Genomes and Genes
Summary: Compounds based on pyrazino[2,3-d]pyrimidine which is a pyrimidine fused to a pyrazine, containing four NITROGEN atoms.
- Mendoza Lopez P, Golby P, Wooff E, Nunez Garcia J, Garcia Pelayo M, Conlon K, et al. Characterization of the transcriptional regulator Rv3124 of Mycobacterium tuberculosis identifies it as a positive regulator of molybdopterin biosynthesis and defines the functional consequences of a non-synonymous SNP in the Mycobacterium bovis BCG . Microbiology. 2010;156:2112-23 pubmed publisher..The SNP in bcg3145 was found to have a subtle effect on the activity of MoaR1, suggesting that this mutation is not a key event in the attenuation of BCG. ..
- Reiss J, Bonin M, Schwegler H, Sass J, Garattini E, Wagner S, et al. The pathogenesis of molybdenum cofactor deficiency, its delay by maternal clearance, and its expression pattern in microarray analysis. Mol Genet Metab. 2005;85:12-20 pubmed..This neuronal damage appears to be triggered by elevated sulfite levels and is ameliorated in affected embryos by maternal clearance. ..
- Klein J, Busch J, Potting C, Baker M, Langer T, Schwarz G. The mitochondrial amidoxime-reducing component (mARC1) is a novel signal-anchored protein of the outer mitochondrial membrane. J Biol Chem. 2012;287:42795-803 pubmed publisher..During mitochondrial import, mARC1 is not processed, and membrane integration proceeds membrane potential independently but requires external ATP, which finally results in the assembly of mARC1 into high oligomeric protein complexes. ..
- Bernard D, Cheng Y, Zhao Y, Balk J. An allelic mutant series of ATM3 reveals its key role in the biogenesis of cytosolic iron-sulfur proteins in Arabidopsis. Plant Physiol. 2009;151:590-602 pubmed publisher..Our data suggest that Arabidopsis ATM3 may transport (1) at least two distinct compounds or (2) a single compound required for both Fe-S and Moco assembly machineries in the cytosol, but not iron. ..
- Schoffski P. Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist. 2009;14:559-70 pubmed publisher..e., ZK-thiazolidinone, NMS-1, CYC-800, DAP-81, and LC-445). If proof of principle is confirmed in large studies, PLK inhibitors will offer a new targeted antitumor therapy for cancer patients. ..
- Mross K, Frost A, Steinbild S, Hedbom S, Rentschler J, Kaiser R, et al. Phase I dose escalation and pharmacokinetic study of BI 2536, a novel Polo-like kinase 1 inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2008;26:5511-7 pubmed publisher..The MTD of BI 2536 when administered as a single-dose, 1-hour infusion was 200 mg; BI 2536 was well tolerated and showed a favorable pharmacokinetic profile. Antitumor activity of BI 2536 was observed. ..
- Chowdhury M, Dosche C, Löhmannsröben H, Leimkuhler S. Dual role of the molybdenum cofactor biosynthesis protein MOCS3 in tRNA thiolation and molybdenum cofactor biosynthesis in humans. J Biol Chem. 2012;287:17297-307 pubmed publisher..The cellular localization results showed that extension of the C terminus with an additional glycine of MOCS2A and URM1 altered the localization of MOCS3 from the cytosol to the nucleus. ..
- Marelja Z, Stöcklein W, Nimtz M, Leimkuhler S. A novel role for human Nfs1 in the cytoplasm: Nfs1 acts as a sulfur donor for MOCS3, a protein involved in molybdenum cofactor biosynthesis. J Biol Chem. 2008;283:25178-85 pubmed publisher..Because MOCS3 was shown to be located in the cytosol, our results suggest that cytosolic Nfs1 has an important role in sulfur transfer for the biosynthesis of Moco. ..
- Zhang Y, Gladyshev V. Molybdoproteomes and evolution of molybdenum utilization. J Mol Biol. 2008;379:881-99 pubmed publisher..Overall, our data provide new insights into Mo utilization and show its wide occurrence, yet limited use of this metal in individual organisms in all three domains of life...
