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Theme 2.1 Medical Biochemistry > Hemoglobin Oxygen transport > Flashcards

Hemoglobin Oxygen transport Flashcards

1
Q
  1. WHAT IS HEMOGLOBIN?
A

.

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2
Q
  1. WHAT ARE THE TYPES OF BONDS THAT STABILISE PROTEIN STRUCTURE?
A

. Hydrogen, ionic, disulfide, hydrophobic interactions.

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3
Q
  1. WHAT IS THE FUNCTION OF HEMOGLOBIN IN THE BODY?
A

.Functions to transport
O2 from lungs to tissues
CO2 from tissues to lungs
H+ from tissues to lungs

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4
Q
  1. WHAT IS THE BASIC STRUCTURE OF HEMOGLOBIN? AND IMPORTANT BONDS?
A

.Four polypeptide chains each with its own haem (tetramer)
Composed of 2 identical dimers
Polypeptide chains within each dimer are held together by hydrophobic interactions, also ionic and hydrogen bonds
Dimers held together by polar bonds

Binds 4 molecules of O2

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5
Q
  1. WHAT ARE THE TWO CONFORMATIONS OF HEMOGLOBIN AND THEIR IMPORTANCE?
A

.Oxygen binding affinity differs between R and T conformations
R binds oxygen 150 to 300 times more tightly than T conformation
Therefore R conformation found in the lungs for oxygen binding and T conformation found in the tissues for unloading (delivery) of oxygen

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6
Q
  1. WHAT ARE THE ALLOSTERIC EFFECTORS OF HEMOGLOBIN?
A

.Role of allosteric effectors in facilitating O2 loading and unloading

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7
Q
  1. WHAT IS THE ROLE OF ALLOSTERIC EFFECTORS IN FACILITATING OXYGEN LOADING AND UNLOADING? [SHIFTING CURVE]
A

.↑ pCO2
↓pH of environment ( H+)
↑ 2,3-bisphosphoglycerate
↑ Temperature

All above are negative allosteric effectors  shift curve to the right  stabilise T-conformation  favours oxygen unloading at the tissues

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8
Q
  1. WHAT IS THE CO-OPERATIVE BINDING OF OXYGEN TO HEMOGLOBIN?
A

.Oxygen dissociation curve

Myoglobin (Mb) binds oxygen tighter than Hb

Mb is half saturated at 1mmHg, Hb at 26mmHg

Oxygen binding to one haem group in Hb increases oxygen affinities of the remaining haem groups = co-operative binding

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9
Q
  1. WHAT IS THE DIFFERENCE BETWEEN OXYGEN AFFINITY BETWEEN Hb AND MYOGLOBIN?
A

.Myoglobin (Mb) binds oxygen tighter than Hb

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10
Q
  1. WHAT IS THE DIFFERENCE BETWEEN OXYGEN AFFINITY BETWEEN HbA AND HbF ?
A

.HbF has more affinity than HbA

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11
Q
  1. WHAT MAKES FETAL HEMOGLOBIN (HbF) SPECIAL?
A

.HbF has Ser in place of lysine, → binds 2,3-BPG weakly → increased O2 affinity → easier transfer of O2 to the foetus

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12
Q

WHAT ARE THE FUNCTIONS ASSOCIATED WITH THESE HAEM-CONTAINING PROTEINS?

A

.HEMOGLOBIN AND MYOGLOBIN AND CYTOCHROMES AND CATALASES AND PEROXIDASES AND TRYPTOPHAN PYRROLASE

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13
Q

WHAT IS HAEM?

