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Автор: Grafiati

Опубліковано: 6 вересня 2023

Оновлено: 7 вересня 2023

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Škerlová, Jana, Judith Unterlass, Mona Göttmann, Petra Marttila, Evert Homan, Thomas Helleday, Ann-Sofie Jemth, and Pål Stenmark. "Crystal structures of human PAICS reveal substrate and product binding of an emerging cancer target." Journal of Biological Chemistry 295, no. 33 (June 22, 2020): 11656–68. http://dx.doi.org/10.1074/jbc.ra120.013695.

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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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Ginder, Nathaniel D., Daniel J. Binkowski, Xiaoming Chen, Jay C. Nix, Herbert J. Fromm, and Richard B. Honzatko. "Entrapment of Phosphoryl Intermediates by SAICAR Synthetase." FASEB Journal 22, S2 (April 2008): 233. http://dx.doi.org/10.1096/fasebj.22.2_supplement.233.

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Wolf, Nina M., Celerino Abad-Zapatero, Michael E. Johnson, and Leslie W. M. Fung. "Structures of SAICAR synthetase (PurC) fromStreptococcus pneumoniaewith ADP, Mg2+, AIR and Asp." Acta Crystallographica Section D Biological Crystallography 70, no. 3 (February 22, 2014): 841–50. http://dx.doi.org/10.1107/s139900471303366x.

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Streptococcus pneumoniaeis a multidrug-resistant pathogen that is a target of considerable interest for antibacterial drug development. One strategy for drug discovery is to inhibit an essential metabolic enzyme. The seventh step of thede novopurine-biosynthesis pathway converts carboxyaminoimidazoleribonucleotide (CAIR) and L-aspartic acid (Asp) to 4-(N-succino)-5-aminoimidazole-4-carboxamide ribonucleotide (SAICAR) in the presence of adenosine 5′-triphosphate (ATP) using the enzyme PurC. PurC has been shown to be conditionally essential for bacterial replication. Two crystal structures of this essential enzyme fromStreptococcus pneumoniae(spPurC) in the presence of adenosine 5′-diphosphate (ADP), Mg2+, aminoimidazoleribonucleotide (AIR) and/or Asp have been obtained. This is the first structural study ofspPurC, as well as the first of PurC from any species with Asp in the active site. Based on these findings, two model structures are proposed for the active site with all of the essential ligands (ATP, Mg2+, Asp and CAIR) present, and a relay mechanism for the formation of the product SAICAR is suggested.

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Manjunath, Kavyashree, Shankar Prasad Kanaujia, Surekha Kanagaraj, Jeyaraman Jeyakanthan, and Kanagaraj Sekar. "Structure of SAICAR synthetase from Pyrococcus horikoshii OT3: Insights into thermal stability." International Journal of Biological Macromolecules 53 (February 2013): 7–19. http://dx.doi.org/10.1016/j.ijbiomac.2012.10.028.

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Wolf, Nina M., Celerino Abad-Zapatero, Michael E. Johnson, and Leslie W. M. Fung. "Structures of SAICAR synthetase (PurC) fromStreptococcus pneumoniaewith ADP, Mg2+, AIR and Asp. Corrigendum." Acta Crystallographica Section D Biological Crystallography 70, no. 11 (October 31, 2014): 3087. http://dx.doi.org/10.1107/s1399004714022597.

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Manjunath, Kavyashree, and Kanagaraj Sekar. "Molecular Dynamics Perspective on the Protein Thermal Stability: A Case Study Using SAICAR Synthetase." Journal of Chemical Information and Modeling 53, no. 9 (September 6, 2013): 2448–61. http://dx.doi.org/10.1021/ci400306m.

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Manjunath, Kavyashree, Jeyaraman Jeyakanthan, and Kanagaraj Sekar. "Catalytic pathway, substrate binding and stability in SAICAR synthetase: A structure and molecular dynamics study." Journal of Structural Biology 191, no. 1 (July 2015): 22–31. http://dx.doi.org/10.1016/j.jsb.2015.06.006.

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Ren, Daan, Mark W. Ruszczycky, Yeonjin Ko, Shao-An Wang, Yasushi Ogasawara, Minje Kim, and Hung-wen Liu. "Characterization of the coformycin biosynthetic gene cluster in Streptomyces kaniharaensis." Proceedings of the National Academy of Sciences 117, no. 19 (April 29, 2020): 10265–70. http://dx.doi.org/10.1073/pnas.2000111117.

