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[PMID]:27181209
[Au] Autor:Bianchi-Smiraglia A; Bagati A; Fink EE; Moparthy S; Wawrzyniak JA; Marvin EK; Battaglia S; Jowdy P; Kolesnikova M; Foley CE; Berman AE; Kozlova NI; Lipchick BC; Paul-Rosner LM; Bshara W; Ackroyd JJ; Shewach DS; Nikiforov MA
[Ad] Endereço:Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
[Ti] Título:Microphthalmia-associated transcription factor suppresses invasion by reducing intracellular GTP pools.
[So] Source:Oncogene;36(1):84-96, 2017 Jan 05.
[Is] ISSN:1476-5594
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Melanoma progression is associated with increased invasion and, often, decreased levels of microphthalmia-associated transcription factor (MITF). Accordingly, downregulation of MITF induces invasion in melanoma cells; however, little is known about the underlying mechanisms. Here, we report for the first time that depletion of MITF results in elevation of intracellular GTP levels and increased amounts of active (GTP-bound) RAC1, RHO-A and RHO-C. Concomitantly, MITF-depleted cells display larger number of invadopodia and increased invasion. We further demonstrate that the gene for guanosine monophosphate reductase (GMPR) is a direct MITF target, and that the partial repression of GMPR accounts mostly for the above phenotypes in MITF-depleted cells. Reciprocally, transactivation of GMPR is required for MITF-dependent suppression of melanoma cell invasion, tumorigenicity and lung colonization. Moreover, loss of GMPR accompanies downregulation of MITF in vemurafenib-resistant BRAF -melanoma cells and underlies the increased invasion in these cells. Our data uncover novel mechanisms linking MITF-dependent inhibition of invasion to suppression of guanylate metabolism.
[Mh] Termos MeSH primário: Guanosina Trifosfato/metabolismo
Fator de Transcrição Associado à Microftalmia/metabolismo
Neoplasias/metabolismo
Neoplasias/patologia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Modelos Animais de Doenças
Progressão da Doença
Expressão Ectópica do Gene
Matriz Extracelular/metabolismo
Feminino
GMP Redutase/genética
GMP Redutase/metabolismo
Regulação Neoplásica da Expressão Gênica
Xenoenxertos
Seres Humanos
Espaço Intracelular/metabolismo
Melanócitos/metabolismo
Melanoma/metabolismo
Melanoma/patologia
Melanoma Experimental
Camundongos
Invasividade Neoplásica
Metástase Neoplásica
Neoplasias/genética
Proteínas rho de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Microphthalmia-Associated Transcription Factor); 86-01-1 (Guanosine Triphosphate); EC 1.7.1.7 (GMP Reductase); EC 3.6.5.2 (rho GTP-Binding Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160517
[St] Status:MEDLINE
[do] DOI:10.1038/onc.2016.178


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[PMID]:27613871
[Au] Autor:Rosenberg MM; Redfield AG; Roberts MF; Hedstrom L
[Ad] Endereço:From the Departments of Biology.
[Ti] Título:Substrate and Cofactor Dynamics on Guanosine Monophosphate Reductase Probed by High Resolution Field Cycling 31P NMR Relaxometry.
[So] Source:J Biol Chem;291(44):22988-22998, 2016 10 28.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Guanosine-5'-monophosphate reductase (GMPR) catalyzes the reduction of GMP to IMP and ammonia with concomitant oxidation of NADPH. Here we investigated the structure and dynamics of enzyme-bound substrates and cofactors by measuring P relaxation rates over a large magnetic field range using high resolution field cycling NMR relaxometry. Surprisingly, these experiments reveal differences in the low field relaxation profiles for the monophosphate of GMP compared with IMP in their respective NADP complexes. These complexes undergo partial reactions that mimic different steps in the overall catalytic cycle. The relaxation profiles indicate that the substrate monophosphates have distinct interactions in E·IMP·NADP and E·GMP·NADP complexes. These findings were not anticipated by x-ray crystal structures, which show identical interactions for the monophosphates of GMP and IMP in several inert complexes. In addition, the motion of the cofactor is enhanced in the E·GMP·NADP complex. Last, the motions of the substrate and cofactor are coordinately regulated; the cofactor has faster local motions than GMP in the deamination complex but is more constrained than IMP in that complex, leading to hydride transfer. These results show that field cycling can be used to investigate the dynamics of protein-bound ligands and provide new insights into how portions of the substrate remote from the site of chemical transformation promote catalysis.