- Choi Y, Kong J, Park Y. Functional role of sepiapterin reductase in the biosynthesis of tetrahydropteridines in Dictyostelium discoideum Ax2. Biochim Biophys Acta. 2006;1760:877-82 pubmed..putative function and biosynthetic regulation, we performed quantitative analysis of not only the intracellular pteridines by HPLC but also the biosynthetic enzymes (GTP cyclohydrolase I, 6-pyruvoyltetrahydropterin synthase, SR, and ..
- Dai X, Hayashi K, Nozaki H, Cheng Y, Zhao Y. Genetic and chemical analyses of the action mechanisms of sirtinol in Arabidopsis. Proc Natl Acad Sci U S A. 2005;102:3129-34 pubmed
- Joshi H, Enemark J. Geometrical control of the active site electronic structure of pyranopterin enzymes by metal-dithiolate folding: aldehyde oxidase. J Am Chem Soc. 2004;126:11784-5 pubmed
- Jeong K, Jeong J, Lee H, Choi E, Lee H. Inhibition of Plk1 induces mitotic infidelity and embryonic growth defects in developing zebrafish embryos. Dev Biol. 2010;345:34-48 pubmed publisher..Furthermore, our study suggests that zebrafish will be an efficient and economical in vivo system for the validation of anti-mitotic drugs...
- Schwarz G. Molybdenum cofactor biosynthesis and deficiency. Cell Mol Life Sci. 2005;62:2792-810 pubmed..Human Moco deficiency is a hereditary metabolic disorder characterized by severe neurodegeneration resulting in early childhood death. Recently, a first substitution therapy was established. ..
- Szakács Z, Noszal B. Determination of dissociation constants of folic acid, methotrexate, and other photolabile pteridines by pressure-assisted capillary electrophoresis. Electrophoresis. 2006;27:3399-409 pubmed
- Zhang W, Urban A, Mihara H, Leimkuhler S, Kurihara T, Esaki N. IscS functions as a primary sulfur-donating enzyme by interacting specifically with MoeB and MoaD in the biosynthesis of molybdopterin in Escherichia coli. J Biol Chem. 2010;285:2302-8 pubmed publisher..These findings indicate that IscS is the primary physiological sulfur-donating enzyme for the generation of the thiocarboxylate of MPT synthase in MPT biosynthesis. ..
- Kozmin S, Schaaper R. Molybdenum cofactor-dependent resistance to N-hydroxylated base analogs in Escherichia coli is independent of MobA function. Mutat Res. 2007;619:9-15 pubmed..Further, we establish that protection against the analogs does not require the common molybdopterin guanine-dinucleotide (MGD) form of the cofactor, but instead the guanosine monophosphate (GMP)-free version of MoCo (MPT) is sufficient. ..
- Kuper J, Llamas A, Hecht H, Mendel R, Schwarz G. Structure of the molybdopterin-bound Cnx1G domain links molybdenum and copper metabolism. Nature. 2004;430:803-6 pubmed
- Serrano M, Lizarraga I, Reiss J, Dias A, Perez Duenas B, Vilaseca M, et al. Cranial ultrasound and chronological changes in molybdenum cofactor deficiency. Pediatr Radiol. 2007;37:1043-6 pubmed..Our report supports the utility of cranial US, a noninvasive bed-side technique, in the detection and follow-up of these rapidly changing lesions. ..
- Dahl J, Urban A, Bolte A, Sriyabhaya P, Donahue J, Nimtz M, et al. The identification of a novel protein involved in molybdenum cofactor biosynthesis in Escherichia coli. J Biol Chem. 2011;286:35801-12 pubmed publisher..coli. We believe that the role of YnjE is to make the sulfur transfer from IscS for Moco biosynthesis more specific because IscS is involved in a variety of different sulfur transfer reactions in the cell. ..
- Rudolph D, Steegmaier M, Hoffmann M, Grauert M, Baum A, Quant J, et al. BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin Cancer Res. 2009;15:3094-102 pubmed publisher..These findings warrant further investigation of BI 6727 as a tailored antimitotic agent; clinical studies have been initiated. ..
