Difference between revisions of "Inorganic pyrophosphatase"

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|caption= Structure of inorganic pyrophosphatase, isolated from ''[[Thermococcus litoralis]]''.
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'''Pyrophosphatase''' (or '''inorganic pyrophosphatase''') is an enzyme that converts one molecule of [[pyrophosphate]] to two [[phosphate]] ions. This highly [[exergonic]] reaction (about -34KJ change in free energy) can be coupled to unfavorable biochemical transformations in order to drive these transformations to completion, as in [[Lipid metabolism|Lipid synthesis]] and  other biochemical transformations.
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<!-- Deleted image removed: [[Image:inorganic pyrophosphatase hexamer.png|thumb|left|275px|'''Image 1:'''The [[hexameric]] structure of inorganic pyrophosphatase isolated from ''[[Thermococcus litoralis]]''.]] -->
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'''Pyrophosphatase''' (or '''inorganic pyrophosphatase''') is an [[enzyme]] ({{EC number|3.6.1.1}}) that catalyzes the conversion of one molecule of [[pyrophosphate]] to two [[phosphate]] ions.<ref name="pmid5342521">{{cite journal |author=Harold FM |title=Inorganic polyphosphates in biology: structure, metabolism, and function |journal=Bacteriol Rev |volume=30 |issue=4 |pages=772–94 |date=December 1966 |pmid=5342521 |pmc=441015 |doi= |url=}}</ref> This is a highly [[exergonic]] reaction, and therefore can be coupled to unfavorable biochemical transformations in order to drive these transformations to completion.<ref name="pmid11401820">{{cite journal |author=Terkeltaub RA |title=Inorganic pyrophosphate generation and disposition in pathophysiology |journal=Am. J. Physiol., Cell Physiol. |volume=281 |issue=1 |pages=C1–C11 |date=July 2001 |pmid=11401820 |doi= |url=}}</ref> The functionality of this [[enzyme]] plays a critical role in [[lipid metabolism]] (including lipid synthesis and degradation), calcium absorption and bone formation,<ref name="pmid4327778">{{cite journal |vauthors=Orimo H, Ohata M, Fujita T |title=Role of inorganic pyrophosphatase in the mechanism of action of parathyroid hormone and calcitonin |journal=Endocrinology |volume=89 |issue=3 |pages=852–8 |date=September 1971 |pmid=4327778 |doi= 10.1210/endo-89-3-852|url=}}</ref><ref name="pmid16181808">{{cite journal |vauthors=Poole KE, Reeve J |title=Parathyroid hormone - a bone anabolic and catabolic agent |journal=Curr Opin Pharmacol |volume=5 |issue=6 |pages=612–7 |date=December 2005 |pmid=16181808 |doi=10.1016/j.coph.2005.07.004 |url=}}</ref> and DNA synthesis,<ref name="lehninger">{{Cite book | last = Nelson | first = David L. |author2=Cox, Michael M. | year = 2000 | title = Lehninger Principles of Biochemistry, 3rd ed. | publisher = Worth Publishers | location = New York | isbn = 1-57259-153-6 | pages = 937}}</ref> as well as other [[biochemical]] transformations.<ref name="pmid17981157">{{cite journal |vauthors=Ko KM, Lee W, Yu JR, Ahnn J |title=PYP-1, inorganic pyrophosphatase, is required for larval development and intestinal function in C. elegans |journal=FEBS Lett. |volume=581 |issue=28 |pages=5445–53 |date=November 2007 |pmid=17981157 |doi=10.1016/j.febslet.2007.10.047 |url=}}</ref><ref name="pmid20332330">{{cite journal |vauthors=Usui Y, Uematsu T, Uchihashi T, etal |title=Inorganic polyphosphate induces osteoblastic differentiation |journal=J. Dent. Res. |volume=89 |issue=5 |pages=504–9 |date=May 2010 |pmid=20332330 |doi=10.1177/0022034510363096 |url=}}</ref>
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==Structure==
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Thermostable pyrophosphatase had been isolated from the [[extremophile]] ''[[Thermococcus litoralis]]''. The 3-dimensional structure was determined using [[x-ray crystallography]], and was found to consist of two [[Alpha helix|alpha-helices]], as well as an [[antiparallel (biochemistry)|antiparallel]] closed [[beta-sheet]]. The form of inorganic pyrophosphatase isolated from ''[[Thermococcus litoralis]]'' was found to contain a total of 174 [[amino acid residue]]s and have a [[hexameric]] [[oligomeric]] organization (Image 1).