7. Copper Metabolism Flashcards
What functions is copper critical for?
Cellular respiration, iron homeostasis, pigment formation, neurotransmitter production, peptide biogenesis
What gives the copper its unique redox nature?
Its electron structure, allows direct interaction with spin restricted dioxygen, allow enzymes which have a copper cofactor to undertake electron transfer reactions
What are the oxidation states of copper ions?
+1 and +2
Give examples of 8 different copper dependant enzymes and what they do
- Ceruloplasmin: A plasma protein ferrooxidase (catalyses ox. of Fe(II)) which transports iron through the blood plasma
- Hephaestin - intestinal ferrooxidase (transports dietary iron from enterocytes into circulatory system)
- Superoxide Dismutase - cytosolic antioxidant defence protecting against oxidative damage
- Extracellular superoxide dismutase
- Amine oxidases - inactivation of bioactive amines
- Lysyl oxidase - cross links collagen/elastin
- Tyrosinase - produces melanin
- Cytochrome C oxidase - complex IV in ETC
Where does most dietary sources of copper come from? What is the average copper intake?
Cereals and meats (27%), and veg (17%)
1.63mg intake - 1.2mg recommended
Which disease causes increased absorption of copper?
Wilson’s disease
Which disease causes decreased absorption of copper?
Menke’s disease
What other things may cause increased/decrease copper absorption?
Increased absorption: low copper intake, human milk, animal protein, fructose
Decreased absorption: high copper intake, cow’s milk, vegetable protein, other metals
In which two ways may copper produce free radicals?
Fenton reaction: O2. + H2O2 + Cu+ –> OH. + O2 + OH- + Fe3+
Ionising (gamma) radiation: causing molecule of water to split into OH. and H.
What is the worst free radical? What’s not so bad about it? :)
OH. is the most highly reactive free radical, will damage anything in it’s vicinity.
It has a small vicinity.
“Every cloud has a silver lining” - Sylvester Stallone
What is a free radical?
An independent species with an unpaired electron
What percentage of the oxygen we breathe becomes free radicals?
1-3%
How does oxidative metabolism lead to production of ROS?
Glucose is completely oxidised to CO2 and H2O to produce ATP - but sometimes electrons leak from the ETC and react with O2 to produce O2. (then react with Cu in fenton reaction to make OH.)
How does a copper-dependent enzyme produce free radical?
Cytochrome P-450 metabolises xenobiotics (foreign chemical substance) to radicals which can react with oxygen to produce superoxide (then react with Cu in fenton reaction)
Which immune system cell produces free radicals?
Macrophages engulf bacteria and produce O2.- and H2O2 which then react with Cu/Fe 2+, undergo the fenton reaction and produce the highly reactive hydroxy free radicals
What are some copper associated diseases and their causes?
Dietary lack of copper: Copper fever, indian childhood cirrhosis, tyrollean infantile cirrhosis
Defective copper metabolism: idiopathic copper toxicosis
Lack of bioavailable copper to brain: Alzheimers disease
Lack of caeruloplasmin (major copper/iron carrying protein in blood): Acaeruloplaminaemia
What are the genetics, symptoms, copper levels and treatment for Wilson Disease?
Genetics: Autosomal recessive
Symptoms: Basal ganglia symptoms, liver disease
Copper Levels: Serum copper levels low and liver copper levels high
Treatment: Chelation
What are the genetics, symptoms, copper levels and treatment for Menkes syndrome Disease?
Genetics: X-linked
Symptoms: Grey matter degeneration, abnormal/kinky hair hypothermia
Copper Levels: Serum copper low, liver copper lower
Treatment: None
What are the genetics, symptoms, copper levels and treatment for acaeruloplasminae Disease?
Genetics: Autosomal recessive
Symptoms: Adult onset dementia, dystonia, diabetes, renal degeneration
Copper Levels: Serum copper low, liver copper higher
Treatment: None
How does copper cause damage in Wilson disease?
