View source for Phosphate homeostasis

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'''Editor-In-Chief:''' Henry A. Hoff

==Overview==

In the [[extracellular]] region near the [[Cell membrane|plasma membrane]], portions of membrane-associated molecules wait to capture [[phosphate]] and transport it into the [[Cell (biology)|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<ref name=Butterworth>{{ cite journal |author=Butterworth PJ |title=Phosphate homeostasis |journal=Mol Aspects Med. |year=1987 |volume=9 |issue=4 |pages=289-386 |pmid=3302583 }}</ref> for that cell.

==Introduction==

Due to its high reactivity, [[phosphorus]] is never found as a free element in nature. [[Phosphate]]s are found pervasively in biology. Phosphate is a component of [[DNA]] and [[RNA]] and an essential element for all [[living cell]]s. 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 [[Cell signaling|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 [http://en.wikipedia.org/wiki/Ecosystem ecosystems] an excess of phosphorus can be problematic, especially in aquatic systems, see [[eutrophication]] and [[algal bloom]]s.

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 [[Ecology|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 [http://en.wikipedia.org/wiki/Ecosystem 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 [[Cell signaling|signaling]].

Outside the cell, phosphate may be dissolved in extracellular fluid (ECF) or form structures such as [[bone]] and [[Tooth|teeth]].

==Phosphate [[metabolism]]==

With respect to the complete set of phosphate chemical reactions that occur in living cells, there are approximately 1385 such reactions.<ref name=phosphatereactions>{{ cite web |title=DBGET Search Result: REACTION phosphate |url=http://www.genome.jp/dbget-bin/www_bfind_sub?mode=bfind&mode=bfind&max_hit=1000&serv=kegg&dbkey=reaction&keywords=phosphate&page=2 }}</ref> Indeed, concerning polyphosphate there are approximately 10 such reactions.<ref name=polyphosphatereactions>{{ cite web |title=DBGET Search Result: REACTION polyphosphate |url=http://www.genome.jp/dbget-bin/www_bfind_sub?mode=bfind&mode=bfind&max_hit=1000&serv=kegg&dbkey=reaction&keywords=polyphosphate&page=1 }}</ref>

In pyrimidine metabolism, EC 3.6.1.2 (trimetaphosphatase) can convert trimetaphosphate into triphosphate per the reaction:

trimetaphosphate + H<sub>2</sub>O <=> triphosphate (ultimately leading to the production of 2'-Deoxy-5-hydroxy-methylcytidine-5'-triphosphate).<ref name=trimetaphosphatase>{{ cite web |title=KEGG PATHWAY: Pyrimidine metabolism - Reference pathway (Reaction) |url=http://www.genome.jp/dbget-bin/show_pathway?rn00240+R02504 }}</ref>

Trimetaphosphatase activity has been found to be localized in the mouse testis during acrosomal formation.<ref name=Jin>{{ cite journal |author=Jin QS, Kamata M, Garcia del Saz E, Seguchi H |title=Ultracytochemical study of trimetaphosphatase activity during acrosomal formation in the mouse testis |journal=Histol Histopathol. |year=1995 |month=Jul |volume=10 |issue=3 |pages=681-9 |pmid=7579818 }}</ref>
Osteoclasts secrete trimetaphosphatase towards the resorbing bone surfaces.<ref name=Shimizu>{{ cite journal |author=Shimizu T, Sasaki T |title=Ultrastructural Study of the Effects of Cytochalasin D Administration on the Structure and Acid Trimetaphosphatase Activity of Osteoclast |journal=J Electron Microsc (Tokyo). |volume=40 |month=Oct |issue=5 |pages=346-55 |year=1991 |pmid=1666644 }}</ref>

==[[Phosphorylation]]==

The addition of a [[phosphate]] (PO<sub>4</sub>) group to another molecule, including any [[protein]], is phosphorylation. Many [[enzyme]]s and [[Receptor (proteomics)|receptors]] are switched "on" or "off" by phosphorylation. Phosphorylation is catalyzed by specific [[protein kinase]]s. Dephosphorylation is catalyzed by [[phosphatase]]s. Phosphorylation of any [[amino acid]] having a free [[hydroxyl group]] on a given protein can change the function, association, or localization of that protein.

[[Oxidative phosphorylation]] is the process of oxidizing [[nutrient]]s to produce [[adenosine triphosphate]] (ATP). [[Substrate-level phosphorylation]] forms ATP by the direct transfer of a phosphate group to [[adenosine diphosphate]] (ADP) from a [[reactive intermediate]]. [[Photophosphorylation]] uses solar energy to synthesize ATP.

Phosphorylation of [[sugar]]s allows cells to accumulate sugars because the phosphate group prevents the molecules from diffusing back across their transporter.

==Phosphate [[bioenergetics]]==

Bioenergetics concerns energy flow through living systems. This area of biological research includes the study of cellular processes such as [[cellular respiration]] that can lead to production and utilization of energy in forms such as ATP molecules. Living cells use phosphate to transport cellular energy via nucleotides such as [[adenosine triphosphate]] (ATP). Nearly every cellular process that uses energy obtains it in the form of ATP.

[[Proton]]s in aqueous solution function in the production of ATP in cell [[Organelle|organelles]] such as [[Mitochondrion|mitochondria]]<ref name=Mitchell>{{cite journal |author=Mitchell PD |title=Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism |journal=Nature. |year=1961 |month=Jul |volume=191 |pages= 144-8 |pmid=13771349 }}</ref>. Other cellular sources of ATP such as [[glycolysis]] for direct coupling of [[enzyme]] activity to ATP production are not the major source of useful chemical energy in most cells. Chemiosmotic coupling is the major energy producing process in most cells, being utilized in [[chloroplast]]s and many [[Three-domain system|single celled]] organisms in addition to mitochondria.

==[[Structural phosphate#Catalytic phosphate|Catalytic phosphate]]==

A phosphate which affects the catalytic activity of an enzyme is a catalytic phosphate.<ref name=Linn>{{ cite journal |author=Linn TC, Srere PA |title=Identification of ATP citrate lyase as a phosphoprotein |journal=J Biol Chem. |volume=254 |issue=5 |month=Mar |year=1979 |pages=1691-8 |pmid= 762167 }}</ref> Occasionally, an enzyme contains a structural phosphate and a catalytic phosphate.<ref name=Linn/>

The γ phosphate of [[ATP]] is the catalytic phosphate.

Catalytic phosphates are acid-labile and base-stable. Structural phosphates are acid-stable, base-labile.<ref name=Janski>{{ cite journal |author=Janski AM, Srere PA, Cornell NW, Veech RL |title=Phosphorylation of ATP Citrate Lyase in Response to Glucagon |journal=J Biol Chem. |month=Oct |volume=254 |issue=19 |pages=9365-8 |year=1979 |pmid= 489538 }}</ref>

==[[Structural phosphate]]==

Inside a cell, phosphate may be structural to a nucleic acid such as [[DNA]] and [[RNA]] or [[phospholipid]]. Outside the cell, phosphate may be dissolved in [[extracellular fluid]] (ECF) or form structures such as [[bone]] and [[teeth]]. Bringing phosphate in any form into the cell from a phosphate containing structure or for such a structure and when needed transporting phosphate out of the cell perhaps to a structure is a necessary activity of phosphate homeostasis for that cell.

