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
