The six enzymes are phosphoribosylpyrophosphate amidotransferase (PPAT), a trifunctional enzyme (TGART) that is composed of glycinamide ribonucleotide synthetase (GARS), GAR formyltransferase (GART) and aminoimidazole ribonucleotide synthetase (AIRS), formylglycinamidine ribonucleotide synthase (FGAMS), a bifunctional enzyme (PAICS) that is composed of carboxyaminoimidazole ribonucleotide synthase (CAIRS) and succinoaminoimidazolecarboxamide ribonucleotide synthetase (SAICARS), adenylosuccinate lyase (ASL), and a bifunctional enzyme (ATIC) that is composed of aminoimidazolecarboxamide ribonucleotide transformylase (AICART) and inosine monophosphate cyclohydrolase (IMPCH).Īlthough it has been postulated that enzymes of biosynthetic pathways may complex in response to cellular signals ( 1, 2) and recent reports have provided strong indications that physiologically significant transient complexes occur ( 3, 4), little direct evidence for such metabolic machines has been reported. In eukaryotes, purines are synthesized in 10 chemical steps that are catalyzed by six enzymes (shown in bold). 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.ĭe novo purine biosynthetic pathway in humans. 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. Knockdown of expression levels of the identified cochaperones leads to disruption of purinosomes. Here, we demonstrate that heat shock protein 90 (Hsp90), heat shock protein 70 (Hsp70), and several cochaperones functionally colocalize with this protein complex. The six enzymes in humans that catalyze the 10 chemical steps from phosphoribosylpyrophosphate to inosine monophosphate were recently shown to associate into a dynamic multiprotein complex called the purinosome. 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.
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