoms
Treatment is abstaining from alcohol, avoiding sunlight, and phlebotomy to reduce iron
37
Q

Acute Intermittent Porphyria

A

Intermittent attacks
Dominant
Neurological dysfunction
Colored urine or stool

38
Q

Hemoglobin Deoxygenated State

A

(T form or taut)
Fe is puckered out from center of heme
Heme plane has a slight dome shape
F helix of the globin chain is at a slight angle
two alpha beta dimers are held by ionic and hydrogen bonds = constrain the movement of the globin chains

39
Q

Hemoglobin Oxygenated State

A

(R form or relaxed)
Globin movement relieves strain
Oxygen binding ruptures some of the bonds between the two dimers = freedom of movement
Affinity for Oxygen

40
Q

Allosteric inhibitors of Hb affinity for O2

A

2,3 BPG
H+
CO2
Increasing temperature

41
Q

2,3 BPG

A

2,3 bisphosphoglycerate

intermediate of glycolysis
binds to a positively charged pocket of 2 Beta globin chains
Stabilizes the T form
Decreases O2 affinity in tissues

42
Q

Why does HbF have a high affinity for O2

A

HbF - a2gamma2

gamma globin chains have fewer positive charges in center pocket so 2,3 BPG cannot bind as well as it does to the Be a globin chain in adult hemoglobin

HbF low affinity for 2,3 BPG

43
Q

2,3 BPG Importance in…

A

Adaptation to altitude
Hypoxia
Anemia
COPD - Cardiopulmonary insufficiency

44
Q

Bohr Effect

A

lower pH = hemoglobin has lower affinity for oxygen

oxygen dissociation curve is shifted to the right

H+ stabilized the T form

45
Q

What converts 70-80% of CO2 produced during aerobic metabolism to bicarbonate in RBC?

A

carbonic anhydrase

46
Q

What happens to the remaining 15-20% of CO2

A

Transported to the lungs on hemoglobin as carbamino-hemoglobin

CO2 binds to N terminal of hemoglobin and produces H+

This reaction promotes the release of O2 from Hb in tissues

47
Q

Hemoglobinopathies

A

Disorders affecting structure, function, or production of globin chains

Co-dominant in inheritance
Common where malaria is present
Severity ranges

Examples:

Thalassemias
Sickle Cell Disease

Acquired:
Methemoglobinemia
CO poisoning

48
Q

Thalassemia

A

Most common single gene genetic disorder
Partial of complete absence of one or more globin chains

Alpha and Beta

49
Q

Alpha Thalassemia

A

Deletion of 1 or more of the alpha globin chains

50
Q

Hemoglobin Barts Syndrome

A

Deletion of all 4 alpha globin chains

51
Q

Types of Hemoglobin Barts Syndrome

A

Hydrops fetalis - abnormal accumulation of interstitial fluid in a fetus or newborn

Hb Barts - Gamma 4
Increased oxygen affinity makes it a poor transporter
Fatal at or before birth

52
Q

Hemoglobin H disease

A

A type of alpha thalassemia -

3 alpha genes deleted

HbH - Beta 4

Unstable tetramer in patients with 3 alpha chains deleted

53
Q

Beta Thalassemia

A

B Thalassemia Minor

B Thalassemia Major

54
Q

B Thalassemia Minor

A 
Heterozygous
Asymptomatic (except mild anemia)
55
Q

B Thalassemia Major (Cooley Anemia)

A

Homozygous
Transfusions for severe anemia
Suffer iron overload

56
Q

Sickle Cell Disease

A

Autosomal recessive
Hemoglobin S == missense

Mutation of glu to val in Beta globin

Decreased solubility but only in deoxy form (insolubility predicates RBC and causes sickling)

Homozygous only have symptoms

57
Q

Sickle Cell Trait

A

Heterozygous

No symptoms

58
Q

Carbon Monoxide Poisoning

A

Acquired Hemoglobinopathies

-Most common fatal poisoning in US

CO competes with O2 for binding to Hb, O2 binding affinity increased in other sites

59
Q

Methemoglobinemia

A

Acquired Hemoglobinopathies

(Fe3+)
Oxidation exceeds capacity of reduction
Mutation limits ability to reduce
"chocolate" blood, cyanosis
certain drugs increase metHb
Infants are vulnerable

Treatment: methane blue reduced metHb

60
Q

Congenital forms of metHb

A

Hemoglobin M

NADH cytochrome b5 reductase deficiency

61
Q

Hemoglobin M

A

Mutation in heme binding pocket

Dominant inheritance

62
Q

NADH cytochrome b5 reductase deficiency

A

Recessive inheritance

Type I - only erythrocytes
Type II - all cells

63
Q

Heme degradation

A

Goal: Perserve Fe and convert protoporphyrin to product that can be safely excreted

