HIS04 Red Cell Metabolism Flashcards Preview

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Flashcards in HIS04 Red Cell Metabolism Deck (14)
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1
Q

Major functions of mature RBC

A

Carrier of oxygen —> effectively deliver oxygen to tissues and cells

2
Q

Oxidative damage to RBC

A
  1. Hb(Fe2+) —(+ O2, H+ (from hydroxonium ion (H3O+)))—> Hb(Fe3+) + ***Superoxide
    —> Superoxide
    —> H2O2 (non-specific oxygen species)
    —> Oxidative damage in RBC

(Hb(Fe2+): Deoxyhaemoglobin; Hb(Fe3+): Methaemoglobin —> cannot bind oxygen)

  1. Neutrophils, Macrophage, Endothelial cells
    —> produce Reactive oxygen species (probably H2O2) (to kill pathogens)
    —> diffuse freely into plasma membrane of RBC
    —> Oxidative damage in RBC
3
Q

***2 major approaches to suppress formation of Methaemoglobin Hb(Fe3+)

A
  1. Chelation of Fe2+ by Histadine residue in Hb (i.e. binding in Porphyrin ring)
    —> ***Histadine residue of Globin blocks access of H+ to participate in Fe2+ oxidation (Steric hindrance)
  2. RBC can protect itself against oxidative damage (**PPP + **Glutathione antioxidant system)
    —> Glucose as source of electrons
    —> Oxidation of G6P by G6PD during Pentose phosphate pathway (PPP)
    —> produces NADPH
    —> **NADPH serves as donor of electrons
    —> Transfer of electrons to **
    GSSG (glutathione disulfide, oxidised form) by **Glutathione reductase (NADPH —> NADH to be recycled again)
    —> **
    GSH (reduced form, carrying electrons)
    —> Reduction of ROS (e.g. H2O2) by antioxidant enzymes (e.g. ***Glutathione peroxidase) (electrons from GSH)
    AND
    —> Inhibit damaging effect of Hydroxyl free radical to lipids, proteins, DNA etc.

簡單而言:
PPP —> NADPH —> donate electron —>
GSSG —(Glutathione reductase)—> GSH (contain electron) —(Glutathione peroxidase)—> Reduction of ROS

(- RBC can produce energy via glycolysis / PPP

  • PPP uses G6P dehydrogenase to oxidise G6P
  • PPP: Glucose —> G6P —> Ribose (for glycolysis / synthesis of nucleotides, unimportant in RBC))
4
Q

Glutathione antioxidant system

A

Glutathione: Tripeptide
- Glutamate + ***Cysteine (most important due to S atom) + Glycine

Oxidised Glutathione (GSSG): Oxidised S atom —> 2 Glutathione dimerised via Disulfide bond —> 2GSH
Reduced Glutathione (GSH): Reduced S atom —> Donate electron for reduction of ROS
5
Q

Adaptation of RBC antioxidant system to high and low oxygen states

A
Lung:
RBC under high O2 partial pressure
—> Hb loaded with O2
—> ↑ chance of oxidation to Hb(Fe3+)
—> ↑ chance of oxidative damage to RBC
—> need more antioxidant capacity
Peripheral tissue:
RBC under low O2 partial pressure
—> ↓ Hb loaded with O2
—> ↓ chance of oxidation to Hb(Fe3+)
—> ↓ chance of oxidative damage to RBC
—> but need to prepare for meeting varying demands for O2 (prepare to unload O2 to tissue)
6
Q

***Expand antioxidant capacity in response to high risk of oxidative damage

A

Spectrin skeleton (cytoskeleton in RBC)
—> Protein framework that gives shape to RBC
—> Anchored to plasma membrane by cluster of ***Band 3 protein

C-terminal region of Band 3 protein
—> contains binding site for **Glycolytic enzymes + **Deoxyhaemoglobin
—> Glycolytic enzymes and Deoxyhaemoglobin compete for same binding sites on Band 3 protein
—> Glycolytic enzymes ***inhibited when bound to Band 3 protein

Competition between Glycolytic enzymes and Deoxyhaemoglobin
—> mediates coupling between O2 level to Glycolytic activity

High oxygen tension (e.g. Lung)
—> ↓ Deoxyhaemoglobin
—> ↑ Glycolytic enzyme bound to Band 3
—> ***↓ Glycolytic activity
—> ***↑ G6P to PPP pathway
—> ↑ NADPH produced
—> Adapts RBC to an environment with high oxidative stress

Low oxygen tension (e.g. Peripheral tissue)
—> ↑ Deoxyhaemoglobin
—> ↓ Glycolytic enzyme bound to Band 3 (displacement of glycolytic enzymes from Band 3)
—> **↑ Glycolytic activity
—> **
↓ G6P to PPP pathway
—> ↓ NADPH produced, ↑ ATP produced
—> enable RBC to respond to demand of O2 by nearby cells + favour unloading of O2

Coordinated changes in Glycolytic and PPP activity at High, Low O2 level
Glucose —(independent of O2 level)—> G6P
—> High O2 —> ↓ G6P to glycolysis —> ↑ G6P to PPP pathway
—> Low O2 —> ↑ G6P to glycolysis —> ↓ G6P to PPP pathway

7
Q

Summary

A
  1. Sequestration of Glycolytic enzymes as a mean to regulate glycolysis in RBC
  2. Relative rates of glycolysis and PPP are ultimately connected to changes in oxygen level in surrounding environment of RBC
  3. Coordinated changes in rates of glycolysis and PPP —> Basis of oxidative defence in RBC
8
Q

