Adenylosuccinate Syntheatase: Recent Developments

Honzatko, Richard B.; Stayton, Mark M.; Formm, Herbett J.

doi:10.1002/9780470123195.ch3

Cited by 14 publications

(23 citation statements)

References 116 publications

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“…While humans exploit both these pathways, protozoan parasites like Plasmodium, Leshmania, Tritrichomonas and Trypanosoma lack the de novo synthesis of nucleotides and rely solely on their ability to salvage free nucleobases into nucleotides. Thus, enzymes of the salvage pathway are identified as potential therapeutic targets against these parasites [1][2][3][4]. Therapeutic intervention that targets these enzymes requires development of effective analogues of the natural substrates and on-enzyme intermediates [5,6].…”

Section: Introductionmentioning

confidence: 99%

Solution structure of ligands involved in purine salvage pathway

Karnawat

Puranik

2015

Spectrochimica Acta Part A: Molecular and Biomolecular Spectros

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Section: Introductionmentioning

confidence: 99%

Solution structure of ligands involved in purine salvage pathway

Karnawat

Puranik

2015

Spectrochimica Acta Part A: Molecular and Biomolecular Spectros

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“…Finally, the selective inactivation of ADSS1 suggests that it confers an advantage for LAC development. ADSS1 is one of two isoforms of adenylosuccinate synthetase (ADSS) that is required for the de novo synthesis of adenosine 5′‐monophosphate (AMP) 36–38. These enzymes convert inosine 5′‐monophosphate (IMP) and aspartate to adenylosuccinate, which is then converted to AMP by adenylosuccinate lyase (ADSL) 37–39.…”

Section: Discussionmentioning

confidence: 99%

Adenylosuccinate synthetase 1 gene is a novel target of deletion in lung adenocarcinoma

Miller

Blake

Herzog

2009

Molecular Carcinogenesis

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Tobacco smoke consists of numerous carcinogens whose effect on lung tumor development includes the induction of mutations in key genes as well as the induction of chromosome instability (CIN). Consequently, carcinogen-induced mouse lung adenocarcinomas (LAC) display many more recurrent site- and chromosome-specific changes in DNA copy number compared with noninduced LAC. Here we identified the Adenylosuccinate synthetase 1 (Adss1) gene located on distal chromosome 12q as a focus of bi-allelic or homozygous deletion (HD) in LAC. HDs of Adss1 were detected in 10 out of 84 carcinogen-induced mouse primary LAC and mouse LAC cell lines. In only four of these cases did the deletions affect either Siva1 or Inverted-formin 2 (Inf2), which immediately flank the Adss1 locus, indicating that Adss1 is a selective target of deletion in LAC. Losses of Adss1 not meeting the quantitative threshold of HD were detected in 36 out of 84 (42.9%) of the mouse tumors and cell lines. A similar frequency of ADSS1 deletion was observed in human LAC cell lines, suggesting relevance in human lung cancer. Adss1 losses were also found to be significantly associated with a more extensive CIN phenotype in the primary mouse tumors. These results implicate ADSS1 inactivation as a novel somatic alteration in lung carcinogenesis, and suggest that its selective deletion in LAC may be triggered by CIN.

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“…AdSS sequences from viruses, archaea and bacteria, as well as from several eukaryotes from Dictyostelium discoideum to humans, have been determined. Although the sequences of AdSS from the vast majority of organisms are 430-457 amino acids in length, AdSS sequences that are 90-120 amino acids shorter have been isolated (Honzatko et al, 1999) from thermotolerant archaea (Mehrotra & Balaram, 2007;Bouyoub et al, 1996), Vibrio phage VP5 (NCBI reference sequence YP_024984.1), Rhodospirillum rubrum (NCBI reference sequence YP_427051.1) and Streptomyces rimosus (McCarty & Bandarian, 2008). Based on sequence length, these short AdSSs may be categorized into a subfamily.…”

Section: Introductionmentioning

confidence: 99%

Overexpression, purification, crystallization and preliminary crystallographic studies of a hyperthermophilic adenylosuccinate synthetase fromPyrococcus horikoshiiOT3

et al. 2011

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Adenylosuccinate synthetase (AdSS) is a ubiquitous enzyme that catalyzes the first committed step in the conversion of inosine monophosphate (IMP) to adenosine monophosphate (AMP) in the purine-biosynthetic pathway. Although AdSS from the vast majority of organisms is 430-457 amino acids in length, AdSS sequences isolated from thermophilic archaea are 90-120 amino acids shorter. In this study, crystallographic studies of a short AdSS sequence from Pyrococcus horikoshii OT3 (PhAdSS) were performed in order to reveal the unusual structure of AdSS from thermophilic archaea. Crystals of PhAdSS were obtained by the microbatch-under-oil method and X-ray diffraction data were collected to 2.50 Å resolution. The crystal belonged to the trigonal space group P3(2)12, with unit-cell parameters a = b = 57.2, c = 107.9 Å. There was one molecule per asymmetric unit, giving a Matthews coefficient of 2.17 Å(3) Da(-1) and an approximate solvent content of 43%. In contrast, the results of native polyacrylamide gel electrophoresis and analytical ultracentrifugation showed that the recombinant PhAdSS formed a dimer in solution.

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Adenylosuccinate Syntheatase: Recent Developments

Cited by 14 publications

References 116 publications

Solution structure of ligands involved in purine salvage pathway

Solution structure of ligands involved in purine salvage pathway

Adenylosuccinate synthetase 1 gene is a novel target of deletion in lung adenocarcinoma

Overexpression, purification, crystallization and preliminary crystallographic studies of a hyperthermophilic adenylosuccinate synthetase fromPyrococcus horikoshiiOT3

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