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The enzymes of the multi-step ''de novo'' ] have been postulated to form a multi-enzyme complex to facilitate ] between each enzyme of the pathway. Slight variations of the pathway exists between phyla; however, there are 13 enzymes that can be considered part of this biosynthetic pathway.<ref name=Kornberg1982>{{cite book|title=Supplement to DNA Replication|author=Kornberg, A.|year=1982|journal=San Francisco:Free­man}}</ref> Several individual enzymatic functions have consolidated onto single bifunctional or trifunctional polypeptide chains in higher organisms, suggesting stable physical interactions exist between enzymes.<ref name=Henikoff>{{cite journal|journal=Proc. The enzymes of the multi-step ''de novo'' ] have been postulated to form a multi-enzyme complex to facilitate ] between each enzyme of the pathway. Slight variations of the pathway exists between phyla; however, there are 13 enzymes that can be considered part of this biosynthetic pathway.<ref name=Kornberg1982>{{cite book|title=Supplement to DNA Replication|author=Kornberg, A.|year=1982|journal=San Francisco:Free­man}}</ref> Several individual enzymatic functions have consolidated onto single bifunctional or trifunctional polypeptide chains in higher organisms, suggesting stable physical interactions exist between enzymes.<ref name=Henikoff>{{cite journal|journal=Proc.
Natl. Acad. Sci. USA|title=Multiple purine pathway enzyme activities are encoded at a single Natl. Acad. Sci. USA|title=Multiple purine pathway enzyme activities are encoded at a single
genetic locus in Drosophila|author=Henikoff, S., Keene, M. A., Sloan, S., Bleskan, J., Hards, R., Patterson, D.|year=1986|volume=83|pages=720–24|doi=10.1073/pnas.83.3.720}}</ref><ref name=Marcotte>{{cite journal|journal=Science|title=Detecting protein function and protein-protein interactions from genome sequences|author=Marcotte EM, Pellegrini M, Ng HL, Rice DW, Yeates TO, Eisenberg D.|year=1999|volume=285|pages=751–3|doi=10.1126/science.285.5428.751|issue=5428|pmid=10427000}}</ref> The functional consolidation of steps 2,3, and 5 of the pathway into a single enzyme in higher organisms such as humans suggests physical local proximity of the enzyme for step 4 to the trifunctional enzyme.<ref name=Henikoff /><ref>{{cite journal|journal=Proceedings of the National Academy of Sciences of the United genetic locus in Drosophila|author=Henikoff, S., Keene, M. A., Sloan, S., Bleskan, J., Hards, R., Patterson, D.|year=1986|volume=83|issue=3|pages=720–24|doi=10.1073/pnas.83.3.720|last2=Keene|last3=Sloan|last4=Bleskan|last5=Hards|last6=Patterson|bibcode=1986PNAS...83..720H}}</ref><ref name=Marcotte>{{cite journal|journal=Science|title=Detecting protein function and protein-protein interactions from genome sequences|author=Marcotte EM, Pellegrini M, Ng HL, Rice DW, Yeates TO, Eisenberg D.|year=1999|volume=285|pages=751–3|doi=10.1126/science.285.5428.751|issue=5428|pmid=10427000|last2=Pellegrini|last3=Ng|last4=Rice|last5=Yeates|last6=Eisenberg}}</ref> The functional consolidation of steps 2,3, and 5 of the pathway into a single enzyme in higher organisms such as humans suggests physical local proximity of the enzyme for step 4 to the trifunctional enzyme.<ref name=Henikoff /><ref>{{cite journal|journal=Proceedings of the National Academy of Sciences of the United
States of America|author=Patterson, D., Graw, S., & Jones, C.|year=1981|title="Demonstration by States of America|volume=78|author=Patterson, D., Graw, S., & Jones, C.|year=1981|title="Demonstration by
somatic cell genetics, of coordinate regulation of genes for two enzymes of purine synthesis assigned to human chromosome 21." somatic cell genetics, of coordinate regulation of genes for two enzymes of purine synthesis assigned to human chromosome 21."
volume=78|pages=405–409|doi=10.1073/pnas.78.1.405}}</ref><ref>{{cite journal|author=Hard, R. G., Benkovic, S. J., Van Keuren, M. L., Graw, S. L., Drabkin, H. A., & Patterson, D.|year= 1986|title=Assignment of a third purine biosynthetic gene (glycinamide ribonucleotide transformylase) to human chromosome 21.|journal=American Journal of Human Genetics|volume=39|pages=179–185}}</ref> volume=78|pages=405–409|doi=10.1073/pnas.78.1.405|last2=Graw|last3=Jones|bibcode=1981PNAS...78..405P}}</ref><ref>{{cite journal|author=Hard, R. G., Benkovic, S. J., Van Keuren, M. L., Graw, S. L., Drabkin, H. A., & Patterson, D.|year= 1986|title=Assignment of a third purine biosynthetic gene (glycinamide ribonucleotide transformylase) to human chromosome 21|journal=American Journal of Human Genetics|volume=39|issue= 2|pages=179–185|pmid= 3529945|pmc= 1683921|last2= Benkovic|last3= Van Keuren|last4= Graw|last5= Drabkin|last6= Patterson}}</ref>