***3 mechanisms of adaptation to high demand for O2 in low O2 environment

A
  1. Unloading more oxygen from oxyHb by ***2,3-BPG
    - Evidence that Glycolysis can affect O2-transport function of RBC (apart from cooperative binding of O2 to Hb)
    - Pyruvate kinase deficient RBC
    —> accumulation of special glycolytic intermediate (Later found to be 2,3-BPG)
    —> lower O2 affinity of Hb
  2. ***Increase blood flow to hypoxic region in response to local hypoxia
  3. **Stress erythropoiesis (in lecture 2)
    Hypoxia
    —> ↑ Erythropoietin from Kidneys
    —> ↑ **
    Erythroferrone (ERFE) from ***bone marrow
    —> ↓ Hepcidin from liver
    —> ↓ Degradation of Ferroportin on enterocyte
    —> ↑ Fe availability
    —> ↑ Porphyrin (i.e. Heme)
    —> ↑ Globin synthesis
    —> ↑ Haemoglobin synthesis
    —> ↑ Erythrocyte synthesis in bone marrow
9
Q

Formation of 2,3-BPG

A
Normal glycolysis:
Glyceraldehyde 3-phosphate
—> 1,3-Bisphosphoglycerate (1,3-BPG)
—> 3-Phosphoglycerate (3-PG)
—> 2-Phosphoglycerate

1,3-BPG (支線)
—(Bisphosphoglycerate mutase)—> 2,3-BPG
—(2,3-BPG phosphatase)—> 3-PG

Bisphosphoglycerate mutase:

  • not a regular enzyme in glycolytic pathway
  • shift phosphate position from 1 to 2
  • activated by ***phosphorylation by AMPK (AMP-activated protein kinase)

2,3-BPG phosphatase:

  • not a regular enzyme in glycolytic pathway
  • removal of phosphate from 2,3-BPG

Balance between **Bisphosphoglycerate mutase and **2,3-BPG phosphatase
—> determines [2,3-BPG] in RBC

10
Q

***Interaction between 2,3-BPG and Haemoglobin

A

2,3-BPG preferentially binds to T-state of Hb (∵ central cavity that accommodates 2,3-BPG is reduced in size in R-state Hb)
—> 2,3-BPG ***stabilise T-state Hb
—> ↓ Affinity of Hb for O2
—> shifts O2-binding curve to right (extent of shifting depend on [2,3-BPG])
—> encourage unloading of O2 from Hb

2,3-BPG:

  • ***allosteric regulator for Hb (by changing affinity of Hb for O2)
  • control ***interconversion of Hb between T-state and R-state
11
Q

***2,3-BPG level and Hypoxic conditions

A

Low O2 level stimulate Glycolysis + BPG mutase

High-altitude / Hypoxic conditions:
—> Body Hypoxia

  1. ↑ Glycolytic activity (Glycolytic enzyme: Aldolase)
    —> ↑ Precursor supply (Glyceraldehyde 3-phosphate) + ↑ ATP production
  2. **sCD73 (ecto 5’-nucleotidase) in plasma
    —> sCD73 catalyse **
    breakdown of ATP
    —> ATP —> Adenosine
    —> **Adenosine bind to ADORA2B receptor on RBC membrane
    —> **
    Stimulate AMPK
    —> Stimulate / **Phosphorylate Bisphosphoglycerate mutase
    —> **
    ↑ 2,3-BPG production in RBC
    —> ↓ Affinity of Hb for O2 (indicated by ↑ P50 (pressure required to saturate 50% of Hb))
    —> Shifting O2-binding curve of Hb to right hand side
    —> Favour ***unloading of O2 from Hb
    —> Resolve body hypoxia
12
Q

***Involvement of membrane lipids in O2 release from OxyHb under low O2 condition

A

Sphingomyelin
—(sphingomyelinase)—> Ceramide
—(ceramidase)—> Sphingosine
—(sphingosine kinase)—> ***Sphingosine-1-phosphate (S1P)

High-altitude / Hypoxic conditions
—> ↑ S1P formation
—> S1P **bind to Deoxyhaemoglobin and recruit it to plasma membrane
—> S1P **
facilitate interaction between Deoxyhaemoglobin and Band 3
—> ***Liberate more glycolytic enzymes
—> ↑ Glycolytic activity
—> ↑ 2,3-BPG

13
Q

***Responding to local hypoxia

A

Local hypoxia
—> Local demand of O2 > total O2 carrying capacity of locally present RBC
—> ↑ Glycolysis
—> Secretion of **ATP by RBC
—> Stimulation of **
purinergic receptors on endothelium
—> Signals generated and propagates to upstream arterioles
—> ***Dilatation of arterioles
—> ↑ Blood flow
—> ↑ RBC in local area
—> ↑ O2 delivery to hypoxia regions

14
Q

Overall summary

A
High oxygen tension:
1. Chelation of Fe2+ by Histadine residue in Hb
2. ↓ Deoxyhaemoglobin
—> ↑ Glycolytic enzyme bound to Band 3
—> ↓ Glycolysis, ↑ PPP
—> ↑ NADPH
—> Glutathione antioxidant system
Low oxygen tension:
1. ↑ Deoxyhaemoglobin + ↑ S1P formation + ↑ sCD73 (ATP breakdown)
—> ↓ Glycolytic enzyme bound to Band 3
—> ↑ Glycolysis + ATP breakdown
—> Stimulate AMPK
—> Phosphorylate Bisphosphoglycerate mutase
—> ↑ 2,3-BPG production in RBC
—> Unloading more oxygen
  1. Increase blood flow to hypoxic region in response to local hypoxia
  2. Stress erythropoiesis

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