- Hofheinz R, Al Batran S, Hochhaus A, Jager E, Reichardt V, Fritsch H, et al. An open-label, phase I study of the polo-like kinase-1 inhibitor, BI 2536, in patients with advanced solid tumors. Clin Cancer Res. 2010;16:4666-74 pubmed publisher..The average terminal half-life was 50 hours. BI 2536 administered in either treatment schedule has adequate safety in patients with advanced solid tumors, warranting further clinical investigation of polo-like kinase-1 inhibitors. ..
- Ackermann S, Goeser F, Schulte J, Schramm A, Ehemann V, Hero B, et al. Polo-like kinase 1 is a therapeutic target in high-risk neuroblastoma. Clin Cancer Res. 2011;17:731-41 pubmed publisher..Inhibition of PLK1 using BI 2536 exhibits strong antitumor activity on human neuroblastoma cells in vitro and in vivo, opening encouraging new perspectives for the treatment of high-risk neuroblastoma. ..
- Mendel R, Bittner F. Cell biology of molybdenum. Biochim Biophys Acta. 2006;1763:621-35 pubmed..This final maturation step is catalyzed by a Moco-sulfurase enzyme, which mobilizes sulfur from l-cysteine in a pyridoxal phosphate-dependent manner as typical for cysteine desulfurases. ..
- Kim J, Suh H, Kim S, Kim K, Ahn C, Yim J. Identification and characteristics of the structural gene for the Drosophila eye colour mutant sepia, encoding PDA synthase, a member of the omega class glutathione S-transferases. Biochem J. 2006;398:451-60 pubmed..The extent of rescue was dependent on the dosage of transgenic CG6781. In conclusion, we have discovered a new catalytic activity for an Omega class GST and that CG6781 is the structural gene for sepia which encodes PDA synthase. ..
- Llamas A, Otte T, Multhaup G, Mendel R, Schwarz G. The Mechanism of nucleotide-assisted molybdenum insertion into molybdopterin. A novel route toward metal cofactor assembly. J Biol Chem. 2006;281:18343-50 pubmed..Together with the strict dependence of the reaction on molybdate the formation of adenylated molybdate as reaction intermediate in the nucleotide-assisted metal transfer reaction to molybdopterin is proposed. ..
- Matthies A, Nimtz M, Leimkuhler S. Molybdenum cofactor biosynthesis in humans: identification of a persulfide group in the rhodanese-like domain of MOCS3 by mass spectrometry. Biochemistry. 2005;44:7912-20 pubmed..By ESI-MS/MS a partially gluconoylated N-terminus of the His6-tagged MOCS3-RLD was identified (mass increment of 178 Da) which resulted in a heterogeneity of the protein but did not influence sulfurtransferase activity. ..
- Matthies A, Rajagopalan K, Mendel R, Leimkuhler S. Evidence for the physiological role of a rhodanese-like protein for the biosynthesis of the molybdenum cofactor in humans. Proc Natl Acad Sci U S A. 2004;101:5946-51 pubmed..In contrast to other mammalian rhodaneses, which are mostly localized within mitochondria, MOCS3 in addition to the subunits of MPT synthase are localized in the cytosol. ..
- H nzelmann P, Schindelin H. Crystal structure of the S-adenosylmethionine-dependent enzyme MoaA and its implications for molybdenum cofactor deficiency in humans. Proc Natl Acad Sci U S A. 2004;101:12870-5 pubmed publisher..The noncysteinyl-ligated unique Fe site of the C-terminal [4Fe-4S] cluster is proposed to be involved in the binding and activation of 5'-GTP...
- Kothe M, Kohls D, Low S, Coli R, Rennie G, Feru F, et al. Selectivity-determining residues in Plk1. Chem Biol Drug Des. 2007;70:540-6 pubmed..The work presented here provides a framework for structure-based drug design of Polo-like kinase 1-specific inhibitors. ..
- Dahl J, Radon C, Bühning M, Nimtz M, Leichert L, Denis Y, et al. The sulfur carrier protein TusA has a pleiotropic role in Escherichia coli that also affects molybdenum cofactor biosynthesis. J Biol Chem. 2013;288:5426-42 pubmed publisher..We propose that in the absence of TusA, more IscS is available for FeS cluster biosynthesis and that the overproduction of FeS clusters leads to a modified expression of several genes. ..