A

.oxygen binding prosthetic group

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14
Q
  1. WHAT DOES HAEM CONSIST OF?
A

.consists of porphyrin ring (protoporphyrin IX) chelated with ferrous iron (Fe2+)

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15
Q
  1. THE BASIC STRUCTURE OF HAEM?
A

Porphyrin ring bound to one iron molecule. We need to make protoporphyrin 9 and chelate 9 to it. Iron can form 6 bonds but here only 4 and other 2 important for stabilizing and the other is with oxygen. = Protoporphyrin IX :Four pyrrole rings. Linked by methene bridges. Eight side chains. Porphyrins vary in the nature of the side chains attached to the 4 pyrrole rings. uroporphyrin  acetate & propionate. coproporphyrin  methyl & propionate. protoporphyrin IX (and haem)  vinyl (yellow), methyl (red) & propionate (purple) groups

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16
Q

WHERE IS HAEM SYNTHESIZED?

A

.Major sites of synthesis liver and bone marrow (erythroblasts)

Haemoglobin in bone marrow
haem production equal to globin synthesis in marrow

Cytochrome P450 in liver

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17
Q

WHAT DETERMINES THE RATE OF HAEM SYNTHESIS?

A

.Synthesis in the liver variable and dependent on
haem pool balance
availability of Fe2+
need

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18
Q
  1. GIVE THE COMPLETE DETAILS OF THE REGULATED STEP OF HAEM BIOSYNTHEIS.
A

.Formation of -aminolevulinic acid (ALA)
rate limiting step
condensation of glycine with succinyl CoA
catalysed by ALA synthase (mitochondrial)
requires pyridoxal phosphate

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19
Q
  1. COMPARE BETWEEN CYTOPLASMIC VS MITOCHONDRIAL STEPS.
A

.First and last 3 reactions take place in mitochondria - all others in cytoplasm

Red blood cells have no mitochondria so can’t make haem

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20
Q
  1. DISCUSS THE + & - REGULATION OF THE BIOSYNTHESIS OF HAEM.
A

.Excess haem oxidised to hemin → hemin ↓activity of ALA synthase by causing ↓ synthesis (mRNA synthesis)

Also negatively regulated by glucose

Many drugs increase ALA synthase activity → ↑CYP450 synthesis → enhanced consumption of haem (decreasing haem)

Low intracellular [haem] → increases ALA synthase synthesis → increase in ALA synthesis

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21
Q
  1. DISCUSS THE COMPLETE DETAILS OF THE FORMATION OF THE PYRROLE RING.
A

.

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22
Q
  1. DISCUSS THE FUNCTION OF DELTA-AMINOLEVULINIC ACID DEHYDRASE ENZYME.
A

.Condensation of 2 ALA molecules PBG (delta-aminolevulinic acid dehydrase)

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23
Q
  1. DISCUSS THE FORMATION OF THE TETRAPYRROLE RING.
A

.

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24
Q
  1. WHAT IS THE BIOSYNTHESIS OF HAEM SENSITIVE TO?
A

.Very sensitive to lead and other heavy metals

25
Q
  1. WHAT IS THE OVERALL SUMMARY OF THE PATHWAY OF HAEM SYNTHESIS?
A

.Begins with succinyl CoA and glycine

STEP 1: is rate limiting, catalysed by ALA synthase and requires pyridoxal phosphate (mitochondria)

Condensation of 2 ALA produce a substituted pyrrole which carries a two carbon and a three carbon side chain (cytoplasmic)

As four pyrroles condense to form a porphyrin ring, the ordering of side chains is regulated by uroporphyrinogen III cosynthase, producing prophyrins of the III series (cytoplasmic)

Subsequent modification of the side chains by decarboxylations and oxidations give rise to uroporphyrins first and then coproporphyrins (cytoplasmic). The distinction from these forms relates to the number of carboxyl groups on the periphery of the porphyrin ring

The last step is the insertion of an Fe2+ atom into the centre of the porphyrin ring (mitochondrial)

26
Q
  1. DISCUSS THE COORDINATED REGULATION OF HAEM SYNTHESIS.
A

. Free haem:
inhibits activity of pre-existing -ALA synthase
diminishes the transport of -ALA synthase from cytoplasm to mitochondria after synthesis
Represses the production of -ALA synthase by regulating gene transcription.
Stimulates globin synthesis to ensure that levels of free haem remain low.

