Human phosphoribosylformylglycineamide amidotransferase (FGARAT): regional mapping, complete coding sequence, isolation of a functional genomic clone, and DNA sequence analysis

Patterson, David; Bleskan, John; Gardiner, Katheleen; Bowersox, Jeffrey

doi:10.1016/s0378-1119(99)00378-9

Cited by 16 publications

(12 citation statements)

References 26 publications

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“…In addition we have published evidence that CHO-K1 AdeB mutants produce undetectable levels of FGAMS (phosphoribosylformylglycinamidine) [31], [32]. We have also reported a mutant CHO-K1 cell that overproduces FGAMS [31].…”

Section: Discussionmentioning

confidence: 99%

Genetic and metabolomic analysis of AdeD and AdeI mutants of de novo purine biosynthesis: Cellular models of de novo purine biosynthesis deficiency disorders

Duval

Luhrs

Wilkinson

et al. 2013

Molecular Genetics and Metabolism

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Purines are molecules essential for many cell processes, including RNA and DNA synthesis, regulation of enzyme activity, protein synthesis and function, energy metabolism and transfer, essential coenzyme function, and cell signaling. Purines are produced via the de novo purine biosynthesis pathway. Mutations in purine biosynthetic genes, for example phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS, E.C. 6.3.2.6/E.C. 4.1.1.21), can lead to developmental anomalies in lower vertebrates. Alterations in PAICS expression in humans have been associated with various types of cancer. Mutations in adenylosuccinate lyase (ADSL, E.C. 4.3.2.2) or 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC, E.C. 2.1.2.3/E.C. 3.5.4.10) lead to inborn errors of metabolism with a range of clinical symptoms, including developmental delay, severe neurological symptoms, renal stones, combined immunodeficiency, and autistic features. The pathogenetic mechanism is unknown for any of these conditions, and no effective treatments exist. The study of cells carrying mutations in the various de novo purine biosynthesis pathway genes provides one approach to analysis of purine disorders. Here we report the characterization of AdeD Chinese hamster ovary (CHO) cells, which carry genetic mutations encoding p.E177K and p.W363* variants of PAICS. Both mutations impact PAICS structure and completely abolish its biosynthesis. Additionally, we describe a sensitive and rapid analytical method for detection of purine de novo biosynthesis intermediates based on high performance liquid chromatography with electrochemical detection. Using this technique we detected accumulation of AIR in AdeD cells. In AdeI cells, mutant for the ADSL gene, we detected accumulation of SAICAR and SAMP and, somewhat unexpectedly, accumulation of AIR. This method has great potential for metabolite profiling of de novo purine biosynthesis pathway mutants, identification of novel genetic defects of purine metabolism in humans, and elucidating the regulation of this critical metabolic pathway.

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Section: Discussionmentioning

confidence: 99%

Genetic and metabolomic analysis of AdeD and AdeI mutants of de novo purine biosynthesis: Cellular models of de novo purine biosynthesis deficiency disorders

Duval

Luhrs

Wilkinson

et al. 2013

Molecular Genetics and Metabolism

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“…Although the sequence identity ranges from 23 to 32%, the E values are quite low, indicating that the homology is significant (Table 2). Among cellular FGARATs encoded by different organisms, including prokaryotes, there are two well-conserved glutamine binding sites as well as an ATP binding site (18,20,47). None of the viral FGARAT homologs appears to have retained these motifs, at least at the primary sequence level ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Murine Gammaherpesvirus 68 Open Reading Frame 75c Tegument Protein Induces the Degradation of PML and Is Essential for Production of Infectious Virus

Ling

Tan

Sewatanon

et al. 2008

J Virol

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Promyelocytic Leukemia nuclear body (PML NB) proteins mediate an intrinsic cellular host defense response against virus infections. Herpesviruses express proteins that modulate PML or PML-associated proteins by a variety of strategies, including degradation of PML or relocalization of PML NB proteins. The consequences of PML-herpesvirus interactions during infection in vivo have yet to be investigated in detail, largely because of the species-specific tropism of many human herpesviruses. Murine gammaherpesvirus 68 (␥HV68) is emerging as a suitable model to study basic biological questions of virus-host interactions because it naturally infects mice. Therefore, we sought to determine whether ␥HV68 targets PML NBs as part of its natural life cycle. We found that ␥HV68 induces PML degradation through a proteasome-dependent mechanism and that loss of PML results in more robust virus replication in mouse fibroblasts. Surprisingly, ␥HV68-mediated PML degradation was mediated by the virion tegument protein ORF75c, which shares homology with the cellular formylglycinamide ribotide amidotransferase enzyme. In addition, we show that ORF75c is essential for production of infectious virus. ORF75 homologs are conserved in all rhadinoviruses but so far have no assigned functions. Our studies shed light on a potential role for this unusual protein in rhadinovirus biology and suggest that ␥HV68 will be a useful model for investigation of PML-herpesvirus interactions in vivo.

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“…ORF75 is the homolog of the FGARAT gene involved in purine biosynthesis, though why this function should be encapsidated is obscure (53,56). ORF33 is homologous to HSV UL16 and HCMV UL94.…”

Section: Discussionmentioning

confidence: 99%

Host and Viral Proteins in the Virion of Kaposi's Sarcoma-Associated Herpesvirus

Bechtel

Winant

Ganem

2005

J Virol

164

185

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Infection of cultured cells with Kaposi's sarcoma associated herpesvirus (KSHV) typically establishes a latent infection, in which only a few viral genes are expressed. Recently, it has been reported that a subset of lytic genes are transiently expressed very early after viral entry but that this burst of abortive lytic gene expression is terminated with the supervention of latency (H. H. Krishnan, P. P. Naranatt, M. S. Smith, L. Zeng, C. Bloomer, and B. Chandran, J. Virol. 78:3601-3620, 2004). To identify molecules imported into cells by KSHV that might influence this gene expression program, we have examined the protein composition of the KSHV particle. Immunoblotting of virus particles demonstrated that RTA, the lytic switch protein, and RAP, a viral protein that is a transcriptional and cell cycle modulator, were both incorporated into virus particles. In a second approach, polypeptides isolated from purified virions were identified by mass-spectrometric analysis of their constituent tryptic peptides. With this approach we were able to identify 18 major virion proteins, including structural, regulatory, and signaling proteins of both viral and cellular origin.

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Human phosphoribosylformylglycineamide amidotransferase (FGARAT): regional mapping, complete coding sequence, isolation of a functional genomic clone, and DNA sequence analysis

Cited by 16 publications

References 26 publications

Genetic and metabolomic analysis of AdeD and AdeI mutants of de novo purine biosynthesis: Cellular models of de novo purine biosynthesis deficiency disorders

Genetic and metabolomic analysis of AdeD and AdeI mutants of de novo purine biosynthesis: Cellular models of de novo purine biosynthesis deficiency disorders

Murine Gammaherpesvirus 68 Open Reading Frame 75c Tegument Protein Induces the Degradation of PML and Is Essential for Production of Infectious Virus

Host and Viral Proteins in the Virion of Kaposi's Sarcoma-Associated Herpesvirus

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