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Coformycin and pentostatin are structurally related N-nucleoside inhibitors of adenosine deaminase characterized by an unusual 1,3-diazepine nucleobase. Herein, the cof gene cluster responsible for coformycin biosynthesis is identified. Reconstitution of the coformycin biosynthetic pathway in vitro demonstrates that it overlaps significantly with the early stages of l-histidine biosynthesis. Committed entry into the coformycin pathway takes place via conversion of a shared branch point intermediate to 8-ketocoformycin-5′-monophosphate catalyzed by CofB, which is a homolog of succinylaminoimidazolecarboxamide ribotide (SAICAR) synthetase. This reaction appears to proceed via a Dieckmann cyclization and a retro-aldol elimination, releasing ammonia and D-erythronate-4-phosphate as coproducts. Completion of coformycin biosynthesis involves reduction and dephosphorylation of the CofB product, with the former reaction being catalyzed by the NADPH-dependent dehydrogenase CofA. CofB also shows activation by adenosine triphosphate (ATP) despite the reaction requiring neither a phosphorylated nor an adenylated intermediate. This may serve to help regulate metabolic partitioning between the l-histidine and coformycin pathways.

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Charoensutthivarakul, Sitthivut, Sherine E. Thomas, Amy Curran, Karen P. Brown, Juan M. Belardinelli, Andrew J. Whitehouse, Marta Acebrón-García-de-Eulate, et al. "Development of Inhibitors of SAICAR Synthetase (PurC) from Mycobacterium abscessus Using a Fragment-Based Approach." ACS Infectious Diseases 8, no. 2 (January 17, 2022): 296–309. http://dx.doi.org/10.1021/acsinfecdis.1c00432.

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Manjunath, Kavyashree, Jeyaraman Jeyakanthan, Noriko Nakagawa, Akeo Shinkai, Masato Yoshimura, Seiki Kuramitsu, Shigeyuki Yokoyama, and Kanagaraj Sekar. "Cloning, expression, purification, crystallization and preliminary X-ray crystallographic study of the putative SAICAR synthetase (PH0239) fromPyrococcus horikoshiiOT3." Acta Crystallographica Section F Structural Biology and Crystallization Communications 66, no. 2 (January 28, 2010): 180–83. http://dx.doi.org/10.1107/s1744309109052026.

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Bazurto, Jannell V., Nicholas J. Heitman, and Diana M. Downs. "Aminoimidazole Carboxamide Ribotide Exerts Opposing Effects on Thiamine Synthesis in Salmonella enterica." Journal of Bacteriology 197, no. 17 (June 22, 2015): 2821–30. http://dx.doi.org/10.1128/jb.00282-15.

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ABSTRACTInSalmonella enterica, the thiamine biosynthetic intermediate 5-aminoimidazole ribotide (AIR) can be synthesizedde novoindependently of the early purine biosynthetic reactions. This secondary route to AIR synthesis is dependent on (i) 5-amino-4-imidazolecarboxamide ribotide (AICAR) accumulation, (ii) a functional phosphoribosylaminoimidazole-succinocarboxamide (SAICAR) synthetase (PurC; EC 6.3.2.6), and (iii) methionine and lysine in the growth medium. Studies presented here show that AICAR is a direct precursor to AIRin vivo. PurC-dependent conversion of AICAR to AIR was recreatedin vitro. Physiological studies showed that exogenous nutrients (e.g., methionine and lysine) antagonize the inhibitory effects of AICAR on the ThiC reaction and decreased the cellular thiamine requirement. Finally, genetic results identified multiple loci that impacted the effect of AICAR on thiamine synthesis and implicated cellular aspartate levels in AICAR-dependent AIR synthesis. Together, the data here clarify the mechanism that allows conditional growth of a strain lacking the first five biosynthetic enzymes, and they provide additional insights into the complexity of the metabolic network and its plasticity.IMPORTANCEIn bacteria, the pyrimidine moiety of thiamine is derived from aminoimidazole ribotide (AIR), an intermediate in purine biosynthesis. A previous study described conditions under which AIR synthesis is independent of purine biosynthesis. This work is an extension of that previous study and describes a new synthetic pathway to thiamine that depends on a novel thiamine precursor and a secondary activity of the biosynthetic enzyme PurC. These findings provide mechanistic details of redundancy in the synthesis of a metabolite that is essential for nucleotide and coenzyme biosynthesis. Metabolic modifications that allow the new pathway to function or enhance it are also described.

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Thomas, Sherine E., Patrick Collins, Rory Hennell James, Vitor Mendes, Sitthivut Charoensutthivarakul, Chris Radoux, Chris Abell, et al. "Structure-guided fragment-based drug discovery at the synchrotron: screening binding sites and correlations with hotspot mapping." Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 377, no. 2147 (April 29, 2019): 20180422. http://dx.doi.org/10.1098/rsta.2018.0422.