==[[Cell signaling|Signaling]]==

[[Lipid signaling]] involves [[G-protein coupled receptor]]s to which [[lysophosphatidic acid]] (LPA) binds, through which [[sphingosine-1-phosphate]] (S1P) acts, and [[platelet-activating factor]] (PAF) signals. The key event of diacylglycerol (DAG) signaling is the hydrolysis of [[phosphatidylinositol (4,5)-bisphosphate]] (PIP2) to DAG and [[inositol triphosphate]] (IP3). IP3 is soluble and diffuses freely into the cytoplasm. It can be recognised by the [[inositol triphosphate receptor]] (IP3R). IP3 contributes to the activation of [[Protein kinase#Protein kinase C|protein kinase C]] (PKC).<ref>{{cite journal | author=Irvine RF | title=Inositol lipids in cell signalling | journal=Curr Opin Cell Biol | year=1992 | volume=4 | issue=2 | pages=212-19 |pmid=1318060 }}</ref><ref>{{cite journal | author=Nishizuka Y | title=Protein kinase C and lipid signaling for sustained cellular responses | journal=FASEB J| year=1995 | volume=9 | issue=7 | pages=484-96 |pmid=7737456 }}</ref>

==[[Extracellular fluid]] (ECF)==

'''Extracellular fluid''' usually denotes all [[Bodily fluid|body fluid]] outside of cells. It is frequently contained within [[Organ (anatomy)|organ]]s. 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 system]]s are usually closed, meaning that the [[blood]] never leaves the network of [[blood vessel]]s. In contrast, [[oxygen]] and [[nutrient]]s diffuse across the blood vessel layers and enter interstitial fluid (ISF), which carries oxygen and nutrients to cells, and [[carbon dioxide]] and [[Metabolic waste|waste]]s 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.

===[[Phosphatidic acid|Phosphatidate]]===

[[Lysophosphatidic acid]] (LPA) is an intermediate in the synthesis of [[phosphatidic acid]] (PA). [[Autotaxin|ENPP2]] functions as a [[phospholipase]], which catalyzes the transformation of lysophosphatidylcholine into LPA in ECF.<ref name=Ferry>{{ cite journal |author=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 |title=Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid synthesis, and activates preadipocyte proliferation. Up-regulated expression with adipocyte differentiation and obesity |journal=J Biol Chem. |year=2003 |month=May |volume=278 |issue=20 |pages=18162-9 |pmid=12642576 |doi=10.1074/jbc.M301158200 }}</ref> LPA has been detected in plasma, [[Ascites|ascitic fluid]], [[follicular fluid]], and [[Aqueous humour|aqueous humor]].<ref name=Ferry/>

===ECF [[Phosphoric acids and phosphates#Orthophosphate|Orthophosphate]] (P<sub>i</sub>)===

The level of inorganic orthophosphate (P<sub>i</sub>) is tightly balanced inside the cell and in the whole vertebrate organism.<ref name=Werner>{{ cite journal |author=Werner A, Dehmelt L, Nalbant P |title=Na+-dependent phosphate cotransporters: the NaPi protein families |journal=J Exp Biol. |year=1998 |month=Dec |volume=201 |issue=Pt 23 |pages=3135-42 |pmid=9808829 }}</ref> The concentration of free P<sub>i</sub> is balanced in the millimolar range in ICF and ECF.<ref name=Werner/> Bacteria, yeast, plants, and vertebrates have developed their own strategies to control P<sub>i</sub> homeostasis.<ref name=Werner/> The daily need for P<sub>i</sub> 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.<ref name=Werner/> The ECF concentration of P<sub>i</sub> is controlled by tightly regulating renal excretion.<ref name=Werner/> Principal properties of mammalian renal P<sub>i</sub> reabsorption are pH-dependency, regulation by parathyroid hormone (PTH), and P<sub>i</sub> availability.<ref name=Werner/> These properties are expressed by SLC34A1-3 (sodium-dependent phosphate transporter 2, NPT2), whereas NPT3 (SLC17A2) mediates Na<sup>+</sup>-dependent P<sub>i</sub> transport.<ref name=Werner/> NPT1 (SLC17A1) does not have a prominent role in regulating body P<sub>i</sub> homeostasis.<ref name=Werner/> Insulin stimulates NPT1 expression and Na<sup>+</sup>/P<sub>i</sub> uptake which is reversed by glucagon.<ref name=Werner/> 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  P<sub>i</sub> concentration.<ref name=Werner/> The expression of NPT3 is compatible with the presence of other NPT.<ref name=Werner/> Members of the NPT1 family are linked with insulin-stimulated glucose metabolism.<ref name=Werner/> NPT2 in the kidney and small intestine
are responsible for intracellular P<sub>i</sub> accumulation in order to establish a transepithelial flux of P<sub>i</sub>.<ref name=Werner/> NPT4 (SLC17A3) is expressed in the small intestine, kidney, liver, and testis.<ref name=Ruddy>{{ cite journal |author=Ruddy DA, Kronmal GS, Lee VK, Mintier GA, Quintana L, Domingo R Jr, Meyer NC, Irrinki A, McClelland EE, Fullan A, Mapa FA, Moore T, Thomas W, Loeb DB, Harmon C, Tsuchihashi Z, Wolff RK, Schatzman RC, Feder JN |title=A 1.1-Mb transcript map of the hereditary hemochromatosis locus |year=1997 |month=May |volume=7 |issue=5 |pages=441-56 |pmid= 9149941 }}</ref>

===ECF [[Pyrophosphate]] (PP<sub>i</sub>)===

PP<sub>i</sub> occurs in synovial fluid, plasma, and urine at levels sufficient to block calcification and may be a natural inhibitor of hydroxyapatite formation in ECF.<ref name=Ho>{{ cite journal |author=Ho AM, Johnson MD, Kingsley DM |title=Role of the mouse ank gene in control of tissue calcification and arthritis |journal=Science. |year=2000 |month=Jul |volume=289 |issue=5477 |pages=265-70 |pmid=10894769 |doi=10.1126/science.289.5477.265 }}</ref>

==[[Blood]]==

Blood is a specialized body ECF contained within the cardiovascular system that is composed of [[blood cell]]s [[Suspension (chemistry)|suspended]] in [[Blood plasma|plasma]]. Its phosphate content is in many forms. Per the [[list of human blood components]]: [[adenosine triphosphate]] (ATP) concentration in whole blood is 3.1-5.7 x 10<sup>-4</sup> g/cm<sup>3</sup>, which is the equivalent of 5-10 x 10<sup>-5</sup> g/cm<sup>3</sup> of phosphorus; diphosphoglycerate is 8-16 x 10<sup>-5</sup> g/cm<sup>3</sup>; [[cGMP]] is 0.6-4.4 x 10<sup>-9</sup> g/cm<sup>3</sup>; hexosephosphate P is 1.4-5 x 10<sup>-5</sup> g/cm<sup>3</sup> (0-2 x 10<sup>-6</sup> g/cm<sup>3</sup> in [[Blood plasma|plasma]] or [[serum]]); [[DNA]] is 0-1.6 x 10<sup>-5</sup> g/cm<sup>3</sup> in plasma or serum; [[phospholipid]] is 2.25-2.85 x 10<sup>-3</sup> g/cm<sup>3</sup> (5-12 x 10<sup>-5</sup> g/cm<sup>3</sup> in plasma or serum); pyrimidine nucleotide is 2.6-4.6 x 10<sup>-5</sup> g/cm<sup>3</sup> (2-12 x 10<sup>-7</sup> g/cm<sup>3</sup> in plasma or serum); and [[RNA]] is 5-8 x 10<sup>-4</sup> g/cm<sup>3</sup> (4-6 x 10<sup>-5</sup> g/cm<sup>3</sup> in plasma or serum). P<sub>i</sub> occurs in blood, blood plasma and blood serum.<ref name=Csapo>{{ cite journal |author=Joseph Csapo |title=The Influence of Proteins on the Solubility of Calcium Phosphate |journal=J Biol Chem. |volume=75 |issue=2 |pages=509-15 |year=1927 }}</ref> The total phosphorus content is 2-3.9 x 10<sup>-5</sup> g/cm<sup>3</sup> as inorganic phosphate and 3.5-4.3 x 10<sup>-4</sup> g/cm<sup>3</sup> total (2.3-4.5 x 10<sup>-5</sup> g/cm<sup>3</sup> and 1-1.5 x 10<sup>-4</sup> g/cm<sup>3</sup> in plasma or serum, respectively).