<ref name="pmid7920256">{{cite journal  |vauthors=Teplyakov A, Obmolova G, Wilson KS, etal |title=Crystal structure of inorganic pyrophosphatase from Thermus thermophilus |journal=Protein Sci. |volume=3 |issue=7 |pages=1098–107 |date=July 1994 |pmid=7920256 |pmc=2142889 |doi=10.1002/pro.5560030713 |url=}}</ref> Though the human form of the enzyme has not yet been isolated, a 1.23 kilobase [[cDNA]] segment has been identified that encodes a 32 kDa [[protein]] that is 94% identical to [[bovine]] inorganic pyrophosphatase.<ref name="pmid10542310">{{cite journal |vauthors=Fairchild TA, Patejunas G |title=Cloning and expression profile of human inorganic pyrophosphatase |journal=Biochim. Biophys. Acta |volume=1447 |issue=2-3 |pages=133–6 |date=October 1999 |pmid=10542310 |doi= 10.1016/s0167-4781(99)00175-x|url=}}</ref> This [[DNA]] sequence has assigned to a [[gene locus]] on human [[chromosome 10]].<ref name="pmid975879">{{cite journal |vauthors=McAlpine PJ, Mohandas T, Ray M, Wang H, Hamerton JL |title=Assignment of the inorganic pyrophosphatase gene locus (PP) to chromosome 10 in man |journal=Cytogenet. Cell Genet. |volume=16 |issue=1-5 |pages=201–3 |year=1976 |pmid=975879 |doi= 10.1159/000130590|url=}}</ref>
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==Mechanism==
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Though the precise mechanism of [[catalysis]] via inorganic pyrophosphatase in most organisms remains uncertain, site-directed [[mutagenesis]] studies in ''[[Escherichia coli]]'' have allowed for analysis of the [[enzyme]] [[active site]] and identification of key [[amino acid]]s. In particular, this analysis has revealed 17 residues of that may be of functional importance in [[catalysis]].<ref name="pmid19366250">{{cite journal |vauthors=Yang L, Liao RZ, Yu JG, Liu RZ |title=DFT study on the mechanism of Escherichia coli inorganic pyrophosphatase |journal=J Phys Chem B |volume=113 |issue=18 |pages=6505–10 |date=May 2009 |pmid=19366250 |doi=10.1021/jp810003w |url=}}</ref>
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Further research suggests that the [[protonation]] state of Asp67 is responsible for modulating the reversibility of the [[Chemical reaction|reaction]] in ''[[Escherichia coli]]''. The [[carboxylate]] functional group of this residue has been shown to perform a [[nucleophilic]] attack on the [[pyrophosphate]] [[substrate (biochemistry)|substrate]] when four [[magnesium]] [[ion]]s are present. Direct coordination with these four [[magnesium]] [[ion]]s and [[hydrogen bonding]] interactions with Arg43, Lys29, and Lys142 (all positively charged residues) have been shown to anchor the substrate to the [[active site]]. The four [[magnesium]] [[ion]]s are also suggested to be involved in the stabilization of the [[trigonal bipyramid]] [[transition state]], which lowers the energetic barrier for the aforementioned [[nucleophilic]] attack.<ref name="pmid19366250"/>
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Several studies have also identified additional [[Substrate (biochemistry)|substrates]] that can act as [[allosteric]] effectors. In particular, the binding of [[pyrophosphate]] (PPi) to the effector site of inorganic pyrophosphatase increases its rate of [[hydrolysis]] at the [[active site]].<ref name="pmid17309439">{{cite journal |vauthors=Sitnik TS, Avaeva SM |title=Binding of substrate at the effector site of pyrophosphatase increases the rate of its hydrolysis at the active site |journal=Biochemistry Mosc. |volume=72 |issue=1 |pages=68–76 |date=January 2007 |pmid=17309439 |doi= 10.1134/s0006297907010087|url=}}</ref> [[Adenosine triphosphate|ATP]] has also been shown to function as an [[allosteric]] activator in ''[[Escherichia coli]]'',<ref name="pmid17309442">{{cite journal |vauthors=Rodina EV, Vorobyeva NN, Kurilova SA, Belenikin MS, Fedorova NV, Nazarova TI |title=ATP as effector of inorganic pyrophosphatase of Escherichia coli. Identification of the binding site for ATP |journal=Biochemistry Mosc. |volume=72 |issue=1 |pages=93–9 |date=January 2007 |pmid=17309442 |doi= 10.1134/s0006297907010117|url=}}</ref> while [[fluoride]] has been shown to inhibit [[hydrolysis]] of [[pyrophosphate]] in [[yeast]].<ref name="pmid6139128">{{cite journal |vauthors=Smirnova IN, Baĭkov AA |title=[Two-stage mechanism of the fluoride inhibition of inorganic pyrophosphatase using the fluoride ion] |language=Russian |journal=Biokhimiia |volume=48 |issue=10 |pages=1643–53 |date=October 1983 |pmid=6139128 |doi= |url=}}</ref>
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==Biological Function and Significance==
 +
 
