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词条 Purinosome
释义

  1. History

     Hypothesis  Evidence for a complex 

  2. Purinosome microbodies

     Additional members of purinosome macrobodies   Proteins excluded from purinosome macrobodies  

  3. References

{{Orphan|date=July 2017}}

The purinosome is a 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 ADSL 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 demonstrated to form a multi-enzyme complex to facilitate the pathway. Slight variations of the pathway exists between phyla; however, there are 13 enzymes that can be considered part of this biosynthetic pathway.[1] Several individual enzymatic functions have consolidated onto single bifunctional or trifunctional polypeptide chains in higher organisms, suggesting stable physical interactions exist between enzymes.[2][3] 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.[2][4][5]

Evidence for a complex

The purine biosynthesis enzymes can be co-purified under certain conditions.[6][7] A complex of two particular pathway enzymes GART and ATIC can be isolated with cofactor production enzyme C1THF synthase and SHMT1.[8] Kinetic studies show evidence of substrate channeling between PPAT and GART, and a tango assay demonstrates their physical protein-protein interaction.[9] However, isolation of a multienzyme complex inclusive of all purine biosynthesis enzymes has not been achieved.

Purinosome microbodies

Purinosome microbodies (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 microbodies are composed of at least 10 additional proteins not involved in purine biosynthesis.

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 microbodies.[11][12] A folate enzyme not directly involved in the purine biosynthesis pathway, 5,10-methenyltetrahydrofolate synthase (MTHFS), was later found to be part of purinosome microbodies by the same approach.[13] The biological relevance of this folate enzyme's inclusion to the purinosome microbody 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 microbodies.[11] Curiously, hypoxanthine levels do not alter purinosome microbodies,[11] but adenosine or guanosine addition suppresses formation of micromolecular bodies formed by the folate enzyme.[13]

Inhibition of microtubule polymerization with nocodazole dissociates the purinosome microbodies, and reduces the flux of de novo purine biosynthesis.[14] 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 microbody formation, while another inhibitor, 4,5,6,7-tetrabromobenzotriazole (TBB) induced purinosome microbody formation at low concentration but not at high concentration, and caused the dissociation of the bodies formed in response to DMAT.[15] 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

  • methenyltetrahydrofolate synthetase (MTHFS) (provides substrate for C1THF synthase)[13]
  • Heat shock protein 70[10][16]
  • Heat shock protein 90[10][16]
  • Ubiquitin[10]
  • Bag5[16]
  • Stip1/Hop[16]
  • p23[16]
  • DnaJ-C7[16]
  • DnaJ-A1[16]

Proteins excluded from purinosome macrobodies

  • C1THF synthase (provides single-carbon units for purine biosynthesis steps 3 and 9)[11][16]
  • SHMT1[11][16]
  • DnaJ-C14[16]
  • DnaJ-B1[16]
  • G3BP[16]
  • Aggresome marker GP250[16] (although its co-localization may be under debate)[17]