===Evidence for a complex=== ===Evidence for a complex===
The purine biosynthesis enzymes can be co-purified under certain conditions.<ref name=Rowe1>{{cite journal|author=Rowe, P. B., McCaims, E., Madsen, G., Sauer, D., Elliott, H.|year=1978|title=De novo purine synthesis in avian liver. Co-purification of the enzymes and properties of the pathway.|journal=J. Biol. Chem.|volume=253|pages=7711–21}}</ref><ref name=McCairns>{{cite journal|author=McCairns, E., Fahey, D., Sauer, D., Rowe, P. B.|year=1983|title=De novo purine synthesis in human lymphocytes. Partial co-purification of the enzymes and some properties of the pathway.|journal=J. Biol. Chem.|volume=258|pages=1851–56}}</ref> A complex of two particular pathway enzymes GART and ATIC can be isolated with cofactor production enzyme C1THF synthase and SHTM1.<ref name=Smith1980>{{cite journal|author=Smith, G. K., Mueller, W. T., Wasser­man, G. F., Taylor, W. D., Benkovic, S. J.|year=1980|journal=Biochemistry|volume=19|pages=4313–21|doi=10.1021/bi00559a026 }}</ref> Kinetic studies show evidence of substrate channeling between PPAT and GART, but evidence could not be obtained for their physical protein-protein interaction.<ref name=Rud1995>{{cite journal|url=http://www.sciencemag.org/content/320/5872/103.long|title=Investigation of the Mechanism of Phosphoribosylamine Transfer from Glutamine Phosphoribosylpyrophosphate Amidotransferase to Glycinamide Ribonucleotide Synthetase|author=J. Rudolph and J. Stubbe|journal=Biochemistry|year=1995|volume=34|pages=224 1-2250|doi=10.1126/science.1152241}}</ref> Thus far, isolation of a multienzyme complex inclusive of all purine biosynthesis enzymes has not been achieved. The purine biosynthesis enzymes can be co-purified under certain conditions.<ref name=Rowe1>{{cite journal|author=Rowe, P. B., McCaims, E., Madsen, G., Sauer, D., Elliott, H.|year=1978|title=De novo purine synthesis in avian liver. Co-purification of the enzymes and properties of the pathway|journal=J. Biol. Chem.|volume=253|issue=21|pages=7711–21|pmid=701284|last2=McCairns|last3=Madsen|last4=Sauer|last5=Elliott}}</ref><ref name=McCairns>{{cite journal|author=McCairns, E., Fahey, D., Sauer, D., Rowe, P. B.|year=1983|title=De novo purine synthesis in human lymphocytes. Partial co-purification of the enzymes and some properties of the pathway.|journal=J. Biol. Chem.|volume=258|pages=1851–56}}</ref> A complex of two particular pathway enzymes GART and ATIC can be isolated with cofactor production enzyme C1THF synthase and SHTM1.<ref name=Smith1980>{{cite journal|author=Smith, G. K., Mueller, W. T., Wasser­man, G. F., Taylor, W. D., Benkovic, S. J.|title=Characterization of the enzyme complex involving the folate-requiring enzymes of de novo purine biosynthesis|year=1980|journal=Biochemistry|volume=19|issue=18|pages=4313–21|doi=10.1021/bi00559a026 |pmid=7417406|last2=Mueller|last3=Wasserman|last4=Taylor|last5=Benkovic}}</ref> Kinetic studies show evidence of substrate channeling between PPAT and GART, but evidence could not be obtained for their physical protein-protein interaction.<ref name=Rud1995>{{cite journal|url=http://www.sciencemag.org/content/320/5872/103.long|title=Investigation of the Mechanism of Phosphoribosylamine Transfer from Glutamine Phosphoribosylpyrophosphate Amidotransferase to Glycinamide Ribonucleotide Synthetase|author=J. Rudolph and J. Stubbe|journal=Biochemistry|year=1995|volume=34|issue=5872|pages=224 1–2250|doi=10.1126/science.1152241|bibcode=2008Sci...320..103A}}</ref> Thus far, isolation of a multienzyme complex inclusive of all purine biosynthesis enzymes has not been achieved.