Copper excess in liver causes build up of copper in neurones which leads to motor neurone degradation
Where is copper absorbed in the body? Where is it transported form there?
- Copper absorbed in stomach/duodenum
- Transported to liver whilst bound to albumin
- Exported to blood (from liver)
- Bound to caeruloplasmin
What genes does Menkes disease affect?
ATP7A gene mutation - this is an ATP copper transporter responsible for Cu uptake into kidney
What genes does wilson disease affect?
ATP7B gene mutation - causes the liver to produce new blood vessels so excessive amount of blood/copper goes into other organs
How does copper traverse from the apical side of the intestine to the blood?
- Cu Reductase reduces Cu2+ to Cu+
- hCTR1/DMT1 take up Cu+/Cu2+ respectively
- Copper travels from hCTR1/hCTR2/DMT1 to ATOX1 chaperone proteins
- ATOX1 takes copper to trans-golgi network where it forms vesicle with ATP7A
- The ATP7A/ATOX1/Copper vesicle is transported to the membrane where it may travel into the blood
What is the role of metallothionine?
Picks up any excess copper that isn’t picked up by ATOX1, high binding affinity
How is the uptake of copper regulated in the intestine?
Hormones/copper/drugs can cause transcriptional changes in the cells leading to hCTR1 being taken in from surface in a vesicle (if too much copper in cell) and increased ATP7A/ATOX1 transcription which excrete copper.
Metallothionein may also act as a buffer, binding extra copper present in the cell. It is regulated by MTF-1 (transcription factor) which is activated by high zinc levels leading to greater MT transcription .
What is the role of metallothionein?
Binding copper/zinc
How many zinc/copper atoms can metallothionein bind?
7 zinc/copper atoms
Give two examples of serum copper binding proteins? What do they do?
Albumin and macroglobulin - bind and transport copper
What are the family of copper importers known as? What substrate do they take up? Describe their structure
Ctr (e.g. hCTR1, hCTR2)
Cu(I)
Small proteins containing 3 transmembrane domains, the N-terminal motif contains Met motifs
What would a copper chaperone do? Give an example
Bind copper with high affinity and deliver it to a specific target protein
ATOX1 delivers copper to ATP7A and ATP7B (ATPase transporters)
Where do the ATPase transporters/chaperones (ATP7A, ATP7B, CCS, Cox17) transport copper to?
ATP7A: delivers copper to copper dependent enzymes in secretory pathways
ATP7B: directs copper incorporation into caeruloplasmin (ferrooxidase- iron/copper storage protein)
CCS: Donates copper to SOD1 (cu, zn superoxide dismutase)
Cox17: delivers copper to cytochrome oxidase
Which four proteins may the copper go to after being imported into a cell by hCtr1?
COX17, CCS, ATOX1/HAH1, Metallothionein pool
Which proteins is used to eliminate excess copper?
Metallothioneins - scavenge/store metals
ATP7’s - eliminate excess copper (particularly ATP7B in liver)
How does transcription of metallothionein vary with metal load? What else may it respond to?
Usually expressed at basal levels but increased heavy metal amount strongly induces transcription.
Will also response to oxidative stress, ionising radiation & stress
How does copper affect MTF (metallothionein transcription factor) expression?
MTF1 is constitutively expressed producing MTF1. MTF1 binds close to the promoter of Metallothionein (MT) and the Ctr1B promoter.
At low copper levels, most MTF1 is exported from the nucleus so it cannot bind to MT promoters and initiate transcription. The remaining MTF1 is bound to MREs (metal response element) upstream of the Ctr1B gene. This up regulates Ctr1B - allowing more copper import into cell. Less MT is produced so less copper stored = overall copper increase in cell.
At high copper levels more MTF-1 is exported into the cell. These are able to bind to the MT promoters and initiate/upregulate MT transcription. A red thing binds the MTF-1’s present on the MRE upstream of Ctr1B and down regulates Ctr1B transcription.