References

1. ^{{Cite journal|title=Supplement to DNA Replication|author=Kornberg, A.|year=1982|journal=San Francisco:Freeman}}
2. ^1 {{cite journal|journal=Proc. Natl. Acad. Sci. USA|title=Multiple purine pathway enzyme activities are encoded at a single genetic locus in Drosophila|author=Henikoff, S.|author2=Keene, M. A.|author3=Sloan, S.|author4=Bleskan, J.|author5=Hards, R.|author6=Patterson, D.| year=1986|volume=83|issue=3|pages=720–24|doi= 10.1073/pnas.83.3.720|pmid = 3080748|pmc=322936}}
3. ^{{cite journal|journal=Science|title=Detecting protein function and protein-protein interactions from genome sequences|author=Marcotte EM|author2=Pellegrini M |author3=Ng HL |author4=Rice DW |author5=Yeates TO |author6=Eisenberg D. |year=1999|volume=285|pages=751–3|doi=10.1126/science.285.5428.751 |issue=5428|pmid=10427000 |citeseerx=10.1.1.535.9650}}
4. ^{{cite journal|journal=Proceedings of the National Academy of Sciences of the United States of America|author=Patterson, D.|author2=Graw, S.|author3=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 |volume=78|issue=1|pages=405–409|doi=10.1073/pnas.78.1.405 |pmid=6941256|bibcode=1981PNAS...78..405P|pmc=319062}}
5. ^{{cite journal|author=Hard, R. G.|author2=Benkovic, S. J.|author3=Van Keuren, M. L.|author4=Graw, S. L.|author5=Drabkin, H. A.|author6=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 }}
6. ^{{cite journal|author=Rowe, P. B.|author2=McCaims, E.|author3=Madsen, G.|author4=Sauer, D.|author5=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 }}
7. ^{{cite journal|author=McCairns, E.|author2=Fahey, D.|author3=Sauer, D.|author4=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}}
8. ^{{cite journal|author=Smith, G. K.|author2=Mueller, W. T.|author3=Wasserman, G. F.|author4=Taylor, W. D.|author5=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 }}
9. ^{{cite journal|title=Investigation of the Mechanism of Phosphoribosylamine Transfer from Glutamine Phosphoribosylpyrophosphate Amidotransferase to Glycinamide Ribonucleotide Synthetase|author1=J. Rudolph |author2=J. Stubbe |journal=Biochemistry|year=1995|volume=34|issue=7|pages=2241–2250|doi=10.1021/bi00007a019 |pmid=7532005}}
10. ^1 2 3 {{cite journal|author=Alice Zhao|author2=Mark Tsechansky|author3=Jagannath Swaminathan|author4=Lindsey Cook|author5=Andrew D. Ellington|author6=Edward M. Marcotte|date=2013-02-06|title=Transiently Transfected Purine Biosynthetic Enzymes Form Stress Bodies|journal=PLoS ONE|volume=8|issue=2|pages=e56203|bibcode=2013PLoSO...856203Z|doi=10.1371/journal.pone.0056203|pmc=3566086|pmid=23405267}}
11. ^1 2 3 4 {{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 |display-authors=etal |bibcode=2008Sci...320..103A }}
12. ^{{cite journal|journal=Chem. Commun.|date=2013-04-03|volume=285|issue=15|pages=11093–11099|doi=10.1039/c3cc41437j|pmid=23575936|title=The purinosome, a multi-protein complex involved in the de novo biosynthesis of purines in humans|author1=Hong Zhao |author2=Jarrod B. French |author3=Ye Fang |author4=Stephen J. Benkovic |pmc=3877848}}
13. ^1 2 {{cite journal|title=Mthfs is an essential gene in mice and a component of the purinosome|author1=Martha S. Field |author2=Donald D. Anderson |author3=Patrick J. Stover |journal=Front Genet|year=2011|volume=2|issue=36|pages=36|doi=10.3389/fgene.2011.00036|pmc=3268590|pmid=22303332}}
14. ^{{Cite journal|pmc=2919939|title=Microtubule-assisted mechanism for functional metabolic macromolecular complex formation|author1=Songon An |author2=Yijun Deng |author3=John W. Tomsho |author4=Minjoung Kyoung |author5=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}}
15. ^{{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|author1=Songon An |author2=Minjoung Kyoung |author3=Jasmina J. Allen |author4=Kevan M. Shokat |author5=Stephen J. Benkovic }}
16. ^1 2 3 4 5 6 7 8 9 10 11 12 {{cite journal | last=French | first=J. B. | last2=Zhao | first2=H. | last3=An | first3=S. | last4=Niessen | first4=S. | last5=Deng | first5=Y. | last6=Cravatt | first6=B. F. | last7=Benkovic | first7=S. J. | title=Hsp70/Hsp90 chaperone machinery is involved in the assembly of the purinosome | journal=Proceedings of the National Academy of Sciences | volume=110 | issue=7 | date=2013-01-28 | issn=0027-8424 | doi=10.1073/pnas.1300173110 | pages=2528–2533|pmid=23359685|displayauthors=1 |bibcode=2013PNAS..110.2528F|pmc=3574928}}
17. ^{{cite web|url=http://www.plosone.org/attachments/pone.0056203.comment2.pdf|author1=Alice Zhao |author2=Mark Tsechansky |author3=Jagannath Swaminathan |author4=Lindsey Cook |author5=Andrew Ellington |author6=Edward Marcotte|title=By the same standards, prior work may not either|accessdate=20 April 2013|archivedate=21 March 2013|archiveurl=http://www.plosone.org/annotation/listThread.action?root=63121}}

2 : Purines|Enzymes
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