Phosphate homeostasis
Editor-In-Chief: Henry A. Hoff
Overview
In the extracellular region near the plasma membrane, portions of membrane-associated molecules wait to capture phosphate and transport it into the cell. The phosphate may occur as inorganic orthophosphate particles or be part of an organic molecule (organophosphate). Bringing phosphate in any form into the cell and when needed transporting phosphate out of the cell is a necessary activity of phosphate homeostasis for that cell.
Introduction
Due to its high reactivity, phosphorus is never found as a free element in nature. Phosphates are found pervasively in biology. Phosphate is a component of DNA and RNA and an essential element for all living cells. Phosphate metabolism is the complete set of phosphate chemical reactions that occur in living cells. Phosphorus (as phosphate usually) is often a limiting nutrient in many environments; i.e. the availability of phosphorus governs the rate of growth of many organisms. Living cells also use phosphate to transport cellular energy via adenosine triphosphate (ATP). Nearly every cellular process that uses energy obtains it in the form of ATP. Inside a cell, phosphate may be structural to a nucleic acid or phospholipid, form high-energy ester bonds (e.g., in adenosine triphosphate), or participate in signaling. Outside the cell, phosphate may be dissolved in extracellular fluid (ECF) or form structures such as bone and teeth.
In medicine, low phosphate syndromes are caused by malnutrition, by failure to absorb phosphate, and by metabolic syndromes which draw phosphate from the blood or pass too much of it into the urine. All are characterized by hypophosphatemia (see article for medical details). Symptoms of low phosphate include muscle and neurological dysfunction, and disruption of muscle and blood cells due to lack of ATP.
In ecosystems an excess of phosphorus can be problematic, especially in aquatic systems, see eutrophication and algal blooms.
Bringing phosphate in any form into the cell and when needed transporting phosphate out of the cell is a necessary activity of phosphate homeostasis for that cell. An organism that can regulate its internal environment so as to maintain equilibrium has the property of homeostasis. ATP is important for phosphorylation, a key regulatory event in cells.
Homeostasis
Homeostasis is a relatively stable state of equilibrium or a tendency toward such a state of an open or closed system, especially a living organism. An organism that can regulate its internal environment so as to maintain equilibrium has the property of homeostasis.
Phosphate
A phosphate can occur as a salt of phosphoric acid or an ester of phosphoric acid (an organophosphate). Phosphates are found pervasively in biology. Phosphorus (as phosphate usually) is an essential macromineral for plants, which is studied extensively in soil conservation in order to understand plant uptake from soil systems. In ecological terms, phosphorus is often a limiting nutrient in many environments; i.e. the availability of phosphorus governs the rate of growth of many organisms. In ecosystems an excess of phosphorus can be problematic, especially in aquatic systems, see eutrophication and algal blooms.
Inside a cell, phosphate may be structural to a nucleic acid or phospholipid, form high-energy ester bonds (e.g., in adenosine triphosphate), or participate in signaling.
Outside the cell, phosphate may be dissolved in extracellular fluid (ECF) or form structures such as bone and teeth.
Extracellular fluid (ECF)
Extracellular fluid usually denotes all body fluid outside of cells. It is frequently contained within organs. The skin, for example, is an organ often referred to as the largest organ of the human body as it covers the body, appearing to have the largest surface area of all the organs. But it is a major container for ECF and other organs. ECF includes interstitial fluid (ISF) and transcellular fluid (TCF).
Cardiovascular systems are usually closed, meaning that the blood never leaves the network of blood vessels. In contrast, oxygen and nutrients diffuse across the blood vessel layers and enter interstitial fluid (ISF), which carries oxygen and nutrients to cells, and carbon dioxide and wastes in the opposite direction. Also, the digestive system, which contains TCF, works with the cardiovascular system to provide the nutrients the system needs to keep a heart, when present, pumping.
