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AP0509 Component 2 Exam > Haemoglobin Structure and Synthesis > Flashcards

Haemoglobin Structure and Synthesis Flashcards

1
Q

Main function of red cells

A
  • carry O2 to tissues and return CO2 from tissues to lungs
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2
Q

What does each molecule of Hb A consist of?

A
  • 4 polypeptide chains, alpha2 and beta2, each with its own haem group
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3
Q

What other 2 Hb’s does normal human blood contain?

A
  • Hb F and Hb A2
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4
Q

What do these other 2 Hb’s contain?

A
  • alpha chains with gamma and delta chains
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5
Q

Where does Haem synthesis occur?

A
  • mitochondria
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6
Q

How does Haem synthesis commence?

A
  • condensation of glycine and succinyl coenzyme A using key rate-limiting enzyme delta-ALA synthase
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7
Q

What is the coenzyme for this reaction?

A
  • pyridoxal phosphate (vitamin B6)
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8
Q

What does protoporphyrin combine with to form haem?

A
  • iron in the ferrous state
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9
Q

Haemoglobin molecular structure

A
  • tetramer of 4 globin chains each w/ own haem group
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10
Q

What percentage of RBC volume and dry weight does Hb occupy?

A
  • 33% RBC volume

- 90% dry weight

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11
Q

What 2 major components does a Hb molecule contain?

A
  • globin chain

- prosthetic group Haem, comprising a tetrapyrolle ring structure w/ Fe(II) at its centre

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12
Q

Step 1 of Haem synthesis (ALA formation)

A
  • succinyl CoA + glycine –> alpha amino beta ketoadipic acid
  • CO2 is removed to form ALA
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13
Q

Step 2 of Haem synthesis (PBG/porphobilinogen formation)

A
  • 2 ALAs
  • ALA dehydratase is catalyst
  • H20 removed to form PBG
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14
Q

Step 3 of Haem synthesis (polymerisation of PBG)

A
  • 2 enzymes (PBG deaminase, Uroporphyrinogen III Consynthetase) work in unison
  • 4 PBG form tetrapyrolle ring structure (Urogen III)
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15
Q

Step 4 of Haem synthesis (decarboxylation; acetyl to methyl)

A
  • acetyl side chains converted to methyl groups through CO2 loss
  • 4 CO2 liberated
  • cytoplasmic structure: uroporphyrinogen III decarboxylase
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16
Q

Step 5 of Haem synthesis (conversion of proprionyl to vinyl)

A
  • oxidative decarboxylation and dehydrogenation of 2 proprionyl groups, converts them to vinyl groups
  • produces protoporphyrinogen IX
  • enzyme: coproporphyrinogen oxidase
17
Q

Step 6 of Haem synthesis (oxidation, removal of 6H+ atoms)

A
  • mitochondrial enzyme; protoporphyrinogen oxidase
  • responsible for removal of 6 H atoms
  • produces protoporphyrin IX
18
Q

Step 7 of Haem synthesis (insertion of Fe(II) into ring)

A
  • insertion of ferrous, Fe2+ ion into centre of protoporphyrin IX
  • inner mitochondrial enzyme; ferrochelatase or haem synthetase
19
Q

Iron absorption and circulation

A
  • Fe2+ readily absorbed by DMT1 by enterocytes
  • Fe transported by transferrin in plasma to BM or liver
  • transferrin; 76-80kD, carries 2 atoms of Fe3+
  • ferroportin transports Fe out off cells
  • carried more efficiently as Fe3+
  • other carriers include albumin and lactoferrin
  • Fe-Tr complex can only enter developing RBC by binding Transferrin receptor (TfR)
20
Q

Hepcidin

A
  • Movement of Fe into plasma by ferroportin regulated by it
  • Produced by liver
  • 25 amino acid peptide, HAMP gene, chromosome 19
  • Controls export of Fe from; enterocytes, macrophages, Kupffer cells, hepatocytes, placental cells
  • Raised hepcidin- anaemia of chronic disease
21
Q

What is the Embden-Meyerhof pathway?

A
  • glycolysis which converts glucose into pyruvate
  • Free energy released forms ATP
  • Oxygen free
  • Due to lack of mitochondria within mature erythrocytes
22
Q

What stage of red cell development does Hb synthesis occur?

A
  • ~65% during the late normoblast stage

- 35% during the reticulocyte stage after loss of nucleus.