Regulated to prevent toxic build up of heme and its breakdown products

First step is rate limiting - Heme oxygenase
Second step produces bilirubin - Biliverdin Reductase

64
Q

Heme oxygenase

A

Cleaves the pyrrole ring and produces biliverdin
Requires: O2 and NADPH
Releases: Cardon Monoxide (CO) and Fe3+

65
Q

Biliverdin Reductase

A

Requires: NADPH
Produces: bilirubin

66
Q

Physiological Source of CO

A

ONLY through Heme oxygenase

-Amount of heme being broken down is correlated to the amount of CO produced

  • CO acts as a signaling molecule in neural tissue
  • CO Role - vasodilatory, anti-inflammatory, autoprotectant properties
67
Q

Bilirubin Conjugation Pathway

A

Bilirubin carried to liver by albumin

Billirubin (BR) + 2 UDP-glucuronate (by bilirubin glucouronyl transferase) = Bilirubin diglucurnide

Br diglucuronide ACTIVELY transported to bile by Multidrug resistance protein 2 (MRP2)

68
Q

Bilirubin Conjugation

A

Increases solubility

Prevents reabsorption from the intestinal lumen and promotes excretion

69
Q

Deconjugation of Bilirubin

A

Excreted from Bile to the intestine and deconjugated by bacterial hydrolyses and converted to urobilinogens

Most –> Urobilinogens are oxidized to urobilins and secreted in feces

Rest –> A small amount is reabsorbed to the blood and excreted in urine

70
Q

Heme Oxygenase HO-1

A

Regulation of Heme degradation –>

Expressed in liver and spleen

71
Q

Jaundice

A

Caused by deposits of bilirubin in skin and sclerae when levels in blood are increased

Increased production or decreased excretion of Br

  • Prehepatic (Hemolysis)
  • Hepatic (Neonatal, hepatitis, genetic)
  • Post-hepatic (Bile duct obstruction)
72
Q

Measurement of Bilirubin

A

Direct = Conjugated
-Coupled to diazonium salts (azo dyes) in a direct van den Bergh reaction

Indirect - unconjugated
-Bilirubin in non-colvanent complex with albumin won’t react with the dyes until albumin is released by an organic solvent

Total - direct = indirect

73
Q

Prehepatic (Hemolysis)

A

EXCESS PRODUCTION OF BILIRUBIN
Indirect hyperbilirubinemia

Cause: Hemolysis

  • Increased production of Br, exceeding capacity of liver to conjugate
  • Increase urobilinogen in blood and urine due to increased conjugated Br reaching intestine
74
Q

Intrahepatic (hepatocellular) jaundice

A

PROBLEM WITH UPTAKE, CONJUGATION OR SECRETION FROM HEPATOCYTES

direct or indirect hyberbilirubinemia

75
Q

Hepatitis

A

No bile duct obstruction

Conjugated bilirubin in urine
Liver enzymes often increased

76
Q

Neonatal Jaundice

A

Most common in pre-mature babies

Bilirubin glucuronyl transferase is low
Bilirubin serum levels exceed levels of albumin it may rise to toxic levels in basal ganglia causing a toxin encephalopathy –> kernicterus

77
Q

Intrahepatic Jaundice

A

Crigler-Najjar Syndrome
Gilbert Syndrome
Dubin-Johnson syndrome

78
Q

Crigler-Najjar Syndrome

A

Rare deficiency bilirubin glucuronyl transferase
Type 1 = total deficiency
Type 2 = less severe

79
Q

Gilbert Syndrome

A

Benign mild elevation indirect bilirubin

Mutation in promoter of bilirubin glucuronyl transferase gene, decreased expression

80
Q

Dubin-Johnson syndrome

A

Defective transport of conjugated bilirubin out of hepatocytes (or liver)
Rare mutation in MRP2 (multidrug resistant protein 2)

81
Q

Post Hepatic (Obstructive) Jaundice

A

BILE DUCT OBSTRUCTION THAT PREVENTS EXCRETION OF CONJUGATED BILIRUBIN

Direct hyperbilirubinemia
Bile acids may also accumulate in plasma
Conjugated bilirubin in urine
No urobilinogens in stool 
Prolonged obstruction can lead to liver damage and increased unconjugated (indirect) Br

Cellular Anatomy (2 decks)

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