 +
The hydrolysis of inorganic [[pyrophosphate]] (PPi) to two [[phosphate]] ions is utilized in many biochemical pathways to render reactions effectively irreversible.<ref name="pmid15522220">{{cite journal |vauthors=Takahashi K, Inuzuka M, Ingi T |title=Cellular signaling mediated by calphoglin-induced activation of IPP and PGM |journal=Biochem. Biophys. Res. Commun. |volume=325 |issue=1 |pages=203–14 |date=December 2004 |pmid=15522220 |doi=10.1016/j.bbrc.2004.10.021 |url=}}</ref> This process is highly [[exergonic]] (accounting for approximately a −19kJ change in [[Thermodynamic free energy|free energy]]), and therefore greatly increases the energetic favorability of reaction system when coupled with a typically less-favorable reaction.<ref name="pmid17079146">{{cite journal |vauthors=Carman GM, Han GS |title=Roles of phosphatidate phosphatase enzymes in lipid metabolism |journal=Trends Biochem. Sci. |volume=31 |issue=12 |pages=694–9 |date=December 2006 |pmid=17079146 |pmc=1769311 |doi=10.1016/j.tibs.2006.10.003 |url=}}</ref>
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Inorganic pyrophosphatase catalyzes this [[hydrolysis]] reaction in the early steps of [[lipid]] degradation, a prominent example of this phenomenon. By promoting the rapid [[hydrolysis]] of [[pyrophosphate]] (PPi), Inorganic pyrophosphatase provides the driving force for the activation of [[fatty acids]] destined for [[beta oxidation]].<ref name="pmid17079146"/>
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Before [[fatty acids]] can undergo degradation to fulfill the metabolic needs of an organism, they must first be activated via a thioester linkage to [[coenzyme A]]. This process is catalyzed by the enzyme [[Long-chain-fatty-acid—CoA ligase|acyl CoA synthetase]], and occurs on the outer [[mitochondrial membrane]]. This activation is accomplished in two reactive steps: (1) the fatty acid reacts with a molecule of [[Adenosine triphosphate|ATP]] to form an enzyme-bound [[acyl adenylate]] and [[pyrophosphate]] (PPi), and (2) the sulfhydryl group of CoA attacks the acyl adenylate, forming [[acyl CoA]] and a molecule of [[Adenosine monophosphate|AMP]]. Each of these two steps is reversible under biological conditions, save for the additional hydrolysis of PPi by inorganic pyrophosphatase.<ref name="pmid17079146"/> This coupled [[hydrolysis]] provides the driving force for the overall forward activation reaction, and serves as a source of [[inorganic phosphate]] used in other biological processes.
 +
 