===Blood Orthophosphate===

A slight increase of [[pH]] in blood plasma above 7.4 causes [[Precipitation (chemistry)|precipitation]] of [[calcium phosphate]] and resulting [[turbidity]], whereas, in the case of blood serum (plasma without clotting proteins) of the same [[Inorganic compound|inorganic]] composition, the pH may vary fairly widely without precipitation occurring.<ref name=Csapo/>

It is the [[Blood proteins|proteins]] that tend to keep [[calcium]] salts in [[solution]] or at least in [[Suspension (chemistry)|suspension]].<ref name=Csapo/> Blood serum is [[Supersaturation|supersaturated]] with [[tricalcium phosphate]] from about pH 6.8 up to about pH 9.25, with a maximum dissolution at pH 7.3.<ref name=Csapo/> The [[Chemical stability|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. [[Blood proteins|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.<ref name=Csapo/>

===Blood [[Pyrophosphate]]===

Blood plasma levels of PP<sub>i</sub> in normal human children can range from approximately 300-700 pmol/µg protein.<ref name=Rutsch>{{ cite journal |author=Rutsch F, Vaingankar S, Johnson K, Goldfine I, Maddux B, Schauerte P, Kalhoff H, Sano K, Boisvert WA, Superti-Furga A, Terkeltaub R |title=PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification |journal=Am J Pathol. |year=2001 |month=Feb |volume=158 |issue=2 |pages=543-54 |pmid=11159191 }}</ref>

==Phosphate in==

Bringing phosphate in any form into a cell possibly from a phosphate containing structure, for such a structure, or whatever the need, may require [[phagocytosis]], [[endocytosis]], or a [[Membrane transport protein|phosphate-importing protein]] or [[symporter]].

EC 3.6.3.20 is a phosphate-importing enzyme that catalyzes the chemical reaction

ATP + H<sub>2</sub>O + glycerol-3-phosphateout <=> ADP + phosphate + glycerol-3-phosphatein.

EC 3.6.3.27 is a phosphate-importing enzyme that catalyzes the chemical reaction

ATP + H<sub>2</sub>O + phosphateout <=> ADP + phosphate + phosphatein.

===Orthophosphate in===

[[Growth hormone]], at least in part mediated by [[insulin-like growth factor]] I (IGF-I), stimulates P<sub>i</sub> cotransport.<ref name=Murer>{{ cite journal |author=Murer H, Hernando N, Forster I, Biber J |title=Proximal tubular phosphate reabsorption: molecular mechanisms |journal=Physiol Rev. |year=2000 |month=Oct |volume=80 |issue=4 |pages=1373-409 |pmid=11015617 }}</ref> [[Thyroid hormone]] stimulates P<sub>i</sub> absorption via a specific increase in P<sub>i</sub> cotransport.<ref name=Murer/> Stanniocalcin 1 ([[STC1]]) stimulates membrane P<sub>i</sub> cotransport.<ref name=Murer/>

Phosphaturic factors reduce the [[Gene expression|expression]] of P<sub>i</sub> transporters or cotransporters in the [[cell membrane]].<ref name=Hernando>{{ cite journal |author=Hernando N, Gisler SM, Pribanic S, Déliot N, Capuano P, Wagner CA, Moe OW, Biber J, Murer H |title=NaPi-IIa and interacting partners |journal=J Physiol. |year=2005 |month=Aug |volume=567 |issue=1 |pages=21-6 |pmid=15890704 |doi=10.1113/jphysiol.2005.087049 }}</ref>

[[Insulin]] enhances P<sub>i</sub> absorption by stimulation of P<sub>i</sub> cotransport and prevents the phosphaturic action of [[parathyroid hormone]] (PTH).<ref name=Murer/> [[Calcitonin]] reduces membrane P<sub>i</sub> cotransport in a PTH- and [[Cyclic adenosine monophosphate|cAMP]]-independent manner.<ref name=Murer/>

Some factors that increase P<sub>i</sub> absorption increase the number of the transporters or cotransporters in the cell membrane.<ref name=Hernando/> Knowledge of the mechanisms that control transporter expression and membrane retrieval of the transporters is essential to understanding how P<sub>i</sub> homeostasis is achieved.<ref name=Hernando/>

Physiological regulation of P<sub>i</sub> 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 (V<sub>max</sub>) of P<sub>i</sub> cotransport activity.<ref name=Murer/>

====[[Interstitial fluid|ISF]] P<sub>i</sub> absorption====

[[SLC20A1|PiT1]] is likely to be a major carrier of phosphate from ISF into most cell types.<ref name=Kavanaugh>{{ cite journal |author=Kavanaugh MP, Miller DG, Zhang W, Law W, Kozak SL, Kabat D, Miller AD |title=Cell-surface receptors for gibbon ape leukemia virus and amphotropic murine retrovirus are inducible sodium-dependent phosphate symporters |journal=Proc Natl Acad Sci U S A. |year=1994 |month=Jul |volume=91 |issue=15 |pages=7071-5 |pmid=8041748 }}</ref> [[Michaelis-Menten kinetics#Determination of constants|V<sub>max</sub>]] can go approximately from 39 to 121, with ISF phosphate to phosphate-free ISF.<ref name=Kavanaugh/> Mammaliam cell internal phosphate levels (75 [[Equivalent (chemistry)|milliequivalents]] per liter) are maintained at higher levels than ISF (4 milliequivalents per liter) in opposition to an [[electrochemical gradient]] that favors phosphateout.<ref name=Kavanaugh/>

Low ECF P<sub>i</sub> levels can result in upregulated PiT1 and [[SLC20A2|PiT2]] expression in mammalian cells.<ref name=Bottger>{{ cite journal |author=Bøttger P, Hede SE, Grunnet M, Høyer B, Klaerke DA, Pedersen L |title=Characterization of transport mechanisms and determinants critical for Na+-dependent Pi symport of the PiT family paralogs human PiT1 and PiT2 |journal=Am J Physiol Cell Physiol. |year=2006 |month=Dec |volume=291 |issue=6 |pages=C1377-87 |pmid=16790504 }}</ref> PiT1 and PiT2 exhibit positve cooperative P<sub>i</sub> uptake. PiT2 supports Na<sup>+</sup>-independent P<sub>i</sub> uptake.<ref name=Bottger/> Ca<sup>2+</sup> or Ca<sup>2+</sup> and Mg<sup>2+</sup> increase PiT1- and PiT2-mediated NaP<sub>i</sub> import.<ref name=Bottger/> V<sub>max</sub> for PiT1 and PiT2 are approximately 453 and 450 pmol·cell<sup>-1</sup>·h<sup>-1</sup>, respectively.<ref name=Bottger/> The average P<sub>i</sub> uptake for PiT2 and PiT1 at pH 7.5 is approximately 118 and 115 pmol·cell<sup>-1</sup>·h<sup>-1</sup>, respectively.<ref name=Bottger/> P<sub>i</sub> transport has similar average P<sub>i</sub> uptake at different pH values: 5.5 to 8.5.<ref name=Bottger/> The Na<sup>+</sup>-independent P<sub>i</sub> uptake of PiT2 is in acidic ECF conditions.<ref name=Bottger/> With physiological Na<sup>+</sup> concentration in the human body in the range of 130–145 mM, there is always plenty to sustain P<sub>i</sub> uptake via PiT1 and PiT2.<ref name=Bottger/>

