Chemistry & Biological Role
Closed d-shell Lewis acid — activates water, stabilises protein folds, gates ion channels
Zinc is the only metal represented in all six enzyme classes (oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases). Its d¹⁰ configuration makes it redox-inert — unlike copper and iron — but an exceptionally strong Lewis acid. It polarises bound water to generate Zn-OH nucleophiles (carbonic anhydrase, carboxypeptidase), stabilises tetrahedral coordination geometries (alcohol dehydrogenase, insulin hexamer), and anchors DNA-binding zinc-finger folds.
Key Catalytic Sites
| Enzyme | Zinc Role | Reaction / Significance |
|---|---|---|
| Carbonic anhydrase II | Zn-OH nucleophile | CO₂ + H₂O → HCO₃⁻ + H⁺; ~10⁶/s; RBC acid-base, proximal tubule, brain |
| Carboxypeptidase A | Water activation | Pancreatic exopeptidase; C-terminal hydrolysis |
| Alcohol dehydrogenase | Catalytic + structural Zn | Ethanol → acetaldehyde; retinol metabolism |
| Matrix metalloproteinases | Active-site Zn²⁺ | ECM degradation; wound healing; tumour invasion |
| Cu/Zn-SOD1 | Structural stabiliser | O₂•⁻ → H₂O₂; SOD1 mutations cause familial ALS |
Zinc-Finger Proteins
~2,500 human proteins use Cys/His-coordinated Zn²⁺ to fold stable domains:
- C2H2 Krüppel (WT1, Sp1, CTCF) — sequence-specific DNA binding
- RING domain (BRCA1, MDM2) — E3 ubiquitin ligase scaffolds
- LIM domains (FHL, zyxin) — protein-protein interaction hubs
- GATA factors (GATA-1, GATA-3) — haematopoiesis and T-cell development
- Nuclear hormone receptors (GR, ER, AR) — ligand-gated transcription
Insulin Hexamer Formation
2 Zn²⁺ coordinate 6 × His10 (B-chain)
↓
Hexameric insulin in secretory granule (T₆ / T₃R₃ / R₆)
↓
~10× more stable than monomer → dense packing in granule
↓
Exocytosis: Zn²⁺ dissociates → bioactive monomer / dimer
↓
Released Zn²⁺ → paracrine signalling to α-cells
→ portal pulse → hepatic insulin sensitivity
Clinical: NPH, glargine exploit hexamer stability for slow-release
Absorption, Transport & Homeostasis
ZIP importers, ZnT exporters, metallothionein buffer
DIETARY ZINC (duodenum / proximal jejunum):
Phytate/oxalate → chelation → ↓ bioavailability (plant-based diets)
Animal protein → competitive chelation release → ↑ absorption
Apical import: ZIP4 (SLC39A4) — primary route (mutated in AE)
ZIP8 — additional uptake; Mn²⁺ co-transport
↓
Intracellular: Metallothionein-1/2 (Cys-rich, 7 Zn²⁺/molecule)
MT induction by IL-6 → zinc sequestration in infection
↓
Basolateral: ZnT1 (SLC30A1) → portal vein
↓
Plasma: ~70% albumin-bound (Cys34 + His67)
~18% α2-macroglobulin
~12% free / amino acid complexes
Normal: 70–120 μg/dL (11–18 μmol/L)
↓
Excretion: Pancreatic secretions ~3–5 mg/day (primary)
Intestinal sloughing; urine/sweat (minor)
Key Transporters
| Transporter | Direction | Tissue | Clinical Note |
|---|---|---|---|
| ZIP4 (SLC39A4) | Import (apical) | Intestine, kidney | LOF → acrodermatitis enteropathica |
| ZnT1 (SLC30A1) | Export (basolateral) | Ubiquitous | First characterised zinc exporter |
| ZnT8 (SLC30A8) | Granule loading | Pancreatic β-cell | T2DM risk allele Arg325Trp; ZnT8A autoantibodies in T1DM |
| ZnT3 (SLC30A3) | Vesicle loading | Brain mossy fibres | Synaptic zinc release; NMDA modulation |
| ZIP8 (SLC39A8) | Import | Lung, brain, placenta | Mn²⁺/Zn²⁺ co-transport; immune cells |
Immune Function & Signalling
Thymulin activation, zinc spark at fertilisation, synaptic Zn²⁺
| Cell / Context | Zinc Function | Deficiency Effect |
|---|---|---|
| T cells / Thymus | Thymulin (nonapeptide + Zn²⁺) drives T-cell maturation; IL-2R expression | Thymic atrophy; lymphopenia; ↓ CD4⁺/CD8⁺ |
| Macrophages | Zn²⁺ burst inside phagosome kills pathogens (Zn toxicity) | ↑ intracellular pathogen survival |
| NK cells | Perforin/granzyme expression; ADCC | ↓ NK cytotoxicity |
| B cells | BCR signalling; AID for class switch recombination | ↓ antibody diversity; IgM dominant |
| Oocyte (fertilisation) | "Zinc spark" — ~10⁹ Zn²⁺ atoms released in milliseconds; ZP3 cross-linking blocks polyspermy | Fertilisation failure in severe deficiency |
| Hippocampal synapse | ZnT3-loaded mossy fibre vesicles release Zn²⁺ → NMDA/AMPA receptor modulation; LTP co-factor | Impaired memory consolidation |
Pathology
Deficiency, toxicity, genetic disorders
Acrodermatitis Enteropathica
Autosomal recessive LOF in ZIP4 (SLC39A4). Triad after weaning: periorificial/extremity dermatitis, alopecia, diarrhoea. Serum zinc <60 μg/dL. Treatment: oral zinc sulfate 1–3 mg/kg/day lifelong.