Phosphatidate
Lysophosphatidic acid (LPA) is an intermediate in the synthesis of phosphatidic acid (PA). ENPP2 functions as a phospholipase, which catalyzes the transformation of lysophosphatidylcholine into LPA in ECF.[1] LPA has been detected in plasma, ascitic fluid, follicular fluid, and aqueous humor.[1]
Orthophosphate (Pi)
The level of inorganic orthophosphate (Pi) is tightly balanced inside the cell and in the whole vertebrate organism.[2] The concentration of free Pi is balanced in the millimolar range in ICF and ECF.[2] Bacteria, yeast, plants, and vertebrates have developed their own strategies to control Pi homeostasis.[2] The daily need for Pi is covered by intestinal absorption from the diet, the major storage compartment is bone, and the metabolic and structural intracellular need is met in part by phosphate cotransporters.[2] The ECF concentration of Pi is controlled by tightly regulating renal excretion.[2] Principal properties of mammalian renal Pi reabsorption are pH-dependency, regulation by parathyroid hormone (PTH), and Pi availability.[2] These properties are expressed by SLC34A1-3 (sodium-dependent phosphate transporter 2, NPT2), whereas NPT3 (SLC17A2) mediates Na+-dependent Pi transport.[2] NPT1 (SLC17A1) does not have a prominent role in regulating body Pi homeostasis.[2] Insulin stimulates NPT1 expression and Na+/Pi uptake which is reversed by glucagon.[2] NPT3 may have a housekeeping role at the cellular level per its broad range of expression and its ability to adapt to changes in extracellular Pi concentration.[2] The expression of NPT3 is compatible with the presence of other NPT.[2] Members of the NPT1 family are linked with insulin-stimulated glucose metabolism.[2] NPT2 in the kidney and small intestine are responsible for intracellular Pi accumulation in order to establish a transepithelial flux of Pi.[2]
Pyrophosphate (PPi)
PPi occurs in synovial fluid, plasma, and urine at levels sufficient to block calcification and may be a natural inhibitor of hydroxyapatite formation in ECF.[3]
Blood
Blood is a specialized body ECF contained within the cardiovascular system that is composed of blood cells suspended in plasma. Pi occurs in blood, blood plasma and blood serum.[4]
Orthophosphate
A slight increase of pH in blood plasma above 7.4 causes precipitation of calcium phosphate and resulting turbidity, whereas, in the case of blood serum (plasma without clotting proteins) of the same inorganic composition, the pH may vary fairly widely without precipitation occurring.[4]
It is the proteins that tend to keep calcium salts in solution or at least in suspension.[4] Blood serum is supersaturated with tricalcium phosphate from about pH 6.8 up to about pH 9.25, with a maximum dissolution at pH 7.3.[4] The stability of calcium phosphate in suspension may be improved by reduction of phosphate ion in proportion to calcium in the mixture. With increasing alkalinity above pH 6.3 monocalcium phosphate is converted into dicalcium phosphate. At about pH 6.7 tricalcium phosphate begins to form yet remains in suspension in the presence of proteins.
Hydroxide ions and protein exert antagonistic effects on the suspension of tricalcium phosphate so that with increasing alkalinity the size of the suspension depends on the protein concentration present. Increasing serum concentration decreases turbidity. Protein exerts an inhibitory effect on the precipitation of calcium phosphate both by holding it in solution against other physical factors and by supporting it in suspension.[4]
Pyrophosphate
Blood plasma levels of PPi in normal human children can range from approximately 300-700 pmol/µg protein.[5]
Phosphate in
EC 3.6.3.20 is a phosphate-importing enzyme that catalyzes the chemical reaction
ATP + H2O + glycerol-3-phosphateout <=> ADP + phosphate + glycerol-3-phosphatein.
EC 3.6.3.27 is a phosphate-importing enzyme that catalyzes the chemical reaction
ATP + H2O + phosphateout <=> ADP + phosphate + phosphatein.