==Purinosome macrobodies== ==Purinosome macrobodies==
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===Initial discovery=== ===Initial discovery===
The human purinosome was thought to have been identified in 2008 by the observation that transiently expressed GFP fusion constructs of purine biosynthesis proteins form macrobodies.<ref name=An2008>{{cite journal|title=Reversible Compartmentalization of de Novo Purine Biosynthetic Complexes in Living Cells|author=Songon An ''et al.''|journal=Science|year=2008|volume=320|number=5872|pages=103–106|doi=10.1126/science.1152241}}</ref><ref name=chemcomm>{{cite journal|journal=Chem Comm.|date=2013-04-03|volume=285|issue=15|pages=11093–11099|doi=10.1039/c3cc41437j|title=The purinosome, a multi-protein complex involved in the de novo biosynthesis of purines in humans|author=Hong Zhao, Jarrod B. French,Ye Fang and Stephen J. Benkovic}}</ref> A folate enzyme not directly involved in the purine biosynthesis pathway, ] synthase (MTHFS), was later found to be part of purinosome macrobodies by the same approach.<ref name=Field>{{cite journal|title=Mthfs is an essential gene in mice and a component of the purinosome|author=Martha S. Field, Donald D. Anderson, and Patrick J. Stover|journal=Front Genet.|year=2011|volume=2|issue=36|doi=10.3389/fgene.2011.00036|pmc=3268590}}</ref> The biological relevance of this folate enzyme's inclusion to the purinosome macrobody is unclear: while it provides substrate for a trifunctional folate enzyme C1THF synthase to generate a key cofactor for purine biosynthesis, C1THF synthase is not a part of purinosome macrobodies.<ref name=An2008 /> Curiously, ] levels do not alter purinosome macrobodies,<ref name=An2008 /> but ] or ] addition suppresses formation of macromolecular bodies formed by the folate enzyme.<ref name=Field /> The human purinosome was thought to have been identified in 2008 by the observation that transiently expressed GFP fusion constructs of purine biosynthesis proteins form macrobodies.<ref name=An2008>{{cite journal|title=Reversible Compartmentalization of de Novo Purine Biosynthetic Complexes in Living Cells|author=Songon An|journal=Science|year=2008|volume=320|number=5872|pages=103–106|doi=10.1126/science.1152241|pmid=18388293|author2=and others|displayauthors=1|bibcode=2008Sci...320..103A|last3=Sheets|last4=Benkovic}}</ref><ref name=chemcomm>{{cite journal|journal=Chem Comm.|date=2013-04-03|volume=285|issue=15|pages=11093–11099|doi=10.1039/c3cc41437j|title=The purinosome, a multi-protein complex involved in the de novo biosynthesis of purines in humans|author=Hong Zhao, Jarrod B. French,Ye Fang and Stephen J. Benkovic}}</ref> A folate enzyme not directly involved in the purine biosynthesis pathway, ] synthase (MTHFS), was later found to be part of purinosome macrobodies by the same approach.<ref name=Field>{{cite journal|title=Mthfs is an essential gene in mice and a component of the purinosome|author=Martha S. Field, Donald D. Anderson, and Patrick J. Stover|journal=Front Genet.|year=2011|volume=2|issue=36|pages=36|doi=10.3389/fgene.2011.00036|pmc=3268590}}</ref> The biological relevance of this folate enzyme's inclusion to the purinosome macrobody is unclear: while it provides substrate for a trifunctional folate enzyme C1THF synthase to generate a key cofactor for purine biosynthesis, C1THF synthase is not a part of purinosome macrobodies.<ref name=An2008 /> Curiously, ] levels do not alter purinosome macrobodies,<ref name=An2008 /> but ] or ] addition suppresses formation of macromolecular bodies formed by the folate enzyme.<ref name=Field />


