Crystal structures of human PAICS reveal substrate and product binding of an emerging cancer target
(2020) In Journal of Biological Chemistry 295(33). p.11656-11668- 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... (More)
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.
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- author
- Škerlová, Jana ; Unterlass, Judith ; Göttmann, Mona ; Marttila, Petra ; Homan, Evert ; Helleday, Thomas ; Jemth, Ann-Sofie and Stenmark, Pål LU
- organization
- publishing date
- 2020-06-22
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 295
- issue
- 33
- pages
- 11656 - 11668
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- pmid:32571877
- scopus:85089787270
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.RA120.013695
- language
- English
- LU publication?
- yes
- additional info
- Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
- id
- bbd72179-f41c-43f5-ae48-292a6ed7c253
- date added to LUP
- 2020-06-26 08:11:29
- date last changed
- 2024-10-03 03:59:42
@article{bbd72179-f41c-43f5-ae48-292a6ed7c253, abstract = {{<p>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.</p>}}, author = {{Škerlová, Jana and Unterlass, Judith and Göttmann, Mona and Marttila, Petra and Homan, Evert and Helleday, Thomas and Jemth, Ann-Sofie and Stenmark, Pål}}, issn = {{1083-351X}}, language = {{eng}}, month = {{06}}, number = {{33}}, pages = {{11656--11668}}, publisher = {{American Society for Biochemistry and Molecular Biology}}, series = {{Journal of Biological Chemistry}}, title = {{Crystal structures of human PAICS reveal substrate and product binding of an emerging cancer target}}, url = {{http://dx.doi.org/10.1074/jbc.RA120.013695}}, doi = {{10.1074/jbc.RA120.013695}}, volume = {{295}}, year = {{2020}}, }