Orthophosphate
Growth hormone, at least in part mediated by insulin-like growth factor I (IGF-I), stimulates Pi cotransport.[6] Thyroid hormone stimulates Pi absorption via a specific increase in Pi cotransport.[6] Stanniocalcin 1 (STC1) stimulates membrane Pi cotransport.[6]
Phosphaturic factors reduce the expression of Pi transporters or cotransporters in the cell membrane.[7]
Insulin enhances Pi absorption by stimulation of Pi cotransport and prevents the phosphaturic action of parathyroid hormone (PTH).[6] Calcitonin reduces membrane Pi cotransport in a PTH- and cAMP-independent manner.[6]
Some factors that increase Pi absorption increase the number of the transporters or cotransporters in the cell membrane.[7] Knowledge of the mechanisms that control transporter expression and membrane retrieval of the transporters is essential to understanding how Pi homeostasis is achieved.[7]
Physiological regulation of Pi absorption involves, as far as it has been studied at the molecular level, an altered expression of cotransporter protein that is related in most cases to changes in the maximum velocity (Vmax) of Pi cotransport activity.[6]
ISF Pi absorption
PiT1 is likely to be a major carrier of phosphate from ISF into most cell types.[8] Vmax can go approximately from 39 to 121, with ISF phosphate to phosphate-free ISF.[8] Mammaliam cell internal phosphate levels (75 milliequivalents per liter) are maintained at higher levels than ISF (4 milliequivalents per liter) in opposition to an electrochemical gradient that favors phosphateout.[8]
Low ECF Pi levels can result in upregulated PiT1 and PiT2 expression in mammalian cells.[9] PiT1 and PiT2 exhibit positve cooperative Pi uptake. PiT2 supports Na+-independent Pi uptake.[9] Ca2+ or Ca2+ and Mg2+ increase PiT1- and PiT2-mediated NaPi import.[9] Vmax for PiT1 and PiT2 are approximately 453 and 450 pmol·cell1-·h1-, respectively.[9] The average Pi uptake for PiT2 and PiT1 at pH 7.5 is approximately 118 and 115 pmol·cell1-·h1-, respectively.[9] Pi transport has similar average Pi uptake at different pH values: 5.5 to 8.5.[9] The Na+-independent Pi uptake of PiT2 is in acidic ECF conditions.[9] With physiological Na+ concentration in the human body in the range of 130–145 mM, there is always plenty to sustain Pi uptake via PiT1 and PiT2.[9]
Small intestine Pi absorption
A low dietary inorganic phosphate (Pi) intake can lead to an almost 100% absorption of filtered Pi, whereas a high dietary Pi intake leads to a decreased Pi absorption.[6] These changes can occur independent of changes in the ECF concentration of different phosphaturic hormones.[6]
In the upper small intestine Vitamin D3 stimulates Pi cotransport.[6]
Renal Pi reabsorption
NPT2 dominates in renal Pi reabsorption, which is exclusive under non-pathological conditions in the mammalian kidney.[2] Na+ interacts in a cooperative way with NPT2 with a stoichiometry of 3Na+ to 1Pi.[2] Protons (H+) decrease the affinity of NPT2 for Na+.[2]
There is a link between the action of PTH, Pi availability, and renal cell membrane integration/retrieval of NPT2.[2] Changes in dietary Pi content have a major regulatory effect on Pi reabsorption.[10] Dietary Pi restriction is associated with an adaptive increase of the overall capacity for Pi uptake mediated by an increase of Vmax of sodium gradient-dependent phosphate transport.[10] In response to chronic (8 day) dietary Pi restriction, the adaptive increase in sodium-Pi cotransport activity is associated with parallel increases in NPT2 and its mRNA abundances.[10] However, in response to acute (2 h) dietary Pi restriction, the rapid adaptive increase in sodium-Pi cotransport activity is associated with parallel increases in NPT2, but without change in its mRNA abundance.[10]
The role of intracellular NPT2 in the rapid adaptation to dietary Pi is correlated with the localization of the Golgi membrane protein 58 kDa and the lysosomal membrane glycoprotein Igp120, as follows[10]: after chronic adaptation to a high Pi diet, NPT2 is in the subcell membrane portion and perinuclear region where in part it spatially coincides with the Golgi-like compartment but not with the lysosomal compartment. Acute adaptation from a high Pi diet to low Pi leads to depletion of intracellular NPT2, with NPT2 only in the Golgi-like compartment. After chronic adaptation to a low Pi diet, intracellular NPT2 is predominantly localized in the region of the Golgi-like compartment and additional sub cell membrane and central cell portions, with minimal localization to Igp120. Acute adaptation from a low Pi to a high Pi diet leads to increased abundance of intracellular NPT2 in the sub cell membrane and central portions, with considerable spatial localization to the lysosomal compartment.
