Abstract
The bifunctional human enzyme phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase (PAICS) catalyzes two essential steps in the de novo purine biosynthesis pathway. PAICS is overexpressed in many cancers and could be a promising target for the development of cancer therapeutics. Here, using gene knockdowns and clonogenic survival and cell viability assays, we demonstrate that PAICS is required for growth and survival of prostate cancer cells. PAICS catalyzes the carboxylation of aminoimidazole ribonucleotide (AIR) and the subsequent conversion of carboxyaminoimidazole ribonucleotide (CAIR) and l-aspartate to N-succinylcarboxamide-5-aminoimidazole ribonucleotide (SAICAR). Of note, we present the first structures of human octameric PAICS in complexes with native ligands. In particular, we report the structure of PAICS with CAIR bound in the active sites of both domains and SAICAR bound in one of the SAICAR synthetase domains. Moreover, we report the PAICS structure with SAICAR and an ATP analog occupying the SAICAR synthetase active site. These structures provide insight into substrate and product binding and the architecture of the active sites, disclosing important structural information for rational design of PAICS inhibitors as potential anticancer drugs.
Highlights
The de novo purine biosynthesis pathway, ubiquitous across the tree of life, includes a series of reactions catalyzing the conversion of phosphoribosyl pyrophosphate into inosine monophosphate, a key intermediate in nucleotide metabolism
All enzymes involved in the de novo purine biosynthesis pathway are potential targets for anticancer drug design, as cancer cells are highly dependent on this pathway for proliferation, in contrast to normal cells that mainly use the nucleotide salvage pathway for purine production [3]
Steps 6 and 7 of the de novo purine biosynthesis pathway comprise the carboxylation of aminoimidazole ribonucleotide (AIR) and the subsequent ATP-dependent conversion of carboxyaminoimidazole ribonucleotide (CAIR) and L-aspartate to N-succinylcarboxamide-5-aminoimidazole ribonucleotide (SAICAR)
Summary
The bifunctional human enzyme phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase (PAICS) catalyzes two essential steps in the de novo purine biosynthesis pathway. Breast, lung cancer, and melanoma, and plays a critical role in cell proliferation, invasion, and efficient tumor growth [4,5,6,7,8,9,10,11]. This suggests that a good strategy to treat these cancers could be to inhibit the enzymatic activity of PAICS. Steps 6 and 7 of the de novo purine biosynthesis pathway comprise the carboxylation of aminoimidazole ribonucleotide (AIR) and the subsequent ATP-dependent conversion of carboxyaminoimidazole ribonucleotide (CAIR) and L-aspartate to N-succinylcarboxamide-5-aminoimidazole ribonucleotide (SAICAR).
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