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==Evolution==
 +
 
 +
Examination of [[prokaryotic]] and [[eukaryotic]] forms of inorganic pyrophosphatase has shown that they differ significantly in both [[amino acid]] sequence, number of residues, and [[oligomeric]] organization. Despite differing structural components, recent work has suggested a large degree of [[evolutionary]] conservation of [[active site]] structure as well as [[reaction mechanism]], based on [[kinetic energy|kinetic]] data.<ref name="pmid1323891">{{cite journal |vauthors=Cooperman BS, Baykov AA, Lahti R |title=Evolutionary conservation of the active site of soluble inorganic pyrophosphatase |journal=Trends Biochem. Sci. |volume=17 |issue=7 |pages=262–6 |date=July 1992 |pmid=1323891 |doi= 10.1016/0968-0004(92)90406-y|url=}}</ref> Analysis of approximately one million genetic sequences taken from [[organisms]] in the [[Sargasso Sea]] identified a 57 residue sequence within the regions coding for inorganic pyrophosphatase that appears to be highly conserved; this region primarily consisted of the four early [[amino acid]] residues [[Gly]], [[Alanine|Ala]], [[Valine|Val]] and [[Aspartic acid|Asp]], suggesting an evolutionarily ancient origin for the [[protein]].<ref name="pmid17054711">{{cite journal |vauthors=Hedlund J, Cantoni R, Baltscheffsky M, Baltscheffsky H, Persson B |title=Analysis of ancient sequence motifs in the H-PPase family |journal=FEBS J. |volume=273 |issue=22 |pages=5183–93 |date=November 2006 |pmid=17054711 |doi=10.1111/j.1742-4658.2006.05514.x |url=}}</ref>
  
 
==External links==
 
==External links==
 
* {{MeshName|pyrophosphatases}}
 
* {{MeshName|pyrophosphatases}}
  
{{enzyme-stub}}
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==References==
{{Acid anhydride hydrolases}}
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{{reflist|colwidth=30em}}
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{{Acid anhydride hydrolases}}{{tlx|Phosphate biochemistry}}
 
{{Proton pumps}}
 
{{Proton pumps}}
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<br>

Latest revision as of 01:55, 17 February 2020

pyrophosphatase (inorganic) 1
File:Inorganic pyrophosphatase.png
Structure of inorganic pyrophosphatase, isolated from Thermococcus litoralis.
Identifiers
SymbolPPA1
Alt. symbolsPP
Entrez5464
HUGO9226
OMIM179030
RefSeqNM_021129
UniProtQ15181
Other data
EC number3.6.1.1
LocusChr. 10 q11.1-q24
pyrophosphatase (inorganic) 2
Identifiers
SymbolPPA2
Entrez27068
HUGO28883
OMIM609988
RefSeqNM_176869
UniProtQ9H2U2
Other data
LocusChr. 4 q25

Pyrophosphatase (or inorganic pyrophosphatase) is an enzyme (EC 3.6.1.1) that catalyzes the conversion of one molecule of pyrophosphate to two phosphate ions.[1] This is a highly exergonic reaction, and therefore can be coupled to unfavorable biochemical transformations in order to drive these transformations to completion.[2] The functionality of this enzyme plays a critical role in lipid metabolism (including lipid synthesis and degradation), calcium absorption and bone formation,[3][4] and DNA synthesis,[5] as well as other biochemical transformations.[6][7]

Structure

Thermostable pyrophosphatase had been isolated from the extremophile Thermococcus litoralis. The 3-dimensional structure was determined using x-ray crystallography, and was found to consist of two alpha-helices, as well as an antiparallel closed beta-sheet. The form of inorganic pyrophosphatase isolated from Thermococcus litoralis was found to contain a total of 174 amino acid residues and have a hexameric oligomeric organization (Image 1).[8] Though the human form of the enzyme has not yet been isolated, a 1.23 kilobase cDNA segment has been identified that encodes a 32 kDa protein that is 94% identical to bovine inorganic pyrophosphatase.[9] This DNA sequence has assigned to a gene locus on human chromosome 10.[10]

Mechanism

Though the precise mechanism of catalysis via inorganic pyrophosphatase in most organisms remains uncertain, site-directed mutagenesis studies in Escherichia coli have allowed for analysis of the enzyme active site and identification of key amino acids. In particular, this analysis has revealed 17 residues of that may be of functional importance in catalysis.[11]