- Oxenkrug G. Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders. J Neural Transm (Vienna). 2011;118:75-85 pubmed publisher..IFNG-inducible KYN/pteridines inflammation cascade is characterized by up-regulation of nitric oxide synthase (NOS) activity (induced by KYN) ..
- Sebastian M, Reck M, Waller C, Kortsik C, Frickhofen N, Schuler M, et al. The efficacy and safety of BI 2536, a novel Plk-1 inhibitor, in patients with stage IIIB/IV non-small cell lung cancer who had relapsed after, or failed, chemotherapy: results from an open-label, randomized phase II clinical trial. J Thorac Oncol. 2010;5:1060-7 pubmed publisher..BI 2536 monotherapy has modest efficacy and favorable safety in relapsed non-small cell lung cancer. The findings support the further development of polo-like kinase-1 inhibitors within this indication. ..
- Schwarz G, Santamaria Araujo J, Wolf S, Lee H, Adham I, Grone H, et al. Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli. Hum Mol Genet. 2004;13:1249-55 pubmed..Precursor Z-substituted mice reach adulthood and fertility. Biochemical analyses further suggest that the described treatment can lead to the alleviation of most symptoms associated with human Moco deficiency. ..
- Hänzelmann P, Hernandez H, Menzel C, Garcia Serres R, Huynh B, Johnson M, et al. Characterization of MOCS1A, an oxygen-sensitive iron-sulfur protein involved in human molybdenum cofactor biosynthesis. J Biol Chem. 2004;279:34721-32 pubmed
- Gleixner K, Ferenc V, Peter B, Gruze A, Meyer R, Hadzijusufovic E, et al. Polo-like kinase 1 (Plk1) as a novel drug target in chronic myeloid leukemia: overriding imatinib resistance with the Plk1 inhibitor BI 2536. Cancer Res. 2010;70:1513-23 pubmed publisher..In conclusion, Plk1 is expressed in CML cells and may represent a novel, interesting target in imatinib-sensitive and imatinib-resistant CML. ..
- Schoffski P, Awada A, Dumez H, Gil T, Bartholomeus S, Wolter P, et al. A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours. Eur J Cancer. 2012;48:179-86 pubmed publisher..Encouraging preliminary antitumour activity has been observed, supporting Plk inhibition as a therapeutic approach. Clinical development of volasertib in phase II monotherapy and combination trials is ongoing. ..
- Chamizo Ampudia A, Galvan A, Fernandez E, Llamas A. The Chlamydomonas reinhardtii molybdenum cofactor enzyme crARC has a Zn-dependent activity and protein partners similar to those of its human homologue. Eukaryot Cell. 2011;10:1270-82 pubmed publisher..Therefore, it is proposed that crARC belongs to the sulfite oxidase family of Moco enzymes. ..
- Grinshtein N, Datti A, Fujitani M, UEHLING D, Prakesch M, Isaac M, et al. Small molecule kinase inhibitor screen identifies polo-like kinase 1 as a target for neuroblastoma tumor-initiating cells. Cancer Res. 2011;71:1385-95 pubmed publisher..Our findings identify candidate kinases that regulate TIC growth and survival and suggest that PLK1 inhibitors are an attractive candidate therapy for metastatic NB. ..
- Stratford A, Reipas K, Hu K, Fotovati A, Brough R, Frankum J, et al. Targeting p90 ribosomal S6 kinase eliminates tumor-initiating cells by inactivating Y-box binding protein-1 in triple-negative breast cancers. Stem Cells. 2012;30:1338-48 pubmed publisher..In conclusion, RSK2 inhibition provides a novel therapeutic avenue for TNBC and holds the promise of eliminating TICs. ..
- Morozkina E, Zvyagilskaya R. Nitrate reductases: structure, functions, and effect of stress factors. Biochemistry (Mosc). 2007;72:1151-60 pubmed..Arguments are presented showing that eukaryotic organisms are capable of nitrate dissimilation. Data concerning new classes of extremophil nitrate reductases, whose active center does not contain molybdocofactor, are summarized. ..