[Mh] Termos MeSH primário: Coenzimas/química
Proteínas de Escherichia coli/química
Escherichia coli/enzimologia
GMP Redutase/química
[Mh] Termos MeSH secundário: Biocatálise
Coenzimas/metabolismo
Cristalografia por Raios X
Escherichia coli/química
Escherichia coli/genética
Proteínas de Escherichia coli/genética
Proteínas de Escherichia coli/metabolismo
GMP Redutase/genética
GMP Redutase/metabolismo
Nucleotídeos de Guanina/química
Nucleotídeos de Guanina/metabolismo
Inosina Monofosfato/química
Inosina Monofosfato/metabolismo
Cinética
Espectroscopia de Ressonância Magnética
NADP/química
NADP/metabolismo
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Coenzymes); 0 (Escherichia coli Proteins); 0 (Guanine Nucleotides); 131-99-7 (Inosine Monophosphate); 53-59-8 (NADP); EC 1.7.1.7 (GMP Reductase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160911
[St] Status:MEDLINE


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[PMID]:27343371
[Au] Autor:Boitz JM; Jardim A; Ullman B
[Ad] Endereço:Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Mail Code L224, Portland, OR 97239, USA.
[Ti] Título:GMP reductase and genetic uncoupling of adenylate and guanylate metabolism in Leishmania donovani parasites.
[So] Source:Mol Biochem Parasitol;208(2):74-83, 2016 Aug.
[Is] ISSN:1872-9428
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Purine acquisition is an essential nutritional process for Leishmania. Although purine salvage into adenylate nucleotides has been investigated in detail, little attention has been focused on the guanylate branch of the purine pathway. To characterize guanylate nucleotide metabolism in Leishmania and create a cell culture model in which the pathways for adenylate and guanylate nucleotide synthesis can be genetically uncoupled for functional studies in intact cells, we created and characterized null mutants of L. donovani that were deficient in either GMP reductase alone (Δgmpr) or in both GMP reductase and its paralog IMP dehydrogenase (Δgmpr/Δimpdh). Whereas wild type parasites were capable of utilizing virtually any purine nucleobase/nucleoside, the Δgmpr and Δgmpr/Δimpdh null lines exhibited highly restricted growth phenotypes. The Δgmpr single mutant could not grow in xanthine, guanine, or their corresponding nucleosides, while no purine on its own could support the growth of Δgmpr/Δimpdh cells. Permissive growth conditions for the Δgmpr/Δimpdh necessitated both xanthine, guanine, or the corresponding nucleosides, and additionally, a second purine that could serve as a source for adenylate nucleotide synthesis. Interestingly, GMPR, like its paralog IMPDH, is compartmentalized to the leishmanial glycosome, a process mediated by its COOH-terminal peroxisomal targeting signal. The restricted growth phenotypes displayed by the L. donovani Δgmpr and Δgmpr/Δimpdh null mutants confirms the importance of GMPR in the purine interconversion processes of this parasite.