Further research suggests that the protonation state of Asp67 is responsible for modulating the reversibility of the reaction in Escherichia coli. The carboxylate functional group of this residue has been shown to perform a nucleophilic attack on the pyrophosphate substrate when four magnesium ions are present. Direct coordination with these four magnesium ions and hydrogen bonding interactions with Arg43, Lys29, and Lys142 (all positively charged residues) have been shown to anchor the substrate to the active site. The four magnesium ions are also suggested to be involved in the stabilization of the trigonal bipyramid transition state, which lowers the energetic barrier for the aforementioned nucleophilic attack.[11]

Several studies have also identified additional substrates that can act as allosteric effectors. In particular, the binding of pyrophosphate (PPi) to the effector site of inorganic pyrophosphatase increases its rate of hydrolysis at the active site.[12] ATP has also been shown to function as an allosteric activator in Escherichia coli,[13] while fluoride has been shown to inhibit hydrolysis of pyrophosphate in yeast.[14]

Biological Function and Significance

The hydrolysis of inorganic pyrophosphate (PPi) to two phosphate ions is utilized in many biochemical pathways to render reactions effectively irreversible.[15] This process is highly exergonic (accounting for approximately a −19kJ change in free energy), and therefore greatly increases the energetic favorability of reaction system when coupled with a typically less-favorable reaction.[16]

Inorganic pyrophosphatase catalyzes this hydrolysis reaction in the early steps of lipid degradation, a prominent example of this phenomenon. By promoting the rapid hydrolysis of pyrophosphate (PPi), Inorganic pyrophosphatase provides the driving force for the activation of fatty acids destined for beta oxidation.[16]

Before fatty acids can undergo degradation to fulfill the metabolic needs of an organism, they must first be activated via a thioester linkage to coenzyme A. This process is catalyzed by the enzyme acyl CoA synthetase, and occurs on the outer mitochondrial membrane. This activation is accomplished in two reactive steps: (1) the fatty acid reacts with a molecule of ATP to form an enzyme-bound acyl adenylate and pyrophosphate (PPi), and (2) the sulfhydryl group of CoA attacks the acyl adenylate, forming acyl CoA and a molecule of AMP. Each of these two steps is reversible under biological conditions, save for the additional hydrolysis of PPi by inorganic pyrophosphatase.[16] This coupled hydrolysis provides the driving force for the overall forward activation reaction, and serves as a source of inorganic phosphate used in other biological processes.

Evolution

Examination of prokaryotic and eukaryotic forms of inorganic pyrophosphatase has shown that they differ significantly in both amino acid sequence, number of residues, and oligomeric organization. Despite differing structural components, recent work has suggested a large degree of evolutionary conservation of active site structure as well as reaction mechanism, based on kinetic data.[17] Analysis of approximately one million genetic sequences taken from organisms in the Sargasso Sea identified a 57 residue sequence within the regions coding for inorganic pyrophosphatase that appears to be highly conserved; this region primarily consisted of the four early amino acid residues Gly, Ala, Val and Asp, suggesting an evolutionarily ancient origin for the protein.[18]

