Hsp70/Hsp90 chaperone machinery is involved in the assembly of the purinosome

Jarrod B. French, Hong Zhao, Songon An, Sherry Niessen, Yijun Deng, Benjamin F. Cravatt, Stephen J. Benkovic

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

The de novo biosynthesis of purines is carried out by a highly conserved metabolic pathway that includes several validated targets for anticancer, immunosuppressant, and anti-inflammatory chemotherapeutics. The six enzymes in humans that catalyze the 10 chemical steps from phosphoribosylpyrophosphate to inosinemonophosphate were recently shown to associate into a dynamic multiprotein complex called the purinosome. Here, we demonstrate that heat shock protein 90 (Hsp90), heat shock protein 70 (Hsp70), and several cochaperones functionally colocalize with this protein complex. Knockdown of expression levels of the identified cochaperones leads to disruption of purinosomes. In addition, small molecule inhibitors of Hsp90 and Hsp70 reversibly disrupt purinosomes and are shown to have a synergistic effect with methotrexate, an anticancer agent that targets purine biosynthesis. These data implicate the Hsp90/Hsp70 chaperone machinery in the assembly of the purinosome and provide a strategy for the development of improved anticancer therapies that disrupt purine biosynthesis.

Original languageEnglish (US)
Pages (from-to)2528-2533
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number7
DOIs
StatePublished - Feb 12 2013

All Science Journal Classification (ASJC) codes

  • General

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