- Schoffski P, Blay J, De Greve J, Brain E, Machiels J, Soria J, et al. Multicentric parallel phase II trial of the polo-like kinase 1 inhibitor BI 2536 in patients with advanced head and neck cancer, breast cancer, ovarian cancer, soft tissue sarcoma and melanoma. The first protocol of the European Organization for Rese. Eur J Cancer. 2010;46:2206-15 pubmed publisher..Derivatives of BI 2536 with a more favourable pharmacological profile are currently explored further in prospective studies. ..
- Schmitz J, Chowdhury M, Hänzelmann P, Nimtz M, Lee E, Schindelin H, et al. The sulfurtransferase activity of Uba4 presents a link between ubiquitin-like protein conjugation and activation of sulfur carrier proteins. Biochemistry. 2008;47:6479-89 pubmed publisher..The functional similarities between Uba4 and MOCS3 further demonstrate the evolutionary link between ATP-dependent protein conjugation and ATP-dependent cofactor sulfuration. ..
- Kim H, Choi Y, Kim D, Park S, Han J, Park Y. Tetrahydropteridine deficiency impairs mitochondrial function in Dictyostelium discoideum Ax2. FEBS Lett. 2007;581:5430-4 pubmed..The results strongly suggested that tetrahydropteridines in Dictyostelium are associated with mitochondrial function, probably via direct protection against oxidative stress. ..
- Lenart P, Petronczki M, Steegmaier M, Di Fiore B, Lipp J, Hoffmann M, et al. The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1. Curr Biol. 2007;17:304-15 pubmed..Our data also show that Plk1 is not required for prophase entry, but delays transition to prometaphase, and that Emi1 destruction in prometaphase is not essential for APC/C-mediated cyclin A degradation. ..
- Steegmaier M, Hoffmann M, Baum A, Lenart P, Petronczki M, Krssak M, et al. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol. 2007;17:316-22 pubmed..For addressing the therapeutic potential of Plk1 inhibition, BI 2536 has progressed into clinical studies in patients with locally advanced or metastatic cancers. ..
- Choi Y, Park J, Kong J, Morio T, Park Y. D-threo-tetrahydrobiopterin is synthesized via 1'-oxo-2'-D-hydroxypropyl-tetrahydropterin in Dictyostelium discoideum Ax2. FEBS Lett. 2005;579:3085-9 pubmed..These results are clear demonstration of the in vivo synthesis of DH4 via 1'-oxo-2'-D-hydroxypropyl-H4-pterin as well as an alternative synthesis of BH4 and DH4 in the complete absence of SR. ..
- Santamaria Araujo J, Fischer B, Otte T, Nimtz M, Mendel R, Wray V, et al. The tetrahydropyranopterin structure of the sulfur-free and metal-free molybdenum cofactor precursor. J Biol Chem. 2004;279:15994-9 pubmed..The 1H chemical shift and coupling constant data are incompatible with previous structural proposals and indicate that precursor Z already is a tetrahydropyranopterin system and carries a geminal diol function in the C1' position. ..
- Rodriguez Trelles F, Tarrio R, Ayala F. Convergent neofunctionalization by positive Darwinian selection after ancient recurrent duplications of the xanthine dehydrogenase gene. Proc Natl Acad Sci U S A. 2003;100:13413-7 pubmed..Caution is appropriate in structural genomics when using sequence similarity for assigning protein function. ..
- Gremer L, Meyer O. Characterization of xanthine dehydrogenase from the anaerobic bacterium Veillonella atypica and identification of a molybdopterin-cytosine-dinucleotide-containing molybdenum cofactor. Eur J Biochem. 1996;238:862-6 pubmed..atypica had a heterotrimeric subunit structure and a single [2Fe-2S] cluster. In addition, the enzyme indicates the presence of a molybdopterin dinucleotide as a constituent of a xanthine dehydrogenase molybdenum cofactor...
- Unkles S, Smith J, Kanan G, Millar L, Heck I, Boxer D, et al. The Aspergillus nidulans cnxABC locus is a single gene encoding two catalytic domains required for synthesis of precursor Z, an intermediate in molybdenum cofactor biosynthesis. J Biol Chem. 1997;272:28381-90 pubmed