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Biochemistry > Hemoglobin > Flashcards

Hemoglobin Flashcards

1
Q

Hb Intersubunit Salt Bridge

A

Between 2 alpha chains

  • C-terminal Arg interacts with Asp and Lys via guanidinium+ and -COO-
  • allows for movement between T and R states
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2
Q

Bohr Effect

A

Allosteric modulation on beta chains

  • T + 4O2 —-> R-(O2)4 + mH+
  • when Hb goes into R state, His releases proton
  • at low pH, His(+) and Asp (- above pH 4) have salt bridge that stabilizes T state. pKa of His = 8
  • in physiological pH/R state, salt bridge is broken, and pKa of His decreases to 7.1
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3
Q

Indirect CO2 Binding To Hb

A

-release of CO2 in blood lowers pH

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4
Q

Direct Binding of CO2 to Hb

A
  • In T state, beta N-terminal arginine or lysine forms adduct with CO2, creating carbamate (-) on free amino group, and an Arg will form salt bridge to stabilize carbamate.
  • when it gets to lungs, T state is destabilized, carbamate is destabilized, CO2 is released.
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5
Q

Diamox (mech of action/generic name)

A
  • acetazolamide
  • promotes excretion of bicarbonate in the kidneys
  • treats altitude sickness by lowering blood pH, which shifts curve to right, increasing payload.
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6
Q

NO Binding to Hb

A
  • binds to R state on 1)heme Fe (competitive) and 2) beta chain Cys via thiol-nitrosyl bond (allosteric)
  • release of NO upon deoxygenation of Hb allows NO to bind vascular endothelium receptors, triggering vasodilation and increased bloodflow to hypoxic tissues.
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7
Q

2,3 BPG Binding to Hb

A
  • BPG sits between 2 beta chains to stabilize T state.
  • BPG is polyanion that forms salt bridges with beta chain residues
  • BPG is critical to aid in release of O2 at PO2 levels in peripheral tissue
  • BPG modulation is long term since its a product of metabolism
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8
Q

T State Stabilizers

A
  • acidosis
  • BPG
  • CO2
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9
Q

R-State Stabilizers

A
  • alkalosis
  • O2
  • NO
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10
Q

Chromosome Where Alpha Chains are Localized

A

16

-zeta also on 16

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11
Q

Chromosome Where Beta Chains are Localized

A

11

-epsilon, delta, and gamma also

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12
Q

Difference Between Gamma Chain and Beta Chain in Fetal Hb

A
  • Gamma chain has a Serine (neutral) instead of His (+) in area that binds BPG, thus destabilizing T state
  • therefore, fetal Hb has lower affinity to BPG
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13
Q

Significance of E Helix Histidine in Hb

A
  • E helix histidine acts as molecular doorstop to keep from optimal binding of CO
  • E helix his also stabilizes binding of O2 in R state
  • this happens when His is in deprotonated state (neutral)
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14
Q

Glycation of Hb-A1c

A
  • Occurs on beta chain N-terminal valine, removing N-terminal charge
  • Not enzymatically catalyzed
  • Allows for electrophoretic separation with normal Hb
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15
Q

Sickle Cell Mutation

A
  • beta chain glutamic acid(-) —> valine (neutral hydrophobic)
  • hemolytic anemia
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16
Q

Sickle Cell Trait

A
  • usually asymptomatic, except in renal medulla, where O2 tensions are low enough to cause sickling and renal damage
  • renal papillary necrosis
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17
Q

Sickle Cell Treatments

A
  • hydroxyurea and butyrate
  • increase O2 tension
  • warm up
  • hydration
  • bone marrow and stem cell transplants
  • gene therapy
  • blood transfusions
  • penicillin prophylaxis
  • routine immunizations
  • narcotic therapy
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18
Q

HbC Mutation and Implications

A

Glu6–>Lys

  • causing intracellular crystallization of the protein
  • cation leakage of K, causing dehydration
  • hemolytic anemia
19
Q

How HbS trait confers advantage over Malaria

A
  • malaria tries to sequester heme to make hemozoim crystals, and anti malarials block formation of these crystals
  • malaria infection of RBCs causes sickling, recruiting phagocytes, which will clear infected cells
20
Q

Causes of Thalassemias

A

-missing gene
-gene is present but expression is impaired (modifications to gene promoter)
-mRNA is produced but encodes dysfunctional Hb b.c of early stop codon
-both thalassemias are hypochromic and microcytic
HPFH(persistence of fetal hemoglobin) is a harmless thalassemia

21
Q

Alpha Thalassemias

A

4 types: silent carrier, trait, disease, hydrops fetalis (death)

  • fetus can survive first few weeks without any alpha chains because of zeta chain production
  • high levels of gamma chain indicative of Hb Barts
  • high levels of only beta chains: HbH tetramers, which have reduced solubility and incapable of cooperativity/allosteric regulation
  • loss of function due to gene DELETION
  • mutations that delete only the LCR of the α-globin complex have also been found to cause α-thalassemia.
22
Q