====Small intestine P<sub>i</sub> absorption====

A low dietary [[Phosphate|inorganic phosphate]] (P<sub>i</sub>) intake can lead to an almost 100% [[Absorption (chemistry)|absorption]] of filtered P<sub>i</sub>, whereas a high dietary P<sub>i</sub> intake leads to a decreased P<sub>i</sub> absorption.<ref name=Murer/> These changes can occur independent of changes in the ECF concentration of different phosphaturic hormones.<ref name=Murer/>

In the upper small intestine [[Vitamin D|Vitamin D<sub>3</sub>]] stimulates P<sub>i</sub> [[Cotransporter|cotransport]].<ref name=Murer/> [[Matrix extracellular phosphoglycoprotein]] (MEPE), a phosphatonin, promotes phosphaturia.<ref name=Marks>{{ cite journal |author=Marks J, Churchill LJ, Debnam ES, Unwin RJ |title=Matrix extracellular phosphoglycoprotein inhibits phosphate transport |journal=J Am Soc Nephrol. |year=2008 |month=Dec |volume=19 |issue=12 |pages=2313-20 |pmid=19005008 }}</ref> Short-term infusion of MEPE inhibits phosphate absorption in the jejunum but not the duodenum.<ref name=Marks/> The short-term inhibitory effect of MEPE on renal and intestinal phosphate handling occurs without any changes in circulating levels of parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3, or [[fibroblast growth factor 23]] (FGF23).<ref name=Marks/> MEPE may be involved in phosphate homeostasis, acting in both the kidney and the gastrointestinal tract.<ref name=Marks/>

There is evidence for a hormone/enzyme/extracellular matrix protein cascade involving [[fibroblastic growth factor 23]] (FGF23), the X-linked phosphate regulating endopeptidase homolog (PHEX), and a matrix extracellular phosphoglycoprotein (MEPE) that regulates systemic phosphate homeostasis and mineralization.<ref name=Quarles>{{ cite journal |author=Quarles LD |title=FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization |journal=Am J Physiol Endocrinol Metab. |month=Jul |year=2003 |volume=285 |issue=1 |pages=E1-9 |pmid=12791601 }}</ref>

====Renal P<sub>i</sub> reabsorption====

[[Sodium/phosphate cotransporter|NPT2]] dominates in renal P<sub>i</sub> reabsorption, which is exclusive under non-pathological conditions in the mammalian kidney.<ref name=Werner/> Na<sup>+</sup> interacts in a cooperative way with NPT2 with a stoichiometry of 3Na<sup>+</sup> to 1P<sub>i</sub>.<ref name=Werner/> Protons (H<sup>+</sup>) decrease the affinity of NPT2 for Na<sup>+</sup>.<ref name=Werner/>

There is a link between the action of PTH, P<sub>i</sub> availability, and renal cell membrane integration/retrieval of NPT2.<ref name=Werner/> Changes in dietary P<sub>i</sub> content have a major regulatory effect on P<sub>i</sub> reabsorption.<ref name=Lotscher>{{ cite journal |author=Lötscher M, Kaissling B, Biber J, Murer H, Levi M |title=Role of microtubules in the rapid regulation of renal phosphate transport in response to acute alterations in dietary phosphate content |journal=J Clin Invest. |year=1997 |month=Mar |volume=99 |issue=6 |pages=1302-12 |pmid=9077540 }}</ref> Dietary P<sub>i</sub> restriction is associated with an adaptive increase of the overall capacity for P<sub>i</sub> uptake mediated by an increase of V<sub>max</sub> of sodium gradient-dependent phosphate transport.<ref name=Lotscher/> In response to chronic (8 day) dietary P<sub>i</sub> restriction, the adaptive increase in sodium-P<sub>i</sub> cotransport activity is associated with parallel increases in NPT2 and its mRNA abundances.<ref name=Lotscher/> However, in response to acute (2 h) dietary P<sub>i</sub> restriction, the rapid adaptive increase in sodium-P<sub>i</sub> cotransport activity is associated with parallel increases in NPT2, but without change in its mRNA abundance.<ref name=Lotscher/>

The role of intracellular NPT2 in the rapid adaptation to dietary P<sub>i</sub> is correlated with the localization of the Golgi membrane protein 58 kDa and the lysosomal membrane glycoprotein Igp120, as follows<ref name=Lotscher/>: after chronic adaptation to a high P<sub>i</sub> 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 P<sub>i</sub> diet to low P<sub>i</sub> leads to depletion of intracellular NPT2, with NPT2 only in the Golgi-like compartment. After chronic adaptation to a low P<sub>i</sub> 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 P<sub>i</sub> to a high P<sub>i</sub> 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 P<sub>i</sub> diet is characterized by an increase in NPT2 mRNA abundance.<ref name=Lotscher/>

=====Role of [[microtubule]]s=====

In the presumable rapid translocation of NPT2 in response to [[Acute (medicine)|acute]] administratiion of a low P<sub>i</sub> 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.<ref name=Lotscher/> Regarding response to an acute administration of a high P<sub>i</sub> diet after [[Chronic (medical)|chronic]] administration of a low P<sub>i</sub>, microtubules are not involved in rapid [[downregulation]] of NPT2 activity or NPT2 abundance.<ref name=Lotscher/>

The rapid adaptive increase in sub cell membrane NPT2 with chronic feeding of a high P<sub>i</sub> diet, after an acute administration of a low P<sub>i</sub> diet, is probably mediated by translocation of presynthesized NPT2 to this portion by microtubule-dependent mechanisms.<ref name=Lotscher/>

The targeting of NPT2 to the cell membrane seems to be dependent on the microtubule network.<ref name=Lotscher/>

=====Role of [[microfilament]]s=====

Microfilaments ([[actin]] cytoskeleton) may play a central role in the rapid downregulation of Na<sup>+</sup>-P<sub>i</sub> cotransport.<ref name=Lotscher/> The dependence of endocytosis on intact microfilaments in polarized epithelial cells has been demonstrated.<ref name=Lotscher/>

===Organophosphates in===

[[Phosphatidate phosphatase|Phosphatidic acid phosphatase]]s (PAPs) transport [[phosphatidic acid]] (PA), [[lysophosphatidic acid]] (LPA), ceramide 1-phosphate (C1P), and [[Sphingosine-1-phosphate|sphingosine 1-phosphate]] (S1P) from ECF through the plasma membrane at different V<sub>max</sub>.<ref name=Roberts>{{ cite journal |author=Roberts R, Sciorra VA, Morris AJ |title=Human type 2 phosphatidic acid phosphohydrolases. Substrate specificity of the type 2a, 2b, and 2c enzymes and cell surface activity of the 2a isoform |journal=J Biol Chem. |year=1998 |month=Aug |volume=273 |issue=34 |pages=22059-67 |pmid=9705349 }}</ref> Once inside the cell, these PAPs ([[PPAP2A]], [[PPAP2B]], and [[Phosphatidic acid phosphatase 2c|PPAP2C]]) hydrolyze each phosphate per EC 3.1.3.4:

a 3-sn-phosphatidate + H<sub>2</sub>O <=> a 1,2-diacyl-sn-glycerol + P<sub>i</sub>.