[Mh] Termos MeSH primário: Monofosfato de Adenosina/metabolismo
GMP Redutase/genética
GMP Redutase/metabolismo
Guanosina Monofosfato/metabolismo
Leishmania donovani/genética
Leishmania donovani/metabolismo
[Mh] Termos MeSH secundário: Técnicas de Silenciamento de Genes
Genótipo
IMP Desidrogenase/genética
IMP Desidrogenase/metabolismo
Leishmania donovani/crescimento & desenvolvimento
Mutação
Fenótipo
Transporte Proteico
Purinas/metabolismo
Interferência de RNA
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Purines); 415SHH325A (Adenosine Monophosphate); 85-32-5 (Guanosine Monophosphate); EC 1.1.1.205 (IMP Dehydrogenase); EC 1.7.1.7 (GMP Reductase); W60KTZ3IZY (purine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160626
[St] Status:MEDLINE


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[PMID]:26853689
[Au] Autor:Smith S; Boitz J; Chidambaram ES; Chatterjee A; Ait-Tihyaty M; Ullman B; Jardim A
[Ad] Endereço:Institute of Parasitology and Centre for Host-Parasite Interactions, Macdonald Campus of McGill University, 21 111 Lakeshore Road, Ste-Anne-de-Bellevue, Quebec, H9X 3V9, Canada.
[Ti] Título:The cystathionine-ß-synthase domains on the guanosine 5''-monophosphate reductase and inosine 5'-monophosphate dehydrogenase enzymes from Leishmania regulate enzymatic activity in response to guanylate and adenylate nucleotide levels.
[So] Source:Mol Microbiol;100(5):824-40, 2016 Jun.
[Is] ISSN:1365-2958
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The Leishmania guanosine 5'-monophosphate reductase (GMPR) and inosine 5'-monophosphate dehydrogenase (IMPDH) are purine metabolic enzymes that function maintaining the cellular adenylate and guanylate nucleotide. Interestingly, both enzymes contain a cystathionine-ß-synthase domain (CBS). To investigate this metabolic regulation, the Leishmania GMPR was cloned and shown to be sufficient to complement the guaC (GMPR), but not the guaB (IMPDH), mutation in Escherichia coli. Kinetic studies confirmed that the Leishmania GMPR catalyzed a strict NADPH-dependent reductive deamination of GMP to produce IMP. Addition of GTP or high levels of GMP induced a marked increase in activity without altering the Km values for the substrates. In contrast, the binding of ATP decreased the GMPR activity and increased the GMP Km value 10-fold. These kinetic changes were correlated with changes in the GMPR quaternary structure, induced by the binding of GMP, GTP, or ATP to the GMPR CBS domain. The capacity of these CBS domains to mediate the catalytic activity of the IMPDH and GMPR provides a regulatory mechanism for balancing the intracellular adenylate and guanylate pools.
[Mh] Termos MeSH primário: Trifosfato de Adenosina/metabolismo
Cistationina beta-Sintase/genética
GMP Redutase/genética
Regulação da Expressão Gênica
IMP Desidrogenase/genética
Leishmania donovani/enzimologia
Leishmania major/enzimologia
[Mh] Termos MeSH secundário: Catálise
Escherichia coli/genética
GMP Redutase/isolamento & purificação
GMP Redutase/metabolismo
Teste de Complementação Genética
Guanosina Monofosfato/metabolismo
IMP Desidrogenase/metabolismo
Cinética
Leishmania donovani/efeitos dos fármacos
Leishmania donovani/genética
Leishmania major/efeitos dos fármacos
Leishmania major/genética
Modelos Moleculares
NADP/metabolismo
Nucleotídeos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nucleotides); 53-59-8 (NADP); 85-32-5 (Guanosine Monophosphate); 8L70Q75FXE (Adenosine Triphosphate); EC 1.1.1.205 (IMP Dehydrogenase); EC 1.7.1.7 (GMP Reductase); EC 4.2.1.22 (Cystathionine beta-Synthase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170726
[Lr] Data última revisão:
170726
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160209
[St] Status:MEDLINE
[do] DOI:10.1111/mmi.13352


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[PMID]:26731263
[Au] Autor:Bessho T; Okada T; Kimura C; Shinohara T; Tomiyama A; Imamura A; Kuwamura M; Nishimura K; Fujimori K; Shuto S; Ishibashi O; Kubata BK; Inui T
[Ad] Endereço:Laboratory of Biological Macromolecules, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan.
