Copper
Copper is a d-block transition metal whose redox cycling between Cu⁺ (cuprous) and Cu²⁺ (cupric) is exploited by a suite of critical enzymes spanning aerobic metabolism, antioxidant defence, ECM architecture, and neurotransmitter synthesis. Living cells maintain free Cu at fewer than one atom per cell — all copper is protein-chaperoned — because the same redox chemistry that makes copper catalytically powerful also generates hydroxyl radicals via Fenton-like reactions. Two genetic diseases of copper transport illustrate this precision: Wilson disease (Cu overload in liver/brain) and Menkes disease (Cu deficiency in brain/connective tissue).
Overview & Atomic Properties
| Property | Value |
|---|---|
| Atomic number (Z) | 29 |
| Atomic mass | 63.55 u (⁶³Cu 69.2%, ⁶⁵Cu 30.8%) |
| Electron configuration | [Ar] 3d¹⁰ 4s¹ |
| Oxidation states in biology | Cu⁺ (cuprous, d¹⁰) and Cu²⁺ (cupric, d⁹) |
| Ionic radius | Cu⁺: 77 pm; Cu²⁺: 73 pm |
| Coordination preference | Cu⁺: linear/tetrahedral (thiolate, His); Cu²⁺: square planar (His, Met, Cys) |
| Redox potential (Cu²⁺/Cu⁺) | +0.15 V (free); +0.18 to +0.80 V in blue copper proteins |
| Body total | 80–100 mg; highest in liver (~15 µg/g ww), brain, kidney, heart |
| Plasma copper | 11–24 µmol/L; ~95% bound to ceruloplasmin |
| Dietary sources | Organ meats (liver), shellfish (oysters), nuts, seeds, legumes, dark chocolate |
| RDA | 900 µg/day adults; UL 10,000 µg/day |
Key Copper Enzymes
CYTOCHROME c OXIDASE (Complex IV — terminal ETC electron acceptor)
4 ferrocyt c + O₂ + 8H⁺(matrix) → 4 ferricyt c + 2H₂O + 4H⁺(IMS)
Cu_A binuclear centre (subunit 2): accepts electrons from cyt c
Cu_B (subunit 1) paired with haem a₃: O₂ reduction site
→ Proton gradient → ATP synthase → aerobic ATP production
SOD1 — Cu/Zn superoxide dismutase (cytosol)
2 O₂•⁻ + 2H⁺ → O₂ + H₂O₂ (then catalase → H₂O + O₂)
Cu cycles: Cu²⁺ + O₂•⁻ → Cu⁺ + O₂
Cu⁺ + O₂•⁻ + 2H⁺ → Cu²⁺ + H₂O₂
Zn²⁺ is structural (not redox active)
ALS: SOD1 mutations destabilise fold → aggregation → motor neuron death
CERULOPLASMIN (plasma ferroxidase)
4 Fe²⁺ + O₂ + 4H⁺ → 4 Fe³⁺ + 2H₂O
Essential for iron export: ferroportin exports Fe²⁺ but transferrin
can only bind Fe³⁺ — ceruloplasmin (6 Cu atoms) bridges this gap
Acute-phase protein: rises in inflammation (IL-6 → ↑CP transcription)
LYSYL OXIDASE (LOX — ECM crosslinking)
Peptidyl-Lys + O₂ + H₂O → peptidyl-allysine + H₂O₂ + NH₃
Crosslinks collagen and elastin → tensile strength of blood vessels, bone
Cu deficiency → fragile connective tissue → aortic aneurysm (Menkes)
DOPAMINE β-HYDROXYLASE (DβH — catecholamine synthesis)
Dopamine + O₂ + 2 ascorbate → Norepinephrine + H₂O + 2 dehydroascorbate
Located in vesicle lumen of noradrenergic neurons + adrenal chromaffin
Requires Cu²⁺ + ascorbate; Cu deficiency impairs NE synthesis
Absorption & Metabolism
Intestinal absorption: Dietary Cu²⁺ is reduced to Cu⁺ by brush-border reductase DCYTB. hCTR1 (SLC31A1) — a homotrimeric high-affinity Cu⁺ importer — translocates Cu⁺ into enterocytes. Free Cu is immediately captured by chaperones (ATOX1 → liver-bound Cu; CCS → SOD1; COX17 → mitochondria). ATP7A (Menkes protein) at the enterocyte TGN exports Cu into portal blood; under Cu excess it redistributes to the basolateral membrane to accelerate efflux.