PPAP2A displays comparable V<sub>max</sub> values for all four substrates, with highest activity for LPA and PA. PPAP2B shows a similarly higher relative V<sub>max</sub> activity with LPA, while PPAP2C displays significantly higher activity with S1P.<ref name=Roberts/> For some cells PPAP2A may be an ectoenzyme that dephosphorylates PA to form [[Diglyceride|diacylglycerol]] (DG) prior to DG transport into the cell.<ref name=Roberts/>

==Phosphate exchange==

Glycerol phosphate transporter (GlpT) transports glycerol-3-phosphate (G3P) into the cytoplasm and P<sub>i</sub> into the [[Periplasmic space|periplasm]].<ref name=Huang>{{ cite journal |author=Huang Y, Lemieux MJ, Song J, Auer M, Wang DN |title=Structure and mechanism of the glycerol-3-phosphate transporter from Escherichia coli |journal=Science. |year=2003 |month=Aug |volume=301 |issue=5633 |pages=616-20 |pmid=12893936 }}</ref> While GlpT transports between cellular compartments through internal membranes, it can also transport across the cell membrane.<ref name=cd06174>{{ cite web |title=Major Facilitator Superfamily |url=http://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=119392 }}</ref> GlpT functions for G3P uptake and is driven by a P<sub>i</sub> gradient. Periplasmic (or ISF) release of P<sub>i</sub> allows its replacement in the substrate-binding site by G3P, which has a higher affinity; on the cytoplasmic side of the membrane, P<sub>i</sub> replaces G3P because of its higher cytosolic concentration.<ref name=Huang/>

==Phosphate out==

===Orthophosphate out===

Under normal or steady-state physiological conditions, [[Urinary system|urinary]] P<sub>i</sub> [[excretion]] corresponds roughly to phosphate intake in the [[gastrointestinal tract]], mainly via the upper [[small intestine]].<ref name=Murer/> To fulfill P<sub>i</sub> homeostasis, i.e., keeping extracellular P<sub>i</sub> concentration within a narrow range, urinary P<sub>i</sub> excretion is under strong [[Physiology|physiological]] control.<ref name=Murer/> In contrast to intestinal P<sub>i</sub> absorption, which adjusts rather slowly, [[Kidney|renal]] P<sub>i</sub> excretion can adjust very rapidly to altered physiological conditions.<ref name=Murer/> Specifically, membrane P<sub>i</sub> cotransporter protein content, and thus P<sub>i</sub> absorption, responds within hours to alterations in dietary P<sub>i</sub> intake.<ref name=Murer/>

[[Parathyroid hormone]] (PTH) induces [[Hypophosphatemia|phosphaturia]] by inhibiting P<sub>i</sub> [[Cotransporter|cotransport]] activity.<ref name=Murer/> [[Glucocorticoids]] increase phosphate excretion by an [[Enzyme inhibitor|inhibition]] of membrane P<sub>i</sub> cotransport, independent of an increase in PTH.<ref name=Murer/>

Stanniocalcin 2 ([[STC2]]) may suppress P<sub>i</sub> cotransport.<ref name=Murer/>

===Pyrophosphate out===

Cells may channel intracellular PP<sub>i</sub> into ECF.<ref name=Rutsch/>  [[ANKH|ANK]] is a nonenzymatic plasma-membrane PP<sub>i</sub> channel that supports extracellular PP<sub>i</sub> levels.<ref name=Rutsch/> Defective function of the membrane PP<sub>i</sub> channel ANK is associated with low extracellular PP<sub>i</sub> and elevated intracellular PP<sub>i</sub>.<ref name=Ho/> [[Ectonucleotide pyrophosphatase/phosphodiesterase 1|Ectonucleotide pyrophosphatase/phosphodiesterase]] (ENPP) may function to raise extracellular PP<sub>i</sub>.<ref name=Rutsch/>

==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 (2-6 x 10<sup>22</sup> molecules). Per the elemental composition of the "standard man" of 70 kg, phosphorus is 780 g or 1.1% (as 1.52 x 10<sup>25</sup> molecules of phosphate).<ref name=Lide>{{ cite book |editor-in-chief=Lide DR |title=CRC Handbook of Chemistry and Physics |year=2007-2008 |edition=88th |publisher=CRC Press |location= Boca Raton, Florida |page=7-18 }}</ref> Of this 1.4 g/kg (98 g, 1.9 x 10<sup>24</sup> molecules of phosphate) are present in soft tissue with the remainder (1.33 x 10<sup>25</sup> molecules of phosphate) in mineralized tissue such as bone and teeth.<ref name=Schwartz>{{ cite journal |author=Schwartz MK |title=Phosphate metabolism |journal=McGraw-Hill Encyclopedia of Science & Technology |volume=13 |edition=9th |pages=343-4 }}</ref> Only about 0.1% of body phosphate (about 2 x 10<sup>22</sup> molecules) circulates in the blood, but this amount reflects the amount of phosphate available to soft tissue cells. Blood plasma contains orthophosphate (as HPO<sub>4</sub><sup>2-</sup>) and H<sub>2</sub>PO<sub>4</sub><sup>-</sup> in the ratio of about 4:1.<ref name=Schwartz/>

The total quantity of ATP in the human body is about 0.1&nbsp;[[Mole (unit)|mole]] (about 6 x 10<sup>22</sup> molecules). 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&nbsp;moles (6 to 9 x 10<sup>25</sup> molecules) of ATP daily which is around 50 to 75&nbsp;kg. Typically, a human will use up their body weight of ATP over the course of the day.<ref name=Buono>{{ cite journal |author=Buono MJ, Kolkhorst FW |title=Estimating ATP resynthesis during a marathon run: a method to introduce metabolism |journal=Adv Physiol Educ. |year=2001 |volume=25 |issue=2 |pages=70-1 |url=http://advan.physiology.org/cgi/reprint/25/2/70.pdf }}</ref> This means that each ATP molecule is recycled 1000 to 1500 times daily, or about once every minute.

PP<sub>i</sub>-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 PP<sub>i</sub> levels in several tissues.<ref name=Rutsch/>

===Intracellular phosphate===

With the number of cells in the human body of 10-100 trillion or 10<sup>13</sup> to 10<sup>14</sup>, there are approximately 1.9-19.0 x 10<sup>10</sup> atoms of phosphorus (1.9 to 19 x 10<sup>10</sup> molecules of phosphate) per [[Cell (biology)|cell]]. A typical cell volume is 5 x 10<sup>-16</sup> m<sup>3</sup>. If a typical cell was totally liquid water, there would be about 1.7 x 10<sup>13</sup> molecules of water present. Then the phosphate concentration would be on the order of 10<sup>-3</sup>. However, a cell is about twice as dense as liquid water, then perhaps only 50% water yielding 5 x 10<sup>-3</sup> for phosphate concentration. As computer simulation has shown the probability of finding a target by diffusion decreases rapidly with distance and becomes <1% when the starting distance exceeds the target's 10-fold radius,<ref name=Guigas2>{{ cite journal |author=Guigas G, Weiss M |title=Sampling the Cell with Anomalous Diffusion—The Discovery of Slowness |journal=Biophys J. |year=2008 |month=Jan |volume=94 |issue=1 |pages=90-4 |pmid=17827216 |doi=10.1529/biophysj.107.117044 }}</ref> which by assumption of a simple spherical volume would put the target's concentration on the order of 10<sup>-3</sup>.

