Phosphorus is the second most abundant mineral in the human body (after calcium), and it is the foundation of all phosphate-based energy transfer in the body — it is present in the ATP molecule as the terminal phosphate bond that stores the chemical energy that is released during the hydrolysis of ATP to ADP and Pi, in the phosphocreatine molecule as the high-energy phosphate bond that stores the energy for the rapid regeneration of ATP in the muscle and the brain, and in the DNA and RNA molecules as the phosphate groups that form the backbone of the genetic material. The total body phosphorus content is approximately 700g (with 85% in the skeleton, 14% in the soft tissues, and 1% in the blood and the extracellular fluid), and the blood phosphorus level is maintained at 0.8-1.5 mmol/L (2.5-4.5mg/dL) by the regulation of the intestinal absorption (which is controlled by the vitamin D-calcitriol axis), by the renal reabsorption (which is regulated by the PTH and by the FGF23), and by the bone turnover (which releases or deposits phosphorus in response to the systemic signals). When the blood phosphorus level falls below 0.8mmol/L (hypophosphataemia), the ATP synthesis is impaired, the cellular energy charge falls, and the cell cannot perform the metabolic functions that are essential for its survival — producing the muscle weakness, the rhabdomyolysis, the haemolysis, the cardiac dysfunction, and the encephalopathy that are the clinical manifestations of severe hypophosphataemia.
ATP and the Phosphate Group Transfer
ATP is the universal energy currency of the cell — it stores the chemical energy that is released during the catabolic reactions (glycolysis, beta-oxidation, the TCA cycle) and it provides this energy for all of the anabolic reactions and the physiological processes that require energy — including the muscle contraction, the nerve impulse conduction, the active transport, the biosynthesis of proteins, nucleic acids, and lipids, and the cell division. The energy that is stored in the ATP molecule is located in the terminal phosphate bond, which has a large,释放 of free energy upon hydrolysis (approximately -30.5 kJ/mol under standard conditions, and approximately -50 to -60 kJ/mol under the physiological conditions of the cell). This large,释放 of free energy is the consequence of the repulsion between the negatively charged phosphate groups of the ADP and the Pi, and it is this energy that is transferred to the cellular processes that require it. The regeneration of ATP from ADP and Pi is achieved by the oxidative phosphorylation in the mitochondria (which generates approximately 90% of the ATP in the aerobic cell) and by the substrate-level phosphorylation in the glycolysis and in the TCA cycle (which generates approximately 10% of the ATP in the aerobic cell). Both of these ATP regeneration pathways require inorganic phosphate (Pi) as a substrate, and when the Pi availability is low (as it is in severe hypophosphataemia), the ATP regeneration is impaired and the cellular energy charge falls.
The phosphocreatine system is an additional energy storage system in the muscle and the brain that uses the high-energy phosphate bond of phosphocreatine to regenerate ATP rapidly during periods of high energy demand — during the burst of activity that is required for the muscle contraction, the phosphocreatine donates its phosphate group to the ADP to regenerate ATP, providing a rapid source of ATP that bridges the gap between the slower oxidative phosphorylation and the immediate energy demand. The phosphocreatine concentration in the skeletal muscle is approximately 25mM (which is approximately 3-4 times the ATP concentration), and this phosphocreatine reserve is essential for the high-intensity muscle contraction that is required for the sprinting, the weight lifting, and the other forms of intense physical activity. When the phosphorus availability is low (as it is in hypophosphataemia), the phosphocreatine synthesis is impaired, the phosphocreatine reserve is depleted, and the capacity for the high-intensity muscle contraction is reduced — this is the mechanism of the exercise intolerance and the muscle weakness that are the early symptoms of phosphorus deficiency.
Phosphorus and the Bone Mineralisation
Phosphorus is an essential component of the hydroxyapatite crystal that is the mineral component of the bone — the hydroxyapatite is a calcium phosphate crystal [Ca10(PO4)6(OH)2] that gives the bone its compressive strength and its rigidity, and without adequate phosphorus, the bone mineralisation is impaired and the bone is soft and prone to deformity. The skeleton contains approximately 85% of the total body phosphorus, and this phosphorus is continuously exchanged with the blood phosphorus pool through the bone remodelling process (which involves the osteoclast-mediated bone resorption and the osteoblast-mediated bone formation). The regulation of this bone phosphorus exchange is tightly integrated with the regulation of the calcium homeostasis — the calcitriol (the active form of vitamin D) increases the intestinal absorption of both calcium and phosphorus, the PTH increases the renal excretion of phosphorus and the bone resorption of both calcium and phosphorus, and the FGF23 increases the renal excretion of phosphorus and decreases the calcitriol synthesis. This integrated regulation of the calcium and phosphorus homeostasis ensures that the blood levels of both minerals are maintained within the narrow range that is required for the normal bone mineralisation and for the normal function of the soft tissue phosphorus-dependent enzymes.
Practical Application
For general phosphorus supplementation, the evidence-based approach is to consume 700-1,000mg of phosphorus daily from food sources (dairy products, meat, fish, poultry, eggs, legumes, nuts, whole grains), which is approximately the RDA of 700mg daily for adults. The majority of the adult population achieves this intake from a varied diet, and phosphorus deficiency is therefore rare in the general population. However, certain clinical conditions are associated with an increased risk of hypophosphataemia — including the chronic alcoholism, the prolonged parenteral nutrition, the severe burns, the recovery from the malnutrition, and the prolonged use of the phosphate-binding antacids. For the treatment of severe hypophosphataemia, phosphorus supplementation at 0.5-1.0 mmol/kg (approximately 15-30mg/kg) of elemental phosphorus is administered intravenously in the acute hospital setting, and oral phosphorus supplementation at 2-4g daily (as sodium phosphate or potassium phosphate) is used in the outpatient setting. For comprehensive bone health support, phosphorus pairs well with calcium (which is the other primary mineral component of the bone), with vitamin D (which enhances the intestinal absorption of both calcium and phosphorus), and with the weight-bearing exercise programme (which stimulates the bone formation and maintains the bone mineral density).
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