===Aggregation=== ===Aggregation===
Later studies in 2013 support the interpretation that those macrobodies could be artifacts of aggregated proteins that commonly result from fusion protein expression.<ref name=Zhao2013>{{cite journal|url=http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056203|title=Transiently Transfected Purine Biosynthetic Enzymes Form Stress Bodies|author=Alice Zhao, Mark Tsechansky, Jagannath Swaminathan, Lindsey Cook, Andrew D. Ellington, Edward M. Marcotte|journal=PLoS ONE|date=2013-02-06|volume=8|number=2|pages=e56203|doi=10.1371/journal.pone.0056203}}</ref> Characteristics of purinosome bodies were found to be shared between those of canonical protein aggregates, such as induction by peroxide. While purinosome bodies were also found to be associated with early cell death, it is unclear whether the bodies were a cause of that stress or rather an indicator of stressed cells. Later studies in 2013 support the interpretation that those macrobodies could be artifacts of aggregated proteins that commonly result from fusion protein expression.<ref name=Zhao2013>{{cite journal|url=http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056203|title=Transiently Transfected Purine Biosynthetic Enzymes Form Stress Bodies|author=Alice Zhao, Mark Tsechansky, Jagannath Swaminathan, Lindsey Cook, Andrew D. Ellington, Edward M. Marcotte|journal=PLoS ONE|date=2013-02-06|volume=8|issue=2|number=2|pages=e56203|doi=10.1371/journal.pone.0056203|pmid=23405267|last2=Tsechansky|last3=Swaminathan|last4=Cook|last5=Ellington|last6=Marcotte|bibcode=2013PLoSO...856203Z}}</ref> Characteristics of purinosome bodies were found to be shared between those of canonical protein aggregates, such as induction by peroxide. While purinosome bodies were also found to be associated with early cell death, it is unclear whether the bodies were a cause of that stress or rather an indicator of stressed cells.


===Discrepancies=== ===Discrepancies===


Inhibition of ] polymerization with ] blocks formation of the purinosome macrobodies, and reduces the flux of ''de novo'' purine biosynthesis.<ref>{{cite web|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919939/|title=Microtubule-assisted mechanism for functional metabolic macromolecular complex formation|author=Songon An, Yijun Deng, John W. Tomsho, Minjoung Kyoung, and Stephen J. Benkovic|journal=Proc. Natl. Acad. Sci. U.S.A.|date=2010-07-20|volume=107|issue=29|pages=12872–12876|doi=10.1073/pnas.1008451107}}</ref> However, nocodazole also blocks formation of ], complicating interpretation of these observations. Partial inhibition of ] by small molecule inhibitors - Inhibition of ] polymerization with ] blocks formation of the purinosome macrobodies, and reduces the flux of ''de novo'' purine biosynthesis.<ref>{{Cite journal|pmc=2919939|title=Microtubule-assisted mechanism for functional metabolic macromolecular complex formation|author=Songon An, Yijun Deng, John W. Tomsho, Minjoung Kyoung, and Stephen J. Benkovic|journal=Proc. Natl. Acad. Sci. U.S.A.|date=2010-07-20|volume=107|issue=29|pages=12872–12876|doi=10.1073/pnas.1008451107|pmid=20615962|bibcode=2010PNAS..10712872A}}</ref> However, nocodazole also blocks formation of ], complicating interpretation of these observations. Partial inhibition of ] by small molecule inhibitors -
] (TBI), ] (DMAT), ] (TBCA) or ] - was found to induce purinosome macrobody formation, while another inhibitor, ] (TBB) induced purinosome macrobody formation at low concentration but not at high concentration, and caused the dissociation of the bodies formed in response to DMAT.<ref name=CK2>{{cite journal|journal=J Biol Chem.|date=2010-04-09|volume=285|issue=15|pages=11093–11099|doi=10.1074/jbc.M110.101139|title=Dynamic regulation of a metabolic multi-enzyme complex by protein kinase CK2|author=Songon An, Minjoung Kyoung, Jasmina J. Allen, Kevan M. Shokat, and Stephen J. Benkovic}}</ref> Complicating the interpretation of these data, inhibition of ] is also known to disrupt hundreds of cellular processes, among them being ] which regulates ]. ] (TBI), ] (DMAT), ] (TBCA) or ] - was found to induce purinosome macrobody formation, while another inhibitor, ] (TBB) induced purinosome macrobody formation at low concentration but not at high concentration, and caused the dissociation of the bodies formed in response to DMAT.<ref name=CK2>{{cite journal|journal=J Biol Chem.|date=2010-04-09|volume=285|issue=15|pages=11093–11099|doi=10.1074/jbc.M110.101139|pmid=20157113|pmc=2856985|title=Dynamic regulation of a metabolic multi-enzyme complex by protein kinase CK2|author=Songon An, Minjoung Kyoung, Jasmina J. Allen, Kevan M. Shokat, and Stephen J. Benkovic}}</ref> Complicating the interpretation of these data, inhibition of ] is also known to disrupt hundreds of cellular processes, among them being ] which regulates ].


