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Chronic Disease > Copper Homeostasis And Disease > Flashcards

Copper Homeostasis And Disease Flashcards

1
Q

What are the 3 targets of copper in a human cell

A

The Tgn, sod1 in cytosol and mt, COX in mt

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2
Q

What is the chaperone at the tgn and what does it deliver cu to

A

Atox1
Atp7a (in all but liver cells) and atp7b

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3
Q

The chaperone in mt is unknown. What is the one delivering sod1

A

Ccs

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4
Q

What does excess cu bind

A

Metallothiopeines (regulated by mtf)

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5
Q

What importer is major for copper and where is it

A

Ctr1
Found in vesicles and plasma membrane

The apical side of eneterocutes for absorption
Baso lateral for liver from the blood

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6
Q

What 2 ways is ctr1 regulation (down reg in how cu)

A

Sp1 transcription factor

Internalisation through methionine residues

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7
Q

What does the sp1 do in high cu

A

Zinc displaced by copper. This stops it binding dna for ctr1 txn

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8
Q

How does sp1 bind dna

A

Zinc finger so when zinc displaced conformation isn’t corrrct

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9
Q

Where is ccs located

A

Intermembrane space next to sod1

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10
Q

What does the unknown copper chaperone in mt deliver cu to first which transfers to next chaperone till it gets to COX

A

Cox17 chaperone

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11
Q

What does cox17 transfer cu to which make up the 2 copper sites in cox enzyme

A

Sco1 and cox11

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12
Q

What is needed for ccs to fully transfer cu to sod1

A

Form a disulfide bond in the sod1

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13
Q

Is the copper sensing mechanism known

A

No. Unlike fe system

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14
Q

How do we know regulation exists then

A

When ctr1 was deleted in heart heart starved of cu

Found high cu levels in serum showing enterocytes increased export
And also reduced cu in liver showing increased export out of liver

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15
Q

How was this increased export achieved

A

Increased atp7a levels (even when normally not expressed in liver as much)

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16
Q

Why is cu needed during hypoxia

A

It is used as a cofactor for fe oxidases, so to make heme you need the ferrous fe form and so cu needed

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17
Q

What’s the difference between atp7a and b transporters action

A

Atp7a needed in cells like enterocytes to in excess deliver cu from tgn to the membrane into bloodstream

Atp7b needed more in liver, when cu received from blood stream, excess exported from tgn to canicular membrane (bile excretion)

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18
Q

What do they do in the tgn

A

Incorporate cu into the enzymes/proteins

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19
Q

What do they use to transport cu

A

Atp

They are p type ATPases

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20
Q

Explain the structure

A

Channel forming helices
Activation domain
Phosphorylation domain
Nucleotide binding domain

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21
Q

What do they have on their n terminus

A

6 metal binding domains (cysteine rich) - binds cu

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22
Q

Where does atox deliver cu to

A

The 6 mbd sites

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23
Q

What happens when mbd are full

A

A cu will be transferred to the cpc motif opening the pore

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24
Q

What happens before conformational change so channel entrance closes but exit opens

A

Phosphorylation - N domain binds atp and phosphate transferred to the P domain

25
Q

What dephosphorylates p domain allowing channel back to basal state

A

A domain

26
Q

What happens when cu levels drop again

A

Recycled back to the tgn

27
Q

Which residues on the c terminus allow retrieval back

A

Leucine

28
Q

Where does atp7b transfer cu post Golgi

A

Sub apical vesicles associated with the bile duct membrane

29
Q

What in the atp7b is there not in 7A which specifically allows this apical targeting and also retention back to tgn (other than leucine sites)

A

The 9 aa within The 63 aa sequence on amino terminal

30
Q

What happens when there’s a mutation in the 9 aa n terminal

A

Baso lateral localisation instead of apical, and scattered through cytosol not tgn

31
Q

Why are kinases speculated to play a regulation role in these atpases

A

They are commonly phos on their serine residues. ESP when cu is low at the tgn stopping exit

32
Q

What is menkes diseased

A

X linked recessive mutations in the atp7a (over 400 mutations)

33
Q

What does severity depend on

A

If the mutation causes complete loss of action

34
Q

Give some symptoms

A

Neurone degeneration, kinky hair

35
Q

Explain the pathogenesis

A

Firstly, a lot of cu lost in diet as no export of it out of enterocytes into blood
Starves cells

36
Q

Where else does cu accumulate other than intestines

A

Brain because has a lot of atp7a dependant movement

37
Q

Where does cu from vlood enter brain

A

Endothelial cells of the BBB

38
Q

What does atp7a move cu to from the BbB cells in normal conditions

A

Astrocyte cells which then transfer to neurones

39
Q

Which cells hve atp7a to pump excess cu out of brain to blood via csf-b barrier

A

The choroid plexus (blocked movement back to blood 6

40
Q

Why is normal movement of cu to synaptic gap needed via atp7a

A

Binds nmda receptor to block it needed for synaptic plasticity and neurone development

41
Q

What does it mean when nmda is active constantly in Menkes

A

Neurone degen and seizures

42
Q

What sort of enzymes are starved due to no action of atp7a at the tgn

A

Cox
Sod
Ceruloplasmin (fe oxidase)
Lox- collagen cross linking

43
Q

Why would blocking sulhydryl oxidase cause kinked hair

A

Causes keratin cross linking

44
Q

Classical menkes is severe loss of function mutations even deletions. What is the name for milder menkes

A

Occipital horn syndrome

45
Q

Is there treatment for classical menkes

A

No they die early due to ceased development and neurone degen

46
Q

How could you diagnose

A

Genotyping
Serum cu levels or ceruloplasmin (low)
By clinical features eg kinky haur

47
Q

What are the treatments for OHS

A

Cu administration
Symptomatic treatment

48
Q

What is Wilson’s

A

Autosomal recessive of atp7b

49
Q

What does this cause

A

Build up of cu in liver as bile duct excretion is impaired

Also then spreads via blood to brain, kidney, eyes and deposits of cu

50
Q

How does excess copper cause damage

A

Fenton chemistry

Radicals cause lipid peroxidation, protein and dna damage

51
Q

What would be severe liver symptoms after a lot of radical build up

A

Cirrhosis and fibrosis (hard to treat£

52
Q

Why would waste build up in blood eg ammonia

A

Hepatocytes usually filter blood eg turn ammonia to urea

53
Q

What is build up in eyes called

A

Kayser fisher rings

54
Q

What sort of brain problems does Wilson’s cause and why

A

Builds up in basal ganglia

Cognitive, psychiatric and nervous

55
Q

Why would there be low xeruloplasmin levels in diagnosis

A

Bc atp7b allows tgn incorporation into enzymes like ceruloplasmin

56
Q

How could you treat it

A

Cu Chelators - excrete in urine

Low cu diet

Liver transplant

Zinc acetate- increases MTs

57
Q

Give the most common mutation in atp7b Wilson’s

A

H1069Q

58
Q

What does it do

A

Causes faster degradation in the er so it can’t traffic post Golgi

Due to the mutant binding hsp70

59
Q

Which mutation in the 9aa n terminus causes no apical/bile movement

A

N41A

Chronic Disease (16 decks)

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