Atlas One · Atomic · Nonmetal / Energy Carrier / Structural
Period 3, Group 15 — phosphate ester and anhydride chemistry dominate biochemistry
| Property | Value |
|---|---|
| Atomic mass | 30.97 Da (monoisotopic) |
| Dominant oxidation state | +5 (phosphate PO₄³⁻) |
| Plasma phosphate | 0.8–1.4 mmol/L (inorganic; varies with meal) |
| Intracellular phosphate | ~5–10 mmol/L; primarily as ATP/ADP/phosphocreatine |
| Bone mineral | Hydroxyapatite Ca₁₀(PO₄)₆(OH)₂; 85% of body P |
| Dietary sources | Dairy, meat, fish, legumes, whole grains, nuts; phosphate additives in processed foods |
Biological Roles
ATP energy currency, DNA/RNA backbone, phospholipid signalling, protein phosphorylation
ATP Phosphoanhydride Bonds — Energy Currency
Adenosine–P~P~P (ATP — 2 phosphoanhydride bonds)
│
Hydrolysis ΔG ~ −30 kJ/mol (γ-phosphate)
│
┌───────┴───────┐
ADP + Pi AMP + PPi (rapidly hydrolysed → 2 Pi by pyrophosphatase)
Coupled reactions (examples):
Hexokinase: Glucose + ATP → Glucose-6-P + ADP (glycolysis entry)
Aminoacyl-tRNA synthetase: AA + ATP → AA-AMP + PPi (protein synthesis activation)
Myosin ATPase: ATP hydrolysis → cross-bridge power stroke (muscle contraction)
Phosphocreatine (PCr) buffer:
PCr + ADP ⇌ Creatine + ATP (creatine kinase; ΔG ~ −43 kJ/mol)
Short-burst high-power energy store (first ~10 sec of maximal exercise)
DNA/RNA Backbone
The phosphodiester backbone (5′-O–P–O–3′) links nucleotide sugars, conferring a negative charge (~−1 per residue at pH 7). This negative charge: prevents diffusion through membranes; attracts histone positive charges for nucleosome assembly; requires Mg²⁺ for DNA polymerase catalysis.
Phospholipid Signalling
PIP₂ (phosphatidylinositol 4,5-bisphosphate) → PLCβ/γ cleavage → IP₃ (inositol trisphosphate, ER Ca²⁺ release) + DAG (diacylglycerol, PKC activation). PI3K phosphorylates PIP₂ → PIP₃ → Akt/mTOR survival signalling. PTEN dephosphorylates PIP₃ → PIP₂ (tumour suppressor).
Protein Phosphorylation
~500 human protein kinases phosphorylate Ser/Thr/Tyr residues; ~150 phosphatases dephosphorylate. Phosphorylation modifies protein conformation, activity, localisation, and interaction partners. Dysregulated kinases are primary oncogene targets (BCR-ABL → imatinib; EGFR → erlotinib; HER2 → lapatinib).
Absorption & Metabolism
PTH, FGF23, and calcitriol form a hormonal triad regulating phosphate homeostasis
~60–70% of dietary phosphate is absorbed, primarily in the duodenum and jejunum via NaPi-IIb (SLC34A2, apical) and passive paracellular transport. Calcitriol upregulates NaPi-IIb.
| Hormone/Factor | Action on Pi | Mechanism |
|---|---|---|
| PTH | ↓ Renal tubular Pi reabsorption | Internalises NaPi-IIa/NaPi-IIc in proximal tubule via cAMP/PKA; urinary phosphaturia |
| FGF23 (osteocyte) | ↓ Pi reabsorption; ↓ calcitriol synthesis | Binds FGFR1/Klotho; downregulates NaPi-IIa/IIc; inhibits CYP27B1; upregulates CYP24A1 |
| Calcitriol (1,25-OH₂D₃) | ↑ GI Pi absorption; ↑ renal Pi reabsorption | VDR-mediated NaPi-IIb upregulation; supports bone mineralisation |
| Insulin | ↑ Intracellular Pi uptake | Drives cellular anabolism (ATP synthesis, nucleotide synthesis) |
Deficiency & Toxicity
| Status | Serum Pi (mmol/L) | Signs | Treatment |
|---|---|---|---|
| Severe hypophosphataemia | <0.32 | Haemolytic anaemia; respiratory failure (↓ ATP in diaphragm); rhabdomyolysis; encephalopathy; cardiac failure | IV sodium/potassium phosphate |
| Moderate hypophosphataemia | 0.32–0.64 | Muscle weakness; bone pain; osteomalacia/rickets; proximal myopathy | Oral phosphate supplements + calcitriol |
| Refeeding syndrome | Rapid ↓ after glucose reintroduction | Cardiomyopathy, arrhythmia, respiratory failure, seizures | Slow caloric advancement; prophylactic phosphate; multivitamins (thiamine) |
| XLH (X-linked hypophosphataemia) | ↓; FGF23 gain-of-function mutation (PHEX loss) | Childhood rickets; short stature; skeletal deformity; dental abscesses | Burosumab (anti-FGF23 antibody) or conventional Pi + calcitriol |
| Hyperphosphataemia (CKD) | >1.6 (CKD stage 4–5) | Vascular calcification; secondary hyperparathyroidism; renal osteodystrophy; pruritis | Dietary Pi restriction; phosphate binders (sevelamer, lanthanum, Ca²⁺-based); dialysis |
Clinical Use
| Application | Details |
|---|---|
| IV phosphate replacement | Sodium phosphate or potassium phosphate in hypophosphataemia; rate-limited by Ca²⁺ precipitants and venous sclerosis risk |
| Phosphate binders (CKD) | Sevelamer HCl/carbonate (non-absorbable polymer); lanthanum carbonate; ferric citrate (also treats iron deficiency in CKD) |
| Burosumab (Crysvita) | Anti-FGF23 IgG1 mAb; FDA-approved XLH and tumour-induced osteomalacia; SC monthly |
| Phosphodiesterase inhibitors | Sildenafil (PDE5→ ↑ cGMP); milrinone (PDE3→ ↑ cAMP); xanthines (non-selective); phosphodiesterases hydrolyse cyclic nucleotides from ATP/GTP |
Connections
References
- Biber J, Hernando N, Forster I. "Phosphate transporters and their function." Annu Rev Physiol 2013;75:535–550.
- Razzaque MS. "The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis." Nat Rev Endocrinol 2009;5:611–619.
- Imel EA, et al. "Burosumab versus conventional therapy in children with XLH." Lancet 2019;393:2416–2427.
- Crook MA, et al. "The importance of the refeeding syndrome." Nutrition 2001;17:632–637.