Although ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) regulates intracellular PP<sub>i</sub> concentrations it does not seem to significantly regulate extracellular PP<sub>i</sub>.<ref name=Rutsch/>

===Extracellular phosphate===

PP<sub>i</sub> inhibits [[Hydroxylapatite|hydroxyapatite]] deposition in [[bone]] and [[cartilage]].<ref name=Rutsch/> Many studies have shown that PP<sub>i</sub> is a potent inhibitor of [[Dystrophic calcification|calcification]], [[Mineralization (biology)|bone mineralization]], and [[bone resorption]].<ref name=Ho/> Human defects in alkaline phosphatase, an enzyme that degrades PP<sub>i</sub>, lead to an increase in PP<sub>i</sub> levels and a severe block in skeletal mineralization.<ref name=Ho/> Genetic defects in a cell surface ectoenzyme that normally generates extracellular PP<sub>i</sub> from nucleotide triphosphate cause ectopic mineralization of joints and ligaments and may be associated with spinal ligament ossification in humans.<ref name=Ho/>

===[[Bone]]===

During [[bone resorption]] high levels of phosphate are released into the ECF as [[osteoclast]]s tunnel into mineralized bone, breaking it down and releasing phosphate, that results in a transfer of phosphate from bone fluid to the blood. During [[Child development|childhood]], bone formation exceeds resorption, but as the [[Ageing|aging process]] occurs, resorption exceeds formation.

==Phosphate [[Chemical regulation|regulation]]==

An [[organism]] that can regulate its internal environment so as to maintain [[chemical equilibrium|equilibrium]] has the property of [[homeostasis]]. Those proteins which stimulate phosphate in or phosphate out regulate phosphate concentration. Specific [[protein kinase]]s catalyze [[phosphorylation]] whereas [[phosphatase]]s dephosphorylate. These kinases and phosphatases regulate phosphate form and phosphate availability.

ATP is important for [[phosphorylation]], a key regulatory event in cells.

[[Fibroblast growth factor 23]] (FGF23) is essential for maintaining phosphate homeostasis. [[Klotho (biology)|Klotho]] is integral to the plasma membrane<ref name=Matsumura>{{ cite journal |author=Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y |title=Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein |journal=Biochem Biophys Res Commun. |year=1998 |month=Jan |volume=242 |issue=3 |pages=626-30 |pmid=9464267 }}</ref> and essential for endogenous FGF23 function<ref name=Urakawa>{{ cite journal |author=Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T |title=Klotho converts canonical FGF receptor into a specific receptor for FGF23 |journal=Nature. |month-Dec |year=2006 |volume=444 |issue=7120 |pages=770-4 |pmid=17086194 }}</ref>. FGF23 regulates [[Sodium/phosphate cotransporter|NPT2a]] independent of [[parathyroid hormone]] (PTH) and serum 1,25-dihydroxyvitamin D level by controlling renal expressions of key enzymes of [[vitamin D]] metabolism.<ref name=Shimada>{{ cite journal |author=Shimada T,  Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T |title=FGF-23 Is a Potent Regulator of Vitamin D Metabolism and Phosphate Homeostasis |journal=J Bone Miner Res. |month=Mar |year=2004 |volume=19 |issue=3 |pages=429-35 |pmid= 15040831 |doi=10.1359/JBMR.0301264 }}</ref> FGF23 inhibits renal tubular phosphate transport.<ref name=FGF23>{{ cite web |title=Entrez Gene: FGF23 fibroblast growth factor 23 |url=http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8074&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum }}</ref> The secretion of FGF23 requires O-glycosylation, which is selectively directed by [[GALNT3]], to block processing of FGF23.<ref name=Kato>{{ cite journal |author=Kato K, Jeanneau C, Tarp MA, Benet-Pagès A, Lorenz-Depiereux B, Bennett EP, Mandel U, Strom TM, Clausen H |title=Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation |journal=J Biol Chem. |year=2006 |month=Jul |volume=281 |issue=27 |pages=18370-7 |pmid=16638743 }}</ref>

Both NPT2a and [[SLC34A3|NPT2c]] are regulated in a similar fashion by parathyroid hormone (PTH), FGF23, and dietary phosphate.<ref name=Bergwitz>{{ cite journal |author=Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H, Frappier D, Burkett K, Carpenter TO, Anderson D, Garabedian M, Sermet I, Fujiwara TM, Morgan K, Tenenhouse HS, Juppner H |title=SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis |journal=Am J Hum Genet. |year=2006 |month=Feb |volume=78 |issue=2 |pages=179-92 |pmid=16358214 }}</ref> Phosphate deprivation increases NPT2a and NPT2c expression.<ref name=Bergwitz/> The relative expression of NPT2a is an order of magnitude higher than that of NPT2c in kidneys of organisms maintained on a normal phosphate diet.<ref name=Bergwitz/> Normal animals exhibit a more robust increase in NPT2c than in NPT2a in response to phosphate deprivation.<ref name=Bergwitz/> NPT2c is regulated by FGF23 and probably downregulated by PTH. SLC34A3 (NPT2c) contributes to the maintenance of inorganic phosphate concentration at the kidney.<ref name=Segawa>{{ cite journal  |author=Segawa H, Kaneko I, Takahashi A, ''et al.'' |title=Growth-related renal type II Na/Pi cotransporter |journal=J Biol Chem. |volume=277 |issue= 22 |pages= 19665-72 |year= 2002 |pmid= 11880379 |doi= 10.1074/jbc.M200943200 }}</ref>

[[PHEX]] may regulate FGF23 expression as part of a potential hormonal axis between [[bone]] and [[kidney]] that controls systemic phosphate homeostasis and mineralization.<ref name=Liu>{{ cite journal |author=Liu S, Guo R, Simpson LG, Xiao ZS, Burnham CE, Quarles LD |title=Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX |journal=J Biol Chem. |year=2003 |month=Sep |volume=278 |issue=39 |pages=37419-26 |pmid=12874285 |doi=10.1074/jbc.M304544200 }}</ref> PHEX is highly expressed in [[cartilage]], bone, and [[teeth]], where it is present in [[osteoblast]]s, [[osteocyte]]s, and [[odontoblast]]s, especially at the transition between the maturation of pre-osteoblasts to mature osteoblasts when PHEX expression is normally up-regulated.<ref name=Liu/>

==Phosphate [[transistasis]]==

The power or tendency of a living thing to keep changing its phosphate needs according to the transformation of circumstances is phosphate transistasis; i.e., to reform its functions to maintain a meaningful condition, by means of multiple [[dynamic equilibrium]] adjustments, controlled by interrelated phosphate regulation mechanisms. Homeostasis and transistasis are needed to maintain stability and to survive. An organism has to endure, adapt, and evolve to modifications of the environment. It does this by testing which way its variables should be adjusted, by being ultraflexible.

[[Negative feedback]] is a reaction in which the system responds in such a way as to reverse the direction of change. Since this tends to keep things constant, it allows the maintenance of homeostasis.

In [[positive feedback]], the response is to amplify the change in the variable, allowing the maintenance of transistasis.