The chronic adaptive response to a low Pi diet is characterized by an increase in NPT2 mRNA abundance.[10]
Role of microtubules
In the presumable rapid translocation of NPT2 in response to acute administratiion of a low Pi diet, microtubules (tubulin) are involved with upregulation of NPT2 activity and translocation from intracellular compartments in the vicinity of the nucleus to the cell membrane, but uninvolved in NPT2 expression.[10] Regarding response to an acute administration of a high Pi diet after chronic administration of a low Pi, microtubules are not involved in rapid downregulation of NPT2 activity or NPT2 abundance.[10]
The rapid adaptive increase in sub cell membrane NPT2 with chronic feeding of a high Pi diet, after an acute administration of a low Pi diet, is probably mediated by translocation of presynthesized NPT2 to this portion by microtubule-dependent mechanisms.[10]
The targeting of NPT2 to the cell membrane seems to be dependent on the microtubule network.[10]
Role of microfilaments
Microfilaments (actin cytoskeleton) may play a central role in the rapid downregulation of Na+-Pi cotransport.[10] The dependence of endocytosis on intact microfilaments in polarized epithelial cells has been demonstrated.[10]
Organophosphates
Phosphatidic acid phosphatases (PAPs) transport phosphatidic acid (PA), lysophosphatidic acid (LPA), ceramide 1-phosphate (C1P), and sphingosine 1-phosphate (S1P) from ECF through the plasma membrane at different Vmax.[11] Once inside the cell, these PAPs (PPAP2A, PPAP2B, and PPAP2C) hydrolyze each phosphate per EC 3.1.3.4:
a 3-sn-phosphatidate + H2O <=> a 1,2-diacyl-sn-glycerol + Pi.
PPAP2A displays comparable Vmax values for all four substrates, with highest activity for LPA and PA. PPAP2B shows a similarly higher relative Vmax activity with LPA, while PPAP2C displays significantly higher activity with S1P.[11] For some cells PPAP2A may be an ectoenzyme that dephosphorylates PA to form diacylglycerol (DG) prior to DG transport into the cell.[11]
Phosphate exchange
Glycerol phosphate transporter (GlpT) transports glycerol-3-phosphate (G3P) into the cytoplasm and Pi into the periplasm.[12] While GlpT transports between cellular compartments through internal membranes, it can also transport across the cell membrane.[13] GlpT functions for G3P uptake and is driven by a Pi gradient. Periplasmic (or ISF) release of Pi allows its replacement in the substrate-binding site by G3P, which has a higher affinity; on the cytoplasmic side of the membrane, Pi replaces G3P because of its higher cytosolic concentration.[12]
Phosphate out
Orthophosphate
Under normal or steady-state physiological conditions, urinary Pi excretion corresponds roughly to phosphate intake in the gastrointestinal tract, mainly via the upper small intestine.[6] To fulfill Pi homeostasis, i.e., keeping extracellular Pi concentration within a narrow range, urinary Pi excretion is under strong physiological control.[6] In contrast to intestinal Pi absorption, which adjusts rather slowly, renal Pi excretion can adjust very rapidly to altered physiological conditions.[6] Specifically, membrane Pi cotransporter protein content, and thus Pi absorption, responds within hours to alterations in dietary Pi intake.[6]
Parathyroid hormone (PTH) induces phosphaturia by inhibiting Pi cotransport activity.[6] Glucocorticoids increase phosphate excretion by an inhibition of membrane Pi cotransport, independent of an increase in PTH.[6]
Stanniocalcin 2 (STC2) may suppress Pi cotransport.[6]
Pyrophosphate
Cells may channel intracellular PPi into ECF.[5] ANK is a nonenzymatic plasma-membrane PPi channel that supports extracellular PPi levels.[5] Defective function of the membrane PPi channel ANK is associated with low extracellular PPi and elevated intracellular PPi.[3] Ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) may function to raise extracellular PPi.[5]
Phosphate reserves
A well-fed adult in the industrialized world consumes and excretes about 1-3 g of phosphorus per day in the form of phosphate. Per the elemental composition of the "standard man" of 70 kg, phosphorus is 780 g or 1.1%.[14] Of this 1.4 g/kg is present in soft tissue with the remainder in mineralized tissue such as bone and teeth.[15] Only about 0.1% of body phosphate circulates in the blood, but this amount reflects the amount of phosphate available to soft tissue cells. Blood plasma contains orthophosphate (as HPO42-) and H2PO41- in the ratio of about 4:1.[15] With the number of cells in the human body of 10-100 trillion or 1013 to 1014, there is approximately 29-290 x 109 atoms of phosphorus per cell or a concentration on the order of 10-3 units of phosphorus probably as phosphate per cell. As computer simulation has shown the probability of finding a target decreases rapidly with distance and becomes <1% when the starting distance exceeds the target's 10-fold radius,[16] which by assumption of a simple spherical volume would put the target's concentration on the order of 10-3.