Hepatic handling: Portal Cu²⁺ is extracted by hCTR1; ATOX1 delivers Cu to ATP7B (Wilson protein) at the hepatocyte TGN. ATP7B pumps Cu into secretory vesicles to be incorporated into ceruloplasmin or excreted in bile (primary route — ~80% of excess copper exits via bile → feces). Under excess Cu, ATP7B redistributes to apical vesicles to increase biliary excretion.
Regulation: No hormonal regulation of Cu excretion analogous to hepcidin for iron. Biliary kinetics are the primary homeostatic control. Urinary Cu excretion is small (~50 µg/day) under normal conditions but markedly elevated (>100 µg/day) in Wilson disease.
Deficiency & Toxicity — Wilson & Menkes Disease
| Condition | Gene / Mechanism | Features | Treatment |
|---|---|---|---|
| Wilson disease | ATP7B (chr 13q14.3) loss-of-function → biliary Cu excretion abolished → hepatic Cu accumulation → overflow to brain, kidney, cornea | Liver: steatosis → cirrhosis → acute liver failure. Brain: dysarthria, dystonia, psychiatric symptoms. Eye: Kayser-Fleischer rings (gold-brown corneal ring — pathognomonic in neurological WD). Blood: Coombs-negative haemolytic anaemia in acute crisis | D-penicillamine (chelator); trientine (less SE); zinc acetate (blocks intestinal absorption; maintenance); liver transplantation (curative for hepatic WD). Serum ceruloplasmin <0.20 g/L, urine Cu >100 µg/day, liver biopsy >250 µg/g dry weight |
| Menkes disease | ATP7A (X-linked) loss → Cu accumulates in enterocytes/kidney but depleted from brain and connective tissue | Kinky/steely hair (LOX deficiency → defective keratin crosslinks), neurodegeneration (CcO + DβH deficiency), vascular tortuosity (LOX → fragile elastin), skeletal deformity. Onset ~2–3 months. Death typically <3 years | Subcutaneous copper-histidine early (pre-symptom onset); genetic counselling; most cases detected only after symptom onset (poorer prognosis) |
| Acquired Cu deficiency | Excess zinc (induces intestinal metallothionein → traps Cu), gastric bypass, TPN without Cu, malabsorption | Myeloneuropathy (posterior column > lateral column; mimics B12 deficiency), peripheral neuropathy, normocytic anaemia, neutropenia | Oral or IV copper supplementation; identify and remove cause (excess zinc supplementation is most common) |
| Copper toxicity | Excess ingestion or impaired excretion (cholestasis); UL 10 mg/day | Nausea, vomiting, hepatotoxicity, haemolytic anaemia; Indian childhood cirrhosis from contaminated water in Cu vessels | Chelation; address source |
Connections
References
- Lutsenko S. Human copper homeostasis: a network of interconnected pathways. Curr Opin Chem Biol. 2010;14(2):211-7. doi:10.1016/j.cbpa.2010.01.003 · PubMed 20117040
- Ala A, Walker AP, Ashkan K, et al. Wilson's disease. Lancet. 2007;369(9559):397-408. doi:10.1016/S0140-6736(07)60196-2 · PubMed 17276780
- Berg JM, Tymoczko JL, Stryer L. Biochemistry. 9th ed. W.H. Freeman; 2019.
- Hall JE, Hall ME. Guyton and Hall Textbook of Medical Physiology. 14th ed. Elsevier; 2021.