===Additional members of purinosome macrobodies=== ===Additional members of purinosome macrobodies===
* ] (MTHFS) (provides substrate for ])<ref name=Field /> * ] (MTHFS) (provides substrate for ])<ref name=Field />
* ]<ref name=Zhao2013 /><ref name=French>{{cite journal|author=Jarrod B French, Hong Zhao ''et al.''|title=Hsp70/Hsp90 chaperone machinery is involved in the assembly of the purinosome|journal=Proc. Natl. Acad. Sci. U.S.A.|year=2013|doi=10.1073/pnas.1300173110}}</ref> * ]<ref name=Zhao2013 /><ref name=French>{{cite journal|author=Jarrod B French, Hong Zhao|title=Hsp70/Hsp90 chaperone machinery is involved in the assembly of the purinosome|journal=Proc. Natl. Acad. Sci. U.S.A.|volume=110|issue=7|pages=2528|year=2013|doi=10.1073/pnas.1300173110|pmid=23359685|author2=and others|displayauthors=1|last3=An|last4=Niessen|last5=Deng|last6=Cravatt|last7=Benkovic|bibcode=2013PNAS..110.2528F}}</ref>
* ]<ref name=Zhao2013 /><ref name=French /> * ]<ref name=Zhao2013 /><ref name=French />
* ]<ref name=Zhao2013 /> * ]<ref name=Zhao2013 />

Revision as of 16:35, 7 October 2014

The synthesis of IMP.The color scheme is as follows: enzymes, coenzymes, substrate names, metal ions, inorganic molecules

The purinosome is a putative multi-enzyme complex that carries out de novo purine biosynthesis within the cell. It is postulated to include all six of the human enzymes identified as direct participants in this ten-step biosynthetic pathway converting phosphoribosyl pyrophosphate to inosine monophosphate:

Step(s) Symbol Description
1 PPAT phosphoribosylpyrophosphate amidotransferase
2,3,5 GART trifunctional phosphoribosylglycinamide formyltransferase/phosphoribosylglycinamide synthetase/phosphoribosylaminoimidazole synthetase
4 PFAS phosphoribosylformylglycinamidine synthase
6,7 PAICS bifunctional phosphoribosylaminoimidazole carboxylase
8 ASDL adenylosuccinate lyase
9,10 ATIC bifunctional 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase

History

Hypothesis

The enzymes of the multi-step de novo purine biosynthesis pathway have been postulated to form a multi-enzyme complex to facilitate substrate channeling between each enzyme of the pathway. Slight variations of the pathway exists between phyla; however, there are 13 enzymes that can be considered part of this biosynthetic pathway. Several individual enzymatic functions have consolidated onto single bifunctional or trifunctional polypeptide chains in higher organisms, suggesting stable physical interactions exist between enzymes. The functional consolidation of steps 2,3, and 5 of the pathway into a single enzyme in higher organisms such as humans suggests physical local proximity of the enzyme for step 4 to the trifunctional enzyme.

Evidence for a complex

The purine biosynthesis enzymes can be co-purified under certain conditions. A complex of two particular pathway enzymes GART and ATIC can be isolated with cofactor production enzyme C1THF synthase and SHTM1. Kinetic studies show evidence of substrate channeling between PPAT and GART, but evidence could not be obtained for their physical protein-protein interaction. Thus far, isolation of a multienzyme complex inclusive of all purine biosynthesis enzymes has not been achieved.