27
Q
  1. WHAT ARE THE MOST IMPORTANT ASPECTS OF BALANCING HEMOGLOBIN PRODUCTION?
A
28
Q

WHAT ARE PORPHYRIAS?

A

.caused by partial deficiency of one of the haem synthesising enzymes other than ALA synthase
accumulation and increased excretion of porphyrins and porphyrin precursors in the urine (each unique)
all porphyrias are autosomal dominant, except congenital erythropoietic porphyria, which is recessive

29
Q

WHAT ARE THE TYPES OF PORPHYRIAS?

A

.can be hepatic or erythropoietic

hepatic can be acute or chronic

those involving accumulation of tetrapyrrole intermediates show photosensitivity
formation of superoxide radicals
skin blisters, itches (pruritis)
skin may darken, grow hair - hypertrichosis

30
Q

WHICH PORPHYRIA IS AUTOSOMAL RECESSIVE?

A

.congenital erythropoietic porphyria

31
Q

PORPHYRIAS THAT INVOLVE ACCUMULATING OF TETRAPYRROLE INTERMEDIATES SHOW WHICH SYMPTOMS?

A

.formation of superoxide radicals
skin blisters, itches (pruritis)
skin may darken, grow hair - hypertrichosis

32
Q

WHAT ARE THE 6 PORPHYRIAS AND THEIR ASSOCIATED ENZYME DEFECT? MUST KNOW:-

A

.Hepatic/ erythropoietic / both?. Photosensitive? Why or why not? Enzyme defect and the molecule that accumulates

33
Q

WHAT ARE THE TWO ENZYME DEFECTS IN LEAD POISONING?

A

.Two enzymes affected
ALA Dehydratase
Ferrochelatase

Increase urinary ALA and protoporphyrin IX in erythrocytes

34
Q

DISCUSS THE HAEM DEGRADATION. WHERE DOES IT OCCUR? [use the summary slide 32]

A

.

35
Q

WHAT SYSTEM IN THE BODY IS RESPONSIBLE FOR THE DEGRADATION OF HAEM?

A

.reticuloendothelial (RE) system

36
Q

WHAT IS BILIRUBIN? AND HOW IS FORMED?

A 
.Formation of Bilirubin
RE cells contain microsomal haem oxygenase & biliverdin reductase
Requires NADPH, O2
Hydroxylates methenyl bridge
Fe2+ oxidised to Fe3+ 
Second reaction cleaves ring
CO released with Fe3+
37
Q

WHERE IS BILIRUBIN EXCRETED INTO?

A

.Excretion of bilirubin into bile
actively transported into bile
requires energy - susceptible to liver disease
unconjugated bilirubin not excreted

38
Q

DISCUSS THE FORMATION OF UROBILINOGEN.

A

.bilirubin diglucuronide hydrolysed and reduced by bacteria to urobilinogen

urobilinogen oxidised by bacteria to stercobilin - brown color of stools

some urobilinogen is reabsorbed into blood

enterohepatic urobilinogen cycle (taken to liver and re-excreted into bile)

urobilinogen to kidney - converted to yellow urobilin - this gives urine its characteristic color

39
Q

WHAT IS JAUDINCE IN ESSENCE? WHAT DOES IT CAUSE?

A

.Hyperbilirubinemia > 50M / 3mg/dL

Deposition of bilirubin in skin, nail beds and sclera of the eyes

Two forms of bilirubin:
Direct bilirubin: Conjugated with glucuronic acid
Indirect bilirubin: unconjugated, insoluble in water.

40
Q

WHAT ARE THE TWO FORMS OF BILIRUBIN?

A

.Two forms of bilirubin:
Direct bilirubin: Conjugated with glucuronic acid
Indirect bilirubin: unconjugated, insoluble in water

41
Q

WHAT ARE THE TYPES OF GLOBIN GENES?

A

ALPHA GLOBIN

BETA GLOBIN

42
Q

WHERE ARE THE BETA GLOBIN LOCATED?