23
Q

What does build up of Haem do?

A
  • inhibits own synthesis and stimulates globin chain production
24
Q

How much Hb does each normal red cell contain?

A
  • 27-32pg
25
Q

What is meant by ineffective erythropoiesis?

A
  • red cell precursor fails to acquire sufficient Hb, so its destroyed before leaving the marrow
26
Q

Primary structure of globin (globin genes)

A
  • derived from 2 families of polypeptides – alpha & beta.
  • Various Hb molecules produced contain 2 globins from each family.
  • Synthesis of the globin chains is under control of globin genes, reside on the long arms of chromosomes 11 and 16
27
Q

Globin genes

A
  • between the active genes in these clusters are non-functional ‘pseudogenes’
  • Two are duplicated; gamma and alpha.
  • One gamma gene codes for alanine at position 136, the other coding for glycine at the same position.
  • a chain gene is duplicated but both are identical and active.
28
Q

Secondary structure of globin

A
  • 75% of a and b globin chains are in form of a-helices
  • All functional Hb molecules have this same helical content – 8 helices labelled A –> H.
  • Remaining 25% of residues are in linear portions which connect the helices.
29
Q

Tertiary structure of globin

A
  • Haem group of each globin chain sits deep in a hydrophobic pocket or crevice between E and F helices.
  • Proline residues within the linear portions of the globin give the chain necessary flexibility to take up its complex globular shape.
30
Q

What does alteration in amino acid composition in Hb?

A
  • may make Hb less stable and liable to precipitation.

- Precipitated Hb within a red cell renders it useless as an oxygen carrier and causes premature red cell destruction.

31
Q

Glucose-6-phosphate dehydrogenase

A
  • converts glucose-6 phosphate to 6-phosphoglucono-d-lactone and maintains NADPH
  • G6PD deficiency can lead to lack of NADPH to maintain reduced glutathione to combat oxidant stress imposed on the cell
  • Heinz Bodies; contain denatured Hb caused by oxidant damage
  • Haemolytic anaemias
32
Q

Structural contacts in a quaternary structure in globin

A
  • Monomers held together by hydrophobic bonds between adjacent areas of the polymer.
  • The monomers interact across various planes of contact.
  • contacts mainly involve the B and H helices.
  • These strong interactions stabilize the molecule and prevents dissociation of the a1b1 and a2b2 dimers into free monomers
33
Q

Functional contacts in quaternary structure in globin

A
  • The a1b2 and a2b1 contact planes are less extensive.
  • Only 9 residues from either chain are involved.
  • Involves contacts between C helix and the F-G corner
34
Q

Functional contacts in O2 binding

A
  • allow conformational changes of the molecule when the oxygenation state of Hb is changed.
  • Deoxygenated Hb has the Fe(II) sitting slightly above the plane of the haem moiety.
  • The haem is slightly concave due to interaction with F8
  • Oxygenation leads to the movement of the Fe(II) into the plane of the porphyrin group.
  • Fe(II) now sits within the plane of the porphyrin ring
  • Simultaneous changes in the conformation of parts of the globins occurs.
35
Q

What makes Hb an allosteric protein?

A
  • Changes in shape of tetramer facilitate O2 uptake and release under physiological conditions.
  • F helix and haem groups swing towards the centre of the molecule.
  • Methaemoglobin (MetHb) contains Fe3+ in Haem. Cannot bind/exchange oxygen. MetHb Reductase pathway ensures MetHb is converted back into functional Hb
36
Q

2,3-Biphosphoglycerate (2,3-BPG)

A
  • binds to the b chains in the middle of the tetramer.
  • combines with deoxyHb; reduces affinity of Hb for O2.
  • Reversibly bound, altering the conformation of the Hb molecule, facilitating O2 release.
  • O2 dissociation curve for Hb is shifted to the right-lower affinity.
  • The greater the level of 2-3 BPG the more O2 is released from the Hb.
37
Q

Factors that affect the release of O2 from Hb

A
  • pH
  • temperature
  • PCO2
  • PO2
  • 2-3 BPG.
38
Q

Foetal Hb

A
  • Foetal Hb (HbF), has a higher affinity for O2 because it cannot bind 2-3 BPG strongly.
  • Allows HbF to carry 20-30% more O2 than maternal HbA at a particular PO2
  • HbF preferentially takes O2 from maternal Hb across the placental membranes.

AP0509 Component 2 Exam (21 decks)

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