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Structure-guided drug discovery emerged in the 1970s and 1980s, stimulated by the three-dimensional structures of protein targets that became available, mainly through X-ray crystal structure analysis, assisted by the development of synchrotron radiation sources. Structures of known drugs or inhibitors were used to guide the development of leads. The growth of high-throughput screening during the late 1980s and the early 1990s in the pharmaceutical industry of chemical libraries of hundreds of thousands of compounds of molecular weight of approximately 500 Da was impressive but still explored only a tiny fraction of the chemical space of the predicted 10 40 drug-like compounds. The use of fragments with molecular weights less than 300 Da in drug discovery not only decreased the chemical space needing exploration but also increased promiscuity in binding targets. Here we discuss advances in X-ray fragment screening and the challenge of identifying sites where fragments not only bind but can be chemically elaborated while retaining their positions and binding modes. We first describe the analysis of fragment binding using conventional X-ray difference Fourier techniques, with Mycobacterium abscessus SAICAR synthetase (PurC) as an example. We observe that all fragments occupy positions predicted by computational hotspot mapping. We compare this with fragment screening at Diamond Synchrotron Light Source XChem facility using PanDDA software, which identifies many more fragment hits, only some of which bind to the predicted hotspots. Many low occupancy sites identified may not support elaboration to give adequate ligand affinity, although they will likely be useful in drug discovery as ‘warm spots’ for guiding elaboration of fragments bound at hotspots. We discuss implications of these observations for fragment screening at the synchrotron sources. This article is part of the theme issue ‘Fifty years of synchrotron science: achievements and opportunities’.

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O'Donnell, Allyson F., Stanley Tiong, David Nash, and Denise V. Clark. "The Drosophila melanogaster ade5 Gene Encodes a Bifunctional Enzyme for Two Steps in the de novo Purine Synthesis Pathway." Genetics 154, no. 3 (March 1, 2000): 1239–53. http://dx.doi.org/10.1093/genetics/154.3.1239.

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Abstract Steps 6 and 7 of de novo purine synthesis are performed by 5-aminoimidazole ribonucleotide carboxylase (AIRc) and 4-[(N-succinylamino)carbonyl]-5-aminoimidazole ribonucleotide synthetase (SAICARs), respectively. In vertebrates, a single gene encodes AIRc-SAICARs with domains homologous to Escherichia coli PurE and PurC. We have isolated an AIRc-SAICARs cDNA from Drosophila melanogaster via functional complementation with an E. coli purC purine auxotroph. This cDNA encodes AIRc yet is unable to complement an E. coli purE mutant, suggesting functional differences between Drosophila and E. coli AIRc. In vertebrates, the AIRc-SAICARs gene shares a promoter region with the gene encoding phosphoribosylamidotransferase, which performs the first step in de novo purine synthesis. In Drosophila, the AIRc-SAICARs gene maps to section 11B4-14 of the X chromosome, while the phosphoribosylamidotransferase gene (Prat) maps to chromosome 3; thus, the close linkage of these two genes is not conserved in flies. Three EMS-induced X-linked adenine auxotrophic mutations, ade41, ade51, and ade52, were isolated. Two gammaradiation-induced (ade53 and ade54) and three hybrid dysgenesis-induced (ade55, ade56, and ade58) alleles were also isolated. Characterization of the auxotrophy and the finding that the hybrid dysgenesis-induced mutations all harbor P transposon sequences within the AIRc-SAICARs gene show that ade5 encodes AIRc-SAICARs.

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Li, Hui, Benshang Li, Fan Yang, Caiwen Duan, Yun Bai, Jun J. Yang, Jing Chen, et al. "De Novo Purine Biosynthesis in Drug Resistance and Tumor Relapse of Childhood ALL." Blood 126, no. 23 (December 3, 2015): 2627. http://dx.doi.org/10.1182/blood.v126.23.2627.2627.