The total quantity of ATP in the human body is about 0.1 mole. This ATP is constantly being broken down into ADP, and then converted back into ATP. At any given time, the total amount of ATP + ADP remains fairly constant. The energy used by human cells requires the hydrolysis of 100 to 150 moles of ATP daily which is around 50 to 75 kg. Typically, a human will use up their body weight of ATP over the course of the day.[17] This means that each ATP molecule is recycled 1000 to 1500 times daily, or about once every minute.
PPi-generating nucleoside triphosphate pyrophosphohydrolase (EC 3.1.4.1) activities of a group of ecto-enzymes in the phosphodiesterase nucleotide pyrophosphatase (PDNP) family have been recognized to contribute to the regulation of intracellular and extracellular PPi levels in several tissues.[5]
Intracellular phosphate
Although ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) regulates intracellular PPi concentrations it does not seem to significantly regulate extracellular PPi.[5]
Extracellular phosphate
PPi inhibits hydroxyapatite deposition in bone and cartilage.[5] Many studies have shown that PPi is a potent inhibitor of calcification, bone mineralization, and bone resorption.[3] Human defects in alkaline phosphatase, an enzyme that degrades PPi, lead to an increase in PPi levels and a severe block in skeletal mineralization.[3] Genetic defects in a cell surface ectoenzyme that normally generates extracellular PPi from nucleotide triphosphate cause ectopic mineralization of joints and ligaments and may be associated with spinal ligament ossification in humans.[3]
Bone
During bone resorption high levels of phosphate are released into the ECF as osteoclasts tunnel into mineralized bone, breaking it down and releasing phosphate, that results in a transfer of phosphate from bone fluid to the blood. During childhood, bone formation exceeds resorption, but as the aging process occurs, resorption exceeds formation.
References
- ↑ 1.0 1.1 Ferry G, Tellier E, Try A, Grés S, Naime I, Simon MF, Rodriguez M, Boucher J, Tack I, Gesta S, Chomarat P, Dieu M, Raes M, Galizzi JP, Valet P, Boutin JA, Saulnier-Blache JS (2003). "Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid synthesis, and activates preadipocyte proliferation. Up-regulated expression with adipocyte differentiation and obesity". J Biol Chem. 278 (20): 18162–9. doi:10.1074/jbc.M301158200. PMID 12642576. Unknown parameter
|month=ignored (help) - ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 Werner A, Dehmelt L, Nalbant P (1998). "Na+-dependent phosphate cotransporters: the NaPi protein families". J Exp Biol. 201 (Pt 23): 3135–42. PMID 9808829. Unknown parameter
|month=ignored (help) - ↑ 3.0 3.1 3.2 3.3 3.4 Ho AM, Johnson MD, Kingsley DM (2000). "Role of the mouse ank gene in control of tissue calcification and arthritis". Science. 289 (5477): 265–70. doi:10.1126/science.289.5477.265. PMID 10894769. Unknown parameter
|month=ignored (help) - ↑ 4.0 4.1 4.2 4.3 4.4 Joseph Csapo (1927). "The Influence of Proteins on the Solubility of Calcium Phosphate". J Biol Chem. 75 (2): 509–15.