===Cell growth and phosphate limitation===

Mathematical modeling of the rate kinetics of growth and acid phosphatase formation under varying degrees of phosphate limitation is concerned with (a) the time lag for exponential growth, (b) the biphasic growth on a substrate (glucose) and its product, (c) sustained growth on conservative phosphate, and (d) the derepression of acid phosphatase. The numerical calculations using appropriate parametric constants describe the variation in the cell mass, glucose, product, and inorganic phosphate concentrations, and the enzyme activity of acid phosphatase during aerobic growth under different conditions of phosphate starvation. Study by simulation revealed that the optimum initial phosphate concentration in the medium giving a high productivity of acid phosphate is 2.0 mg phosphorus/g glucose liter.<ref name=Toda>{{ cite journal |author=Toda K, Yabe I |title=Mathematical model of cell growth and phosphatase biosynthesis in Saccharomyces carlsbergensis under phosphate limitation |journal=Biotech Bioeng. |year=2004 |month=Feb |volume=21 |issue=3 |pages=487-502 |doi=10.1002/bit.260210310 }}</ref>

===Regulation of phosphate transporters===

The regulation of phosphate transporters by nutrient-responsive signaling pathways allows cells to tailor phosphate uptake to environmental conditions.<ref name=Wykoff>{{ cite journal |author=Wykoff DD, Rizvi AH, Raser JM, Margolin B, O'Shea EK |title=Positive Feedback Regulates Switching of Phosphate Transporters in ''S. cerevisiae'' |journal=Molecular Cell. |month=Sep |year=2007 |volume=27 |issue=6 |pages=1005-13 |doi=10.1016/j.molcel.2007.07.022 }}</ref> Cells starved for phosphate activate positive and negative feedback loops in an interplay that leads to bistability in phosphate transporter usage.<ref name=Wykoff/> Positive feedback can be generated by a negative regulator of low-affinity phosphate, where individual cells express predominantly either low- or high-affinity transporters and both can yield similar phosphate uptake capacity.<ref name=Wykoff/>

===Coagulation cascade===

Up-regulation of tissue factor (TF) is induced by the interplay between thrombin and sphingosine 1-phosphate (S1P).<ref name=Takeya>{{ cite journal |author=Takeya H, Gabazza EC, Aoki S, Ueno H, Suzuki K |title=Synergistic effect of sphingosine 1-phosphate on thrombin-induced tissue factor expression in endothelial cells |journal=Blood. |month=Sep |year=2003 |volume=102 |issue=5 |pages=1693-1700 |doi=10.1182/blood-2002-11-3607 }}</ref> Expression of TF after thrombin and S1P stimulation activates the coagulation cascade leading to further generation of thrombin and S1P; hence, a positive feedback loop.<ref name=Takeya/>

===Cell proliferation===

There is a positive feedback loop in which Ras signaling promotes CD44v6 splicing, and CD44v6 then sustains late Ras signaling, which is important for cell cycle progression.<ref name=Cheng>{{ cite journal |author=Cheng C, Yaffe MB, Sharp PA |title=A positive feedback loop couples Ras activation and CD44 alternative splicing |journal=Genes Dev. |month= |year=2006 |volume=20 |issue=13 |pages=1715-20 |doi= 10.1101/gad.1430906 }}</ref> The production of CD44 variants is stimulated by Ras/MAPK signaling (Ras-Raf-MEK-ERK) and regulated by splicing factors which promote the inclusion of CD44 variable exons, controlled by Ras/MAPK signaling, at least in part through modification of splicing factors at the level of phosphorylation.<ref name=Cheng/>

===Growth and regrowth of phosphate reserves===

From the phosphate point of view inside a cell, changes in the allocation of phosphate or phosphate needs that come from a force that can transform circumstances becomes a phosphate transistasis. The interplay of [[Feedback#In biology|feedback]]s then determines either a new equilibrium state; hence, a new homeostasis, or returns the circumstances back to the original state.

One such force internal to the cell is the [[autonomously replicating sequence]] (ARS). [[Eukaryote]]s often have multiple origins of replication on each linear chromosome, with up to 100,000 present in a single human cell.<ref name=Nasheuer>{{cite journal |author=Nasheuer HP, Smith R, Bauerschmidt C, Grosse F, Weisshart K |title=Initiation of eukaryotic DNA replication: regulation and mechanisms |journal=Prog Nucleic Acid Res Mol Biol. |volume=72 |issue= |pages=41–94 |year=2002 |pmid=12206458 |doi=10.1016/S0079-6603(02)72067-9}}</ref> This small [[DNA]] sequence can initiate replication of itself unless kept in check by feedbacks.

In addition, there are many [[genome]]s that create [[Phosphate homeostasis#Phosphate reserves|phosphate reserves]]. Or, the particular genome needs to alter its [[Phosphate homeostasis#Phosphate budget|phosphate budget]], e.g., to create more [[structural phosphate]], such as by mitosis, or more [[Structural phosphate#Catalytic phosphate|catalytic phosphate]].

When any of these demands are placed on the current state of phosphate homeostasis, and the demand is not readily negated by [[negative feedback]], a dynamic state of change occurs. A [[zygote]], e.g., happily feeding and replicating itself in homeostatic bliss may eventually reach a polycellular situation when a phosphate reserve is needed. [[Endochondral ossification]] and [[intramembranous ossification]] are two processes resulting in the formation of normal, healthy bone tissue.<ref name=Caetano>{{cite journal |author=Caetano-Lopes J, Canhão H, Fonseca JE |title=Osteoblasts and bone formation |journal=Acta reumatológica portuguesa |volume=32 |issue=2 |pages=103–10 |year=2007 |pmid=17572649}}</ref>

Several hypotheses have been proposed for how bone evolved as a structural element in [[vertebrates]]. One hypothesis is that bone developed from tissues that evolved to store [[mineral]]s, such as [[hydroxyapatite]]. Up to fifty percent of [[osseous tissue|bone]] is made up of a modified form of the inorganic mineral hydroxylapatite.<ref name=Junqueira>
{{cite book |last= Junqueira|first= Luiz Carlos|coauthors= José Carneiro|editor1-last Foltin|editor1-first Janet|editor2-last Lebowitz|editor2-first Harriet|editor3-last Boyle|editor3-first Peter J.|title= Basic Histology, Text & Atlas|edition= 10th|year= 2003|publisher= McGraw-Hill Companies|isbn=0071378294|page= 144|quote= Inorganic matter represents about 50% of the dry weight of bone ... crystals show imperfections and are not identical to the hydroxyapatite found in the rock minerals }}</ref>

Or, specifically, calcium-based minerals were stored in [[cartilage]] and bone was an [[exaptation]] development from this calcified cartilage.<ref name=Donoghue>{{cite journal |author=Donoghue PC, Sansom IJ |title=Origin and early evolution of vertebrate skeletonization |journal=Microsc Res Tech.|issue=5 |pages=352–72 |year=2002 |pmid=12430166 |doi=10.1002/jemt.10217 |volume=59 }}</ref> However, other possibilities include bony tissue evolving as an osmotic barrier, or as a protective structure.

Then again, carbonated-calcium deficient hydroxyapatite is the main mineral of which [[bone]], [[dental enamel]] and [[dentin]] are comprised.<ref name=Jui>{{ cite patent |author=Jui C, Sanghamitra B, Kumar SM, Debabrata B |title=PROCESS FOR THE PREPARATION OF PROTEIN MEDIATED CALCIUM HYDROXYAPATITE (HAP) COATING ON METAL SUBSTRATE |United States Patent Application=20090181161 |url=http://www.freepatentsonline.com/y2009/0181161.html }}</ref>

==Phosphate budget==

The amount of phosphate needed or available for a purpose, including estimates of phosphate in and phosphate out, and the phosphate form, determine the phosphate budget for a cell or an entire organism.

