BMS3020 L3 Copper and Disease 29/10/18
BMS3020 CHRONIC DISEASE
LECTURE 3 – Molecular Mechanisms Human Copper
Distribution
Important Copper Enzymes:
1. Cellular respiration - cytochrome c oxidase
2. Neurotransmitter biosynthesis - dopamine β-hydroxylase (DA to norepinephrine)
3. Maturation of peptide hormones - peptidyl α-amidating enzyme
4. Free-radical scavenging - superoxide dismutase
5. Cross-linking of elastin, collagen - lysyl oxidase
6. Cross-linking of keratin - sulfhydryl oxidase
7. Melanin production – tyrosinase
8. Iron homeostasis - ceruloplasmin and hephaestin ferroxidases
- Copper has also been implicated in myelination, regulation of the circadian rhythm and may
be necessary for coagulation and angiogenesis.
- Lacking any of these enzymes can lead to illness
- Relatively few copper enzymes, but they are extremely important in processes – especially in
the brain (10% of copper in body)
Human Copper Homeostasis
Figure represents a normal body cell (not enterocyte or hepatocyte). It shows the three pathways of
copper in a human cell:
- IMPORT: Copper enters the cell via two
transporters, CTR1 and CTR2
- CHAPERONE AND TARGET: Copper
becomes associated with one of 3
chaperones:
o Unknown copper chaperone takes
it to mitochondria for use in
respiratory chain, the target being
cytochrome c oxidase (CCO)
o CCS takes it to the enzyme
superoxide dismutase (SOD1)
o Atox1 takes it to the transporters, ATP7A and ATP7B at the TGN for incorporation
into copper enzymes which can then be exported from the cell
- At high copper, the ATP7A/7B transporters translocate with 7A pumping copper into blood
and 7B pump copper into bile
Transcription Factor
REGULATION: CTR1 regulated by Sp1 in response to copper
- CTR1 gene is induced by a copper chelator – when copper levels are low, the transcripts rise
- CTR1 transcript levels are regulated by Sp1 (transcription factor)
TRANSCRIPTION FACTOR SP1 PLAYS AN IMPORTANT ROLE IN THE REGULATION OF COPPER HOMEOSTASIS IN
MAMMALIAN CELLS. SONG IS ET AL. MOLECULAR PHARMACOLOGY. 2008; 74(3) 705-13
1
BMS3020 CHRONIC DISEASE
LECTURE 3 – Molecular Mechanisms Human Copper
Distribution
Important Copper Enzymes:
1. Cellular respiration - cytochrome c oxidase
2. Neurotransmitter biosynthesis - dopamine β-hydroxylase (DA to norepinephrine)
3. Maturation of peptide hormones - peptidyl α-amidating enzyme
4. Free-radical scavenging - superoxide dismutase
5. Cross-linking of elastin, collagen - lysyl oxidase
6. Cross-linking of keratin - sulfhydryl oxidase
7. Melanin production – tyrosinase
8. Iron homeostasis - ceruloplasmin and hephaestin ferroxidases
- Copper has also been implicated in myelination, regulation of the circadian rhythm and may
be necessary for coagulation and angiogenesis.
- Lacking any of these enzymes can lead to illness
- Relatively few copper enzymes, but they are extremely important in processes – especially in
the brain (10% of copper in body)
Human Copper Homeostasis
Figure represents a normal body cell (not enterocyte or hepatocyte). It shows the three pathways of
copper in a human cell:
- IMPORT: Copper enters the cell via two
transporters, CTR1 and CTR2
- CHAPERONE AND TARGET: Copper
becomes associated with one of 3
chaperones:
o Unknown copper chaperone takes
it to mitochondria for use in
respiratory chain, the target being
cytochrome c oxidase (CCO)
o CCS takes it to the enzyme
superoxide dismutase (SOD1)
o Atox1 takes it to the transporters, ATP7A and ATP7B at the TGN for incorporation
into copper enzymes which can then be exported from the cell
- At high copper, the ATP7A/7B transporters translocate with 7A pumping copper into blood
and 7B pump copper into bile
Transcription Factor
REGULATION: CTR1 regulated by Sp1 in response to copper
- CTR1 gene is induced by a copper chelator – when copper levels are low, the transcripts rise
- CTR1 transcript levels are regulated by Sp1 (transcription factor)
TRANSCRIPTION FACTOR SP1 PLAYS AN IMPORTANT ROLE IN THE REGULATION OF COPPER HOMEOSTASIS IN
MAMMALIAN CELLS. SONG IS ET AL. MOLECULAR PHARMACOLOGY. 2008; 74(3) 705-13
1