Acquired Zinc Deficiency
Global prevalence ~17% (WHO). Risk: plant-heavy diets (phytate), alcoholism, IBD, short-gut, elderly. Features: hypogonadism, growth failure, impaired wound healing, ageusia/hyposmia, night blindness, lymphopenia.
Zinc Toxicity
UL 40 mg/day. Acute: nausea/vomiting (>200 mg). Chronic >150 mg/day: copper deficiency (competition at ZIP transporters) → sideroblastic anaemia, myelopathy. Denture adhesive creams historically caused copper deficiency neurological syndrome.
ZnT8 & Diabetes
Anti-ZnT8 autoantibodies in 60–70% of T1DM at diagnosis (5-Ab panel: IA-2, IAA, GADA, ZnT8A, ICA). ZnT8 Trp325 allele (rs13266634) is a T2DM GWAS risk hit — reduced β-cell zinc loading impairs insulin granule formation.
SOD1 Mutations — ALS
Cu/Zn-SOD1 mutations (A4V, G93A, H46R; >200 known) cause familial ALS (~20% fALS). Zinc loss weakens SOD1 dimer interface → misfolding and toxic gain-of-function aggregation. Tofersen (ASO) approved 2023 for SOD1-ALS.
Clinical Uses
AMD, common cold, diarrhoea, Wilson disease
| Indication | Evidence / Dose | Notes |
|---|---|---|
| Zinc deficiency | RDA 8 mg/day (F), 11 mg/day (M); therapeutic 25–45 mg/day elemental | Acetate form best tolerated |
| Age-related macular degeneration | AREDS2: 80 mg zinc oxide + 2 mg Cu + antioxidants | 25% RR reduction in progression to advanced AMD |
| Common cold | Zinc acetate lozenges ≥75 mg/day within 24h of symptom onset | Cochrane: −3 days duration; ionic Zn²⁺ blocks rhinovirus ICAM-1 attachment |
| Paediatric diarrhoea | WHO/UNICEF: 20 mg/day × 10–14 days | ↓ duration 25%, ↓ severity; standard of care LMICs |
| Wilson disease | Zinc acetate 50 mg TID (150 mg/day elemental) maintenance | Induces intestinal MT → sequesters copper; reduces Cu absorption |
| Acrodermatitis enteropathica | 1–3 mg/kg/day lifelong | ZIP4 bypass via alternative absorption routes |
Atlas Connections
- Andreini C et al. (2006). Counting the zinc-proteins encoded in the human genome. J Proteome Res 5(1):196–201.
- Prasad AS (2013). Discovery of human zinc deficiency: its impact on human health and disease. Adv Nutr 4(2):176–190. doi:10.3945/an.112.003210
- AREDS Research Group (2001). High-dose supplementation with vitamins C and E, beta carotene, and zinc for AMD. Arch Ophthalmol 119(10):1417–36.
- Hemilä H & Chalker E (2015). Zinc acetate lozenges on common cold symptoms. PeerJ 3:e1515. doi:10.7717/peerj.1515
- WHO/UNICEF (2004). Clinical management of acute diarrhoea — zinc supplementation joint statement.
- Rink L & Gabriel P (2000). Zinc and the immune system. Proc Nutr Soc 59(4):541–52.
- Chimienti F et al. (2006). ZnT8 as a major zinc transporter in insulin-secreting cells. J Cell Sci 119:4199–4206.