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Abstract Background: Relapse is the leading cause of mortality in children with acute lymphoblastic leukemia (ALL). Studies have shown that most ALL cases are polyclonal at diagnosis and that genetic changes in individual subclones influence sensitity to therapy and subsequent clonal evolution during therapy; but the molecular details remain to be worked out. Among different pathways enriched for mutations at relapse, purine metabolism is particularly interesting for two reasons: first, thiopurines are widely used in the ALL combination chemotherapy regimens, and are prodrugs that are converted by the purine salvage pathway to cytotoxic metabolites. Second, de novo nucleotide biosynthesis is often upregulated in cancer cells, and it is believed that sufficient nucleotide pools are required to maintain genomic stability, could bypass oncogene-induced senescence and promote tumor progression1. Therefore, we focus our current study on de novo purine biosynthesis in drug resistance and tumor relapse of childhood ALL. Methods and Results: Using whole-exome sequencing, we identified relapse-specific mutations in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes a rate-limiting purine biosynthesis enzyme, in 24/358 (6.7%) relapsed childhood B cell ALL (B-ALL) cases. Targeted sequencing identified mutations in additional genes in de novo purine biosynthesis pathway, providing further genetic evidence for its importance in relapsed ALL. All individuals with PRPS1 mutation relapsed early on-treatment (P <0.001), having an inferior prognosis1. Using various functional assays, we demonstrated that rather than causing a simple gain-of-function effect, the mutations in PRPS1 resulted in the disruption of the normal feedback inhibition of purine synthesis, in which the enzyme remained active despite an increased concentration of nucleoside analogs. PRPS1 mutants increased synthesis of the nucleoside inosine monophosphate, its metabolite hypoxanthine (HX) and de novo purine biosynthesis intermediates (e.g. AICAR, SAICAR) in Reh cells. Increased intracellular HX can competively inhibit the conversion of thiopurines into their active metabolites. Furthermore, inhibition of de novo purine biosynthesis in vitro, either by CRISPR-Cas9 genome editing of de novo purine synthesis pathway genes (GART, ATIC etc.) or treatment with a pathway inhibitor lometrexol (GART inhibitor) alleviated the metabolic disturbance and drug resistance induced by PRPS1 mutations. Using ultra-deep sequencing of unique serial remission samples before clinical relapse, we noticed that the PRPS1 mutant allele fraction increased drastically before clinical relapse, suggesting rapid clonal expansion occurs after the acquisition of a PRPS1 mutation. Interestingly, we also noticed that PPRS1 mutation coexist with RAS mutation in many relapse cases and at single cell resolution. Functional analysis revealed that tumor cells which harbored RAS and PRPS1 double mutations are more drug resistant than those with RAS or PRPS1 mutation alone. Previous studies have shown that oncogenic RAS mutation can also induce various stress responses including oncogene-induced senensence and DNA damage response (DDR), which all could impede tumor cell proliferation during relapse. In vitro, we found PRPS1 mutation can release the replication and metabolic stress caused by RAS mutation, in addition to their role in thiopurine resistance. The PRPS1 mutants not only increase the nucleotide pools but also elevate purine biosynthesis intermediate AICAR, which can activate AMPK and reduce the RAS mutant-induced DDR. We are currently working on in vitro and in vivo models (including patient derived xenograft models) to further test the double mutant's effects on tumor-reinitiation and clonal evolution during ALL relapse. Conclusions: We demonstrated that negative feedback-defective PRPS1 mutants can drive de novo purine biosynthesis, which can exert drug resistance and reduce genomic instability during tumor relapse. Our study highlights the importance of de novo purine biosynthesis in the pathogenesis of relapse, and suggests a diagnostic approach to predicting early relapse and a therapeutic strategy to circumventing resistance in ALL. 1 Li et al. Negative feedback-defective PRPS1 mutants drivee thiopurine resistance in relapsed childhood ALL. Nature Medicine,21(6): 563-571 (2015) Disclosures No relevant conflicts of interest to declare.

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Pelet, Anna, Vaclava Skopova, Ulrike Steuerwald, Veronika Baresova, Mohammed Zarhrate, Jean-Marc Plaza, Ales Hnizda, et al. "PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome." Human Molecular Genetics 28, no. 22 (October 10, 2019): 3805–14. http://dx.doi.org/10.1093/hmg/ddz237.

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Abstract We report for the first time an autosomal recessive inborn error of de novo purine synthesis (DNPS)—PAICS deficiency. We investigated two siblings from the Faroe Islands born with multiple malformations resulting in early neonatal death. Genetic analysis of affected individuals revealed a homozygous missense mutation in PAICS (c.158A>G; p.Lys53Arg) that affects the structure of the catalytic site of the bifunctional enzyme phosphoribosylaminoimidazole carboxylase (AIRC, EC 4.1.1.21)/phosphoribosylaminoimidazole succinocarboxamide synthetase (SAICARS, EC 6.3.2.6) (PAICS). The mutation reduced the catalytic activity of PAICS in heterozygous carrier and patient skin fibroblasts to approximately 50 and 10% of control levels, respectively. The catalytic activity of the corresponding recombinant enzyme protein carrying the mutation p.Lys53Arg expressed and purified from E. coli was reduced to approximately 25% of the wild-type enzyme. Similar to other two known DNPS defects—adenylosuccinate lyase deficiency and AICA-ribosiduria—the PAICS mutation prevented purinosome formation in the patient’s skin fibroblasts, and this phenotype was corrected by transfection with the wild-type but not the mutated PAICS. Although aminoimidazole ribotide (AIR) and aminoimidazole riboside (AIr), the enzyme substrates that are predicted to accumulate in PAICS deficiency, were not detected in patient’s fibroblasts, the cytotoxic effect of AIr on various cell lines was demonstrated. PAICS deficiency is a newly described disease that enhances our understanding of the DNPS pathway and should be considered in the diagnosis of families with recurrent spontaneous abortion or early neonatal death.

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