Purinosome macrobodies

Macrobodies composed of purinosome members.Purine biosynthesis enzymes cluster into discrete intracellular bodies when transiently expressed as fusions to enhanced green fluorescent protein (EGFP) in HeLa cells. FGAMS is an alternate name for PFAS.

Purinosome macrobodies (also may be referred to as bodies, clusters, foci, puncta) describe the assembly of fluorescent-tagged human purine biosynthetic enzymes into bodies visible by fluorescence microscopy. The purinosome body theory states that purinosome bodies are assembled from proteins normally dispersed in the cell, and this assembly manifests when the demand for purines exceeds the amount supplied by the purine salvage pathway, such as when the extracellular medium is depleted of purines. In addition to the 6 purine biosynthesis pathway proteins, purinosome macrobodies are composed of at least 10 additional proteins not involved in purine biosynthesis. Due to the nature of their expression and association with cellular stress response proteins, purinosome macrobodies may actually be aggregated protein bodies.

Initial discovery

The human purinosome was thought to have been identified in 2008 by the observation that transiently expressed GFP fusion constructs of purine biosynthesis proteins form macrobodies. A folate enzyme not directly involved in the purine biosynthesis pathway, 5,10-methenyltetrahydrofolate synthase (MTHFS), was later found to be part of purinosome macrobodies by the same approach. The biological relevance of this folate enzyme's inclusion to the purinosome macrobody is unclear: while it provides substrate for a trifunctional folate enzyme C1THF synthase to generate a key cofactor for purine biosynthesis, C1THF synthase is not a part of purinosome macrobodies. Curiously, hypoxanthine levels do not alter purinosome macrobodies, but adenosine or guanosine addition suppresses formation of macromolecular bodies formed by the folate enzyme.

Aggregation

Later studies in 2013 support the interpretation that those macrobodies could be artifacts of aggregated proteins that commonly result from fusion protein expression. Characteristics of purinosome bodies were found to be shared between those of canonical protein aggregates, such as induction by peroxide. While purinosome bodies were also found to be associated with early cell death, it is unclear whether the bodies were a cause of that stress or rather an indicator of stressed cells.

Discrepancies

Inhibition of microtubule polymerization with nocodazole blocks formation of the purinosome macrobodies, and reduces the flux of de novo purine biosynthesis. However, nocodazole also blocks formation of aggresomes, complicating interpretation of these observations. Partial inhibition of casein kinase 2 by small molecule inhibitors - 4,5,6,7-tetrabromo-1H-benzimidazole (TBI), 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), tetrabromocinammic acid (TBCA) or ellagic acid - was found to induce purinosome macrobody formation, while another inhibitor, 4,5,6,7-tetrabromobenzotriazole (TBB) induced purinosome macrobody formation at low concentration but not at high concentration, and caused the dissociation of the bodies formed in response to DMAT. Complicating the interpretation of these data, inhibition of casein kinase 2 is also known to disrupt hundreds of cellular processes, among them being protein homeostasis which regulates protein aggregation.

Additional members of purinosome macrobodies

Proteins excluded from purinosome macrobodies

  • C1THF synthase (provides single-carbon units for purine biosynthesis steps 3 and 9)
  • SHMT1
  • DnaJ-C14
  • DnaJ-B1
  • G3BP
  • Aggresome marker GP250 (although its co-localization may be under debate)