Beta Thalassemias

A
  • premature stop codons/missense mutations via single base substitution are the usual cause
  • alpha chains aggregate into heinz bodies
  • higher levels of HbF or HbA2 possible(exclusive to beta heterozygotes)
  • not expressed until after birth
  • major thalassemia: normal until age 2, then anemia follows
  • bone marrow replacement can cure beta thalassemias
23
Q

Methemoglobinemia

A
  • can be induced by certain antibiotics (ones that drive oxidation of Hb)
  • inherited methemoglobinemia due to mutations in Hb, cytochrome-b5 or cytochrome-b5-reductase (soluble form found in RBCs)
  • Polar mutations of heme binding site allow water in, oxidizing heme
  • HbM Hyde Park beta His–> Tyr effects interactions with cytochrome b5 reductase, the enzyme that helps recycle methemoglobin back to normal
24
Q

Treatment for Cyanide Poisoning

A
  • amyl nitrate
  • oxidizes Hb, which readily binds cyanide, producing cyanohemoglobin. This keeps HCN from binding cyanide C oxidase critical for cellular respiration.
  • methemoglobin irreversibly binds HCN
25
Q

Hb Kempsey

A
  • locks Hb in R state, thereby reducing delivery to tissues
  • missense
  • polycythemia
  • autosomal dominant
26
Q

Hb Hammersmith

A
  • because of bad protein folding due to substitutions or deletions, protein product is prematurely degraded
  • autosomal dominant
  • hemolytic
  • unstable Hb, it precipitates, lower O2 affinity
27
Q

Hereditary Persistence of Fetal Hemoglobin

A

-caused by increased post-natal transcription of gamma genes because of difference in gene regulatory sequence

28
Q

Temporal Switching of Fetal Hb Genes

A

-Embryonic globin synthesis occurs in the yolk sac from the 3rd to 8th weeks of gestation, but at about the 5th week of gestation, the major site of hematopoiesis begins to move from the yolk sac to the fetal liver.

29
Q

Beta Globin Gene LCR

A
  • begins 6kb upstream of epsilon

- mutation in LCR leads to εγδβ-thalassemia

30
Q

HbM Hyde Park

A
  • autosomal dominant
  • beta His–> Tyr effects interactions with cytochrome b5 reductase (methemoglobin reductase), the enzyme that helps recycle methemoglobin back to normal
  • affected Hb cannot carry O2
  • cyanosis, but usually asymptomatic
31
Q

HbE

A
  • autosomal recessive

- causes mild thalassemia

32
Q

HbSC

A
  • disease when person has HbS trait and HbC
  • milder anemia than full blown Hbs
  • may have no clinical problems until, unexpectedly, a serious complication develops as a result of vascular occlusion, particularly in the retina.
33
Q

Hb Barts

A

Beta thalassemia that uses gamma chains

34
Q

β0 Thalassemia

A
  • When the β-thalassemia alleles allow so little production of β- globin that no Hb A is present
  • If some Hb A is detectable, the patient is said to have β+ thalassemia
35
Q

Treatments For Thalassemias

A
  • correction of the anemia
  • increased marrow expansion by blood transfusion
  • on control of the consequent iron accumulation by the administration of chelating agents
  • Bone marrow transplantation
36
Q

Fe Chelators

A

-desferrioxamine, deferasirox, and deferiprone

37
Q

Hydroxyurea

A
  • increases total and fetal hemoglobin in children with sickle cell
  • reduces levels of circulating leukocytes, which decreases the adherence of neutrophils to the vascular endothelium
  • reduce the incidence of pain episodes and acute chest syndrome episodes.
  • its target is the enzyme ribonucleotide reductase, and its inhibition by hydroxyurea results in S-phase cell cycle arrest.
38
Q

K Type Allosteric Activators

_____ Km
_____ Vmax

A

K Type Allosteric Activators

LOWER Km
DOESN’T CHANGE Vmax

39
Q

K Type Allosteric Inhibitors

_____ Km
_____ Vmax

A

K Type Allosteric Inhibitors

INCREASE Km
DOESN’T CHANGE Vmax

40
Q

V Type Allosteric Inhibitors

_____ Km
_____ Vmax

A

V Type Allosteric Inhibitors

DOESN’T CHANGE Km
LOWERS Vmax

41
Q

V Type Allosteric Activators

_____ Km
_____ Vmax

A

V Type Allosteric Activators

DOESN’T AFFECT Km
LOWERS Vmax

42
Q

Irreversible Enzymatic Inhbitors

A

Penicillin, aspirin

43
Q

Methotrexate

A

Inhibitor of DHF reductase (cell proliferation)

-it’s an analog of DHF, it’s chemotherapy. Competitive inhibitor

44
Q

ddI and Nevirapine

A

Inhibitors of HIV RT, analogs

Biochemistry (35 decks)

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