External links

References

  1. Harold FM (December 1966). "Inorganic polyphosphates in biology: structure, metabolism, and function". Bacteriol Rev. 30 (4): 772–94. PMC 441015. PMID 5342521.
  2. Terkeltaub RA (July 2001). "Inorganic pyrophosphate generation and disposition in pathophysiology". Am. J. Physiol., Cell Physiol. 281 (1): C1–C11. PMID 11401820.
  3. Orimo H, Ohata M, Fujita T (September 1971). "Role of inorganic pyrophosphatase in the mechanism of action of parathyroid hormone and calcitonin". Endocrinology. 89 (3): 852–8. doi:10.1210/endo-89-3-852. PMID 4327778.
  4. Poole KE, Reeve J (December 2005). "Parathyroid hormone - a bone anabolic and catabolic agent". Curr Opin Pharmacol. 5 (6): 612–7. doi:10.1016/j.coph.2005.07.004. PMID 16181808.
  5. Nelson, David L.; Cox, Michael M. (2000). Lehninger Principles of Biochemistry, 3rd ed. New York: Worth Publishers. p. 937. ISBN 1-57259-153-6.
  6. Ko KM, Lee W, Yu JR, Ahnn J (November 2007). "PYP-1, inorganic pyrophosphatase, is required for larval development and intestinal function in C. elegans". FEBS Lett. 581 (28): 5445–53. doi:10.1016/j.febslet.2007.10.047. PMID 17981157.
  7. Usui Y, Uematsu T, Uchihashi T, et al. (May 2010). "Inorganic polyphosphate induces osteoblastic differentiation". J. Dent. Res. 89 (5): 504–9. doi:10.1177/0022034510363096. PMID 20332330.
  8. Teplyakov A, Obmolova G, Wilson KS, et al. (July 1994). "Crystal structure of inorganic pyrophosphatase from Thermus thermophilus". Protein Sci. 3 (7): 1098–107. doi:10.1002/pro.5560030713. PMC 2142889. PMID 7920256.
  9. Fairchild TA, Patejunas G (October 1999). "Cloning and expression profile of human inorganic pyrophosphatase". Biochim. Biophys. Acta. 1447 (2–3): 133–6. doi:10.1016/s0167-4781(99)00175-x. PMID 10542310.
  10. McAlpine PJ, Mohandas T, Ray M, Wang H, Hamerton JL (1976). "Assignment of the inorganic pyrophosphatase gene locus (PP) to chromosome 10 in man". Cytogenet. Cell Genet. 16 (1–5): 201–3. doi:10.1159/000130590. PMID 975879.
  11. 11.0 11.1 Yang L, Liao RZ, Yu JG, Liu RZ (May 2009). "DFT study on the mechanism of Escherichia coli inorganic pyrophosphatase". J Phys Chem B. 113 (18): 6505–10. doi:10.1021/jp810003w. PMID 19366250.
  12. Sitnik TS, Avaeva SM (January 2007). "Binding of substrate at the effector site of pyrophosphatase increases the rate of its hydrolysis at the active site". Biochemistry Mosc. 72 (1): 68–76. doi:10.1134/s0006297907010087. PMID 17309439.
  13. Rodina EV, Vorobyeva NN, Kurilova SA, Belenikin MS, Fedorova NV, Nazarova TI (January 2007). "ATP as effector of inorganic pyrophosphatase of Escherichia coli. Identification of the binding site for ATP". Biochemistry Mosc. 72 (1): 93–9. doi:10.1134/s0006297907010117. PMID 17309442.
  14. Smirnova IN, Baĭkov AA (October 1983). "[Two-stage mechanism of the fluoride inhibition of inorganic pyrophosphatase using the fluoride ion]". Biokhimiia (in Russian). 48 (10): 1643–53. PMID 6139128.
  15. Takahashi K, Inuzuka M, Ingi T (December 2004). "Cellular signaling mediated by calphoglin-induced activation of IPP and PGM". Biochem. Biophys. Res. Commun. 325 (1): 203–14. doi:10.1016/j.bbrc.2004.10.021. PMID 15522220.
  16. 16.0 16.1 16.2 Carman GM, Han GS (December 2006). "Roles of phosphatidate phosphatase enzymes in lipid metabolism". Trends Biochem. Sci. 31 (12): 694–9. doi:10.1016/j.tibs.2006.10.003. PMC 1769311. PMID 17079146.
  17. Cooperman BS, Baykov AA, Lahti R (July 1992). "Evolutionary conservation of the active site of soluble inorganic pyrophosphatase". Trends Biochem. Sci. 17 (7): 262–6. doi:10.1016/0968-0004(92)90406-y. PMID 1323891.
  18. Hedlund J, Cantoni R, Baltscheffsky M, Baltscheffsky H, Persson B (November 2006). "Analysis of ancient sequence motifs in the H-PPase family". FEBS J. 273 (22): 5183–93. doi:10.1111/j.1742-4658.2006.05514.x. PMID 17054711.

{{Phosphate biochemistry}}



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