References

  1. Kornberg, A. (1982). Supplement to DNA Replication. {{cite book}}: |journal= ignored (help); soft hyphen character in |journal= at position 19 (help)
  2. ^ Henikoff, S., Keene, M. A., Sloan, S., Bleskan, J., Hards, R., Patterson, D.; Keene; Sloan; Bleskan; Hards; Patterson (1986). "Multiple purine pathway enzyme activities are encoded at a single genetic locus in Drosophila". Proc. Natl. Acad. Sci. USA. 83 (3): 720–24. Bibcode:1986PNAS...83..720H. doi:10.1073/pnas.83.3.720. {{cite journal}}: line feed character in |journal= at position 6 (help); line feed character in |title= at position 66 (help)CS1 maint: multiple names: authors list (link)
  3. Marcotte EM, Pellegrini M, Ng HL, Rice DW, Yeates TO, Eisenberg D.; Pellegrini; Ng; Rice; Yeates; Eisenberg (1999). "Detecting protein function and protein-protein interactions from genome sequences". Science. 285 (5428): 751–3. doi:10.1126/science.285.5428.751. PMID 10427000.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. Patterson, D., Graw, S., & Jones, C.; Graw; Jones (1981). ""Demonstration by somatic cell genetics, of coordinate regulation of genes for two enzymes of purine synthesis assigned to human chromosome 21." volume=78". Proceedings of the National Academy of Sciences of the United States of America. 78: 405–409. Bibcode:1981PNAS...78..405P. doi:10.1073/pnas.78.1.405. {{cite journal}}: Missing pipe in: |title= (help); line feed character in |journal= at position 62 (help); line feed character in |title= at position 18 (help)CS1 maint: multiple names: authors list (link)
  5. Hard, R. G., Benkovic, S. J., Van Keuren, M. L., Graw, S. L., Drabkin, H. A., & Patterson, D.; Benkovic; Van Keuren; Graw; Drabkin; Patterson (1986). "Assignment of a third purine biosynthetic gene (glycinamide ribonucleotide transformylase) to human chromosome 21". American Journal of Human Genetics. 39 (2): 179–185. PMC 1683921. PMID 3529945.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. Rowe, P. B., McCaims, E., Madsen, G., Sauer, D., Elliott, H.; McCairns; Madsen; Sauer; Elliott (1978). "De novo purine synthesis in avian liver. Co-purification of the enzymes and properties of the pathway". J. Biol. Chem. 253 (21): 7711–21. PMID 701284.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. McCairns, E., Fahey, D., Sauer, D., Rowe, P. B. (1983). "De novo purine synthesis in human lymphocytes. Partial co-purification of the enzymes and some properties of the pathway". J. Biol. Chem. 258: 1851–56.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. Smith, G. K., Mueller, W. T., Wasser­man, G. F., Taylor, W. D., Benkovic, S. J.; Mueller; Wasserman; Taylor; Benkovic (1980). "Characterization of the enzyme complex involving the folate-requiring enzymes of de novo purine biosynthesis". Biochemistry. 19 (18): 4313–21. doi:10.1021/bi00559a026. PMID 7417406. {{cite journal}}: soft hyphen character in |author= at position 37 (help)CS1 maint: multiple names: authors list (link)
  9. J. Rudolph and J. Stubbe (1995). "Investigation of the Mechanism of Phosphoribosylamine Transfer from Glutamine Phosphoribosylpyrophosphate Amidotransferase to Glycinamide Ribonucleotide Synthetase". Biochemistry. 34 (5872): 224 1–2250. Bibcode:2008Sci...320..103A. doi:10.1126/science.1152241.
  10. ^ Alice Zhao, Mark Tsechansky, Jagannath Swaminathan, Lindsey Cook, Andrew D. Ellington, Edward M. Marcotte; Tsechansky; Swaminathan; Cook; Ellington; Marcotte (2013-02-06). "Transiently Transfected Purine Biosynthetic Enzymes Form Stress Bodies". PLoS ONE. 8 (2): e56203. Bibcode:2013PLoSO...856203Z. doi:10.1371/journal.pone.0056203. PMID 23405267. {{cite journal}}: More than one of |number= and |issue= specified (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  11. ^ Songon An; Sheets; Benkovic; et al. (2008). "Reversible Compartmentalization of de Novo Purine Biosynthetic Complexes in Living Cells". Science. 320 (5872): 103–106. Bibcode:2008Sci...320..103A. doi:10.1126/science.1152241. PMID 18388293. {{cite journal}}: Explicit use of et al. in: |author2= (help); Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
  12. Hong Zhao, Jarrod B. French,Ye Fang and Stephen J. Benkovic (2013-04-03). "The purinosome, a multi-protein complex involved in the de novo biosynthesis of purines in humans". Chem Comm. 285 (15): 11093–11099. doi:10.1039/c3cc41437j.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  17. "By the same standards, prior work may not either". Archived from the original (PDF) on 21 March 2013. Retrieved 20 April 2013. {{cite web}}: Unknown parameter |authors= ignored (help)
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