A dynamic phosphate budget can be modeled by determining the relations between the external phosphate loading, recycling through the formation of [[structural phosphate]]s, and the resulting productivity, which are complicated by feed-back mechanisms, periodic variations and trends.<ref name=Lijklema>{{ cite journal |author=Lijklema L, Hieltjes AHM |title=A dynamic phosphate budget model for a eutrophic lake |journal=Hydrobiologia |month=Jul |volume=91-92 |issue=1 |year=1982 |pages=227-33 |doi=10.1007/BF00940113 }}</ref> In a dynamic phosphate budget model the variables include inorganic and organic particulate phosphate and dissolved phosphate, in both structural phosphate and [[nucleosol]]. [[Structural phosphate]] may be aerobic or anaerobic, depending on localization, temperature (or pH) and composition. The major describeable processes are primary production, mineralization, precipitation, adsorption and diffusion. The precipitate dilution rate, the extent of anaerobic conditions and the number and character of adsorption sites are important controlling factors.<ref name=Lijklema/>

A simplified phosphate-cycling model for a periodic phosphate budget is used to examine how changes in circulation might influence phosphate export production via the supply of phosphate to the phosphate utilization zone and the preservation of organic phosphate which is controlled by the oxygen content.<ref name=Stratford>{{ cite journal |author=Stratford K, Williams RG, Myers PG |title=Impact of the circulation on sapropel formation in the eastern Mediterranean |journal=Global Biogeochemical Cycles |month=Jun |volume=14 |issue=2 |pages=683-95 |year=2000 }}</ref> The model uses coupled equations: phosphate utilization, phosphate [[remineralization]], and the oxygen concentration. The initial conditions for all the integrations of the model consist of uniform values for the concentration of each component.

For a "standard man" of 70 kg the available phosphate is ~1.52 x 10<sup>25</sup> molecules of phosphate in some form. The available phosphate of an adult human female may differ from the "standard man".

{| class="wikitable sortable"
|+ Likely Cellular Phosphate Budget Human Adult
|-
! Component !! Type !! Number of molecules !! Accumulating total.
|-
| [[Cell membrane]] || [[structural phosphate]] || ~1.6 x 10<sup>8</sup> || ~1.6 x 10<sup>8</sup>
|-
| [[Endoplasmic reticulum]] || [[structural phosphate]] || ~1.7 x 10<sup>8</sup> || ~3.3 x 10<sup>8</sup>
|-
| [[mitochondrial DNA]] || [[structural phosphate]] || ~3.3 x 10<sup>8</sup> || ~6.6 x 10<sup>8</sup>
|-
| [[ATP]] || 2 [[structural phosphate]]s, 1 catalytic phosphate || ~2.7 x 10<sup>9</sup> || ~3.4 x 10<sup>9</sup>
|-
| [[Cytidine triphosphate|CTP]] || 2 [[structural phosphate]]s, 1 catalytic phosphate || ~2.7 x 10<sup>9</sup> || ~6.1 x 10<sup>9</sup>
|-
| [[Guanosine triphosphate|GTP]] || 2 [[structural phosphate]]s, 1 catalytic phosphate || ~2.7 x 10<sup>9</sup> || ~8.8 x 10<sup>9</sup>
|-
| [[Uridine triphosphate|UTP]] || 2 [[structural phosphate]]s, 1 catalytic phosphate || ~2.7 x 10<sup>9</sup> || ~12 x 10<sup>9</sup>
|-
| [[chromatin]] [[DNA]] || [[structural phosphate]] || ~6.8 x 10<sup>9</sup> || ~19 x 10<sup>9</sup>
|-
| others || all || ~0.4 x 10<sup>9</sup> || ~19 x 10<sup>9</sup>
|-
| all || all || ~19 x 10<sup>9</sup> || ~19 x 10<sup>9</sup>
|-
|}

==Phosphate recycling==

When a [[mRNA]] is transcribed for a particular protein ~80% of the [[structural phosphate]] is internal to the [[intron]]s. As these are composed of a line of nucleotide monophosphates (NMP), once finished and spliced out of the transcript, they can be taken apart by a variety of enzymes EC 2.7.7.6, 2.7.7.8, 2.7.7.19, and 2.7.7.48. The newly formed nucleotide diphosphates and triphosphates can then be reused to make additional RNA or DNA.

==Phosphate 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.

Hyperphosphoric acid can be added to blood to release CO<sub>2</sub>.<ref name=Sidossis>{{ cite journal |author=Sidossis LS, Mittendorfer B, Chinkes D, Walser E, Wolfe RR |title=Effect of hyperglycemia-hyperinsulinemia on whole body and regional fatty acid metabolism |journal=Am J Physiol. |volume=276 |pages=E427-34 |year=1999 |month=Mar |issue=(3 Pt 1) |pmid=10070006 }}</ref>

Hyperphosphates (salts or esters) or oleophosphates can result from the use of [[Phosphorus oxoacids#Hyperphosphoric acid|hyperphosphoric acid]]. Hyperphosphate, when used to induce [[hyperphosphatemia]], may directly promote calcium deposition and [[osteocalcin]] expression.<ref name=Lu>{{ cite journal |author=Lu W, Wang X, Zhao X |title=Study of vascular smooth muscle cell calcification induced by hyperphosphate and intervented by phosphonoformic acid |year=2007 |journal=J Nanjing Med Univ. |volume=21 |issue=6 |month=Nov |pages=377-81 |doi=10.1016/S1007-4376(07)60082-3 }}</ref>

Two rare autosomal recessive metabolic disorders characterized by hyperphosphatemia: [[Calcinosis#Tumoral calcinosis|hyperphosphatemic familial tumoral calcinosis]] (HFTC) and [[Hyperostosis|hyperphosphatemia-hyperostosis syndrome]] (HHS) appear to be caused by mutations in [[GALNT3]]<ref name=Specktor>{{ cite journal |author=Specktor P, Cooper JG, Indelman M, Sprecher E |title=Hyperphosphatemic familial tumoral calcinosis caused by a mutation in GALNT3 in a European kindred |journal=J Hum Genet. |year=2006 |volume=51 |issue=5 |pages=487-90 |pmid=16528452 }}</ref><ref name=Ichikawa>{{ cite journal |author=Ichikawa S, Guigonis V, Imel EA, Courouble M, Heissat S, Henley JD, Sorenson AH, Petit B, Lienhardt A, Econs MJ |title=Novel GALNT3 mutations causing hyperostosis-hyperphosphatemia syndrome result in low intact fibroblast growth factor 23 concentrations |journal=J Clin Endocrinol Metab. |year=2007 |month=May |volume=92 |issue=5 |pages=1943-7 |pmid=17311862 }}</ref> which in turn affects FGF23<ref name=Kato/>.

==Acknowledgements==

The content on this page was first contributed by: Henry A. Hoff.

Initial content for this page in some instances came from [http://www.wikipedia.org Wikipedia].

==References==

{{reflist|2}}

==See also==

* [[Structural phosphate]]
* [[Organophosphate]]
* [[Pyrophosphoric acid]]
* [[Pyrophosphate]]
* [[Phosphate]]
* [[Phosphoric acid]]
* [[Phosphoric acids and phosphates]]
* [[Phosphorus oxoacids]]
* [[Organophosphorus]]

* [[Human ATP synthase]]

* [[Nucleosol]]

==External links==

* {{Dorlands|f_10|12369270}}
* {{eMedicineDictionary|extracellular+fluid}}

{{Protein posttranslational modification}}
{{Pentose phosphate pathway enzymes}}
{{Phospholipids}}
{{Nucleobases, nucleosides, and nucleotides}}
{{Enzyme cofactors}}
{{Nucleotide metabolism enzymes}}
{{Nucleic acids}}
{{Polymerases}}
{{Mitochondrial DNA}}
{{Membrane lipids}}
{{Organelles}}
{{Structures of the cell membrane}}
{{Cybernetics}}
{{Molecular Biology}}
{{Neurotransmitters}}
{{Bone and cartilage}} 
{{Renal physiology}}{{tlx|Phosphate biochemistry}}

[[Category:Organophosphates]]
[[Category:Phosphates]]
[[Category:Inorganic compounds]]
[[Category:Chemical elements]]
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[[Category:Dietary minerals]]
[[Category:Phosphorus]]
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[[Category:Gene expression]]
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[[Category:Posttranslational modification]]
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