A
  • Short arm of chromosome 11

- Single gene for β-globin chain

43
Q

WHERE ARE THE ALPHA GENES LOCATED?

A

Alpha-globin genes
located on chromosome 16

2 genes for α-globin chains
4 aplha-genes per diploid genome
Located as pairs 2.5kb apart

44
Q

WHAT ARE GLOBINS?

A

Polypeptide chains constitute the globin portion of the molecule

L-valine at the amino terminus

High proportion of α-helical structure

45
Q

WHAT ARE THE TYPES OF GLOBIN CHAINS?

A 
Types of globin chains
Alpha-globins
Beta-globins
Delta-globins
Gamma-globins
Epsilon-globins
Zeta-globins
46
Q

DISEASES OF GLOBIN METABOLISM

A

Structurally abnormal Hb

Insufficient production of Hb

Inherited as autosomal recessive

47
Q

WHAT ARE THE DISEASE IN GLOBIN METABOLISM DUE TO?

A

Substitution of one amino acid for another
Deletion of a portion of the amino acid sequence
Abnormal hybridisation between two chains
Abnormal elongation of the globin chain

48
Q

WHERE IS THE MUTATION LOCATED FOR SICKLE CELL ANEMIA?

A

Results from mutations in the genes coding for β-chains

49
Q

WHY IS THE Amino acid substitution in the β-chains (Glu6β –> Val) DANGEROUS?

A

Val-Val interaction –> long linear polymers –> sickle shaped RBCs –> cell lysis (haemolysis)

Low pO2 –> deoxy Hb S polymerises –> fibrous network –> cell stiffens and distorts –> blocks capillaries –> anoxia –> pain –> death

50
Q

What is methemoglobinemia?

A

Fe2+ oxidised to Fe3+
NADH methaemoglobin reductase reverses this reaction and keeps Fe2+, other antioxidants eg ascorbic acid and glutathione
If enzyme is lacking  blue baby syndrome, “Chocolate cyanosis”

51
Q

WHAT ARE THE CAUSES OF METHAEMOGLOBINEMIA?

A

Causes : Drugs, nitrates, reactive oxygen species, mutations in globin genes  HbM, NADH-methaemoglobin reductase deficiency

52
Q

WHAT ARE THE SYMPTOMS OF METHEMOGLOBINEMIA?

A

Symptoms: Hypoxia, Anxiety, headache, dyspnea

53
Q

WHAT IS THE TREATMENT OF METHEMOGLOBINEMIA?

A

Treatment: methylene blue, ascorbic acid

54
Q

WHAT IS THALASSEMIA?

A

Imbalance in the synthesis of α- and β- globin chains

Most common gene disorders

Mutations –> single deletions, substitutions, multiple substitutions/deletions

55
Q

WHAT IS THALASSEMIA CLASSIFIED BASED ON?

A

Classified by:
>no globin synthesis
>some chain synthesis
>reduced chain synthesis

56
Q

SO WHAT ARE THE CLASSIFICATIONS OF THALASSEMIA?

A

alpha-thalassemia: relative/ absolute deficiency of alpha chains

beta-thalassemia: relative/ absolute deficiency of beta chains

Thalassemia minor: heterozygous alpha or beta thalassemia (mild anaemia)

Thalassemia major: homozygous alpha or beta thalassemia (severe anaemia)

57
Q

WHAT IS MICROCYTIC HYPOCHROMIC ANAEMIA?

A

-cause by impaired Hb synthesis

RBC abnormally small (microcytic) and Hb content reduced (hypochromic)

It May be caused by :-
Thalassemia
Vitamin B6 deficiency
Iron deficiency (most common)

58
Q

WHAT IS MACROCYTIC ANAEMIA ?

A

AKA megaloblastic anaemia

Abnormally large RBC in peripheral blood (macrocytes)

Reduced number of erythrocytes

Caused by conditions that impair DNA replication in the bone marrow I.E., *Folic acid and Vitamin B12 deficiency

Theme 2.1 Medical Biochemistry (1 decks)

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