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Rutsch F, Vaingankar S, Johnson K, Goldfine I, Maddux B, Schauerte P, Kalhoff H, Sano K, Boisvert WA, Superti-Furga A, Terkeltaub R (2001). "PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification". Am J Pathol. 158 (2): 543–54. PMID 11159191. Unknown parameter
|month=ignored (help) - ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 6.14 6.15 Murer H, Hernando N, Forster I, Biber J (2000). "Proximal tubular phosphate reabsorption: molecular mechanisms". Physiol Rev. 80 (4): 1373–409. PMID 11015617. Unknown parameter
|month=ignored (help) - ↑ 7.0 7.1 7.2 Hernando N, Gisler SM, Pribanic S, Déliot N, Capuano P, Wagner CA, Moe OW, Biber J, Murer H (2005). "NaPi-IIa and interacting partners". J Physiol. 567 (1): 21–6. doi:10.1113/jphysiol.2005.087049. PMID 15890704. Unknown parameter
|month=ignored (help) - ↑ 8.0 8.1 8.2 Kavanaugh MP, Miller DG, Zhang W, Law W, Kozak SL, Kabat D, Miller AD (1994). "Cell-surface receptors for gibbon ape leukemia virus and amphotropic murine retrovirus are inducible sodium-dependent phosphate symporters". Proc Natl Acad Sci U S A. 91 (15): 7071–5. PMID 8041748. Unknown parameter
|month=ignored (help) - ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 Bøttger P, Hede SE, Grunnet M, Høyer B, Klaerke DA, Pedersen L (2006). "Characterization of transport mechanisms and determinants critical for Na+-dependent Pi symport of the PiT family paralogs human PiT1 and PiT2". Am J Physiol Cell Physiol. 291 (6): C1377–87. PMID 16790504. Unknown parameter
|month=ignored (help) - ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 10.11 Lötscher M, Kaissling B, Biber J, Murer H, Levi M (1997). "Role of microtubules in the rapid regulation of renal phosphate transport in response to acute alterations in dietary phosphate content". J Clin Invest. 99 (6): 1302–12. PMID 9077540. Unknown parameter
|month=ignored (help) - ↑ 11.0 11.1 11.2 Roberts R, Sciorra VA, Morris AJ (1998). "Human type 2 phosphatidic acid phosphohydrolases. Substrate specificity of the type 2a, 2b, and 2c enzymes and cell surface activity of the 2a isoform". J Biol Chem. 273 (34): 22059–67. PMID 9705349. Unknown parameter
|month=ignored (help) - ↑ 12.0 12.1 Huang Y, Lemieux MJ, Song J, Auer M, Wang DN (2003). "Structure and mechanism of the glycerol-3-phosphate transporter from Escherichia coli". Science. 301 (5633): 616–20. PMID 12893936. Unknown parameter
|month=ignored (help) - ↑ "Major Facilitator Superfamily".
- ↑ CRC Handbook of Chemistry and Physics (88th ed.). Boca Raton, Florida: CRC Press. 2007–2008. p. 7-18. Unknown parameter
|editor-in-chief=ignored (help) - ↑ 15.0 15.1 Schwartz MK. "Phosphate metabolism". McGraw-Hill Encyclopedia of Science & Technology (9th ed.). 13: 343–4.
- ↑ Guigas G, Weiss M (2008). "Sampling the Cell with Anomalous Diffusion—The Discovery of Slowness". Biophys J. 94 (1): 90–4. doi:10.1529/biophysj.107.117044. PMID 17827216. Unknown parameter
|month=ignored (help) - ↑ Buono MJ, Kolkhorst FW (2001). "Estimating ATP resynthesis during a marathon run: a method to introduce metabolism" (PDF). Adv Physiol Educ. 25 (2): 70–1.
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