[Ti] Título:Novel Characteristics of Trypanosoma brucei Guanosine 5'-monophosphate Reductase Distinct from Host Animals.
[So] Source:PLoS Negl Trop Dis;10(1):e0004339, 2016 Jan.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The metabolic pathway of purine nucleotides in parasitic protozoa is a potent drug target for treatment of parasitemia. Guanosine 5'-monophosphate reductase (GMPR), which catalyzes the deamination of guanosine 5'-monophosphate (GMP) to inosine 5'-monophosphate (IMP), plays an important role in the interconversion of purine nucleotides to maintain the intracellular balance of their concentration. However, only a few studies on protozoan GMPR have been reported at present. Herein, we identified the GMPR in Trypanosoma brucei, a causative protozoan parasite of African trypanosomiasis, and found that the GMPR proteins were consistently localized to glycosomes in T. brucei bloodstream forms. We characterized its recombinant protein to investigate the enzymatic differences between GMPRs of T. brucei and its host animals. T. brucei GMPR was distinct in having an insertion of a tandem repeat of the cystathionine ß-synthase (CBS) domain, which was absent in mammalian and bacterial GMPRs. The recombinant protein of T. brucei GMPR catalyzed the conversion of GMP to IMP in the presence of NADPH, and showed apparent affinities for both GMP and NADPH different from those of its mammalian counterparts. Interestingly, the addition of monovalent cations such as K+ and NH4+ to the enzymatic reaction increased the GMPR activity of T. brucei, whereas none of the mammalian GMPR's was affected by these cations. The monophosphate form of the purine nucleoside analog ribavirin inhibited T. brucei GMPR activity, though mammalian GMPRs showed no or only a little inhibition by it. These results suggest that the mechanism of the GMPR reaction in T. brucei is distinct from that in the host organisms. Finally, we demonstrated the inhibitory effect of ribavirin on the proliferation of trypanosomes in a dose-dependent manner, suggesting the availability of ribavirin to develop a new therapeutic agent against African trypanosomiasis.
[Mh] Termos MeSH primário: GMP Redutase/metabolismo
Trypanosoma brucei brucei/enzimologia
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Antimetabólitos/farmacologia
GMP Redutase/genética
Regulação Enzimológica da Expressão Gênica
Concentração de Íons de Hidrogênio
Dados de Sequência Molecular
Proteínas Recombinantes
Ribavirina/farmacologia
Especificidade da Espécie
Temperatura Ambiente
Tripanossomicidas/farmacologia
Trypanosoma brucei brucei/genética
Trypanosoma brucei brucei/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antimetabolites); 0 (Recombinant Proteins); 0 (Trypanocidal Agents); 49717AWG6K (Ribavirin); EC 1.7.1.7 (GMP Reductase)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:160116
[Lr] Data última revisão:
160116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160106
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0004339


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[PMID]:24387760
[Au] Autor:D'Angiolella V
[Ad] Endereço:Vincenzo.dangiolella@oncology.ox.ac.uk.
[Ti] Título:Beyond survival: fine-tuning GTP production to boost melanoma invasion.
[So] Source:Pigment Cell Melanoma Res;27(2):159-61, 2014 Mar.
[Is] ISSN:1755-148X
[Cp] País de publicação:England
[La] Idioma:eng
[Mh] Termos MeSH primário: GMP Redutase/metabolismo
Melanoma/enzimologia
Nucleosídeos de Purina/biossíntese
[Mh] Termos MeSH secundário: Animais
Seres Humanos
[Pt] Tipo de publicação:COMMENT; NEWS
[Nm] Nome de substância:
0 (Purine Nucleosides); EC 1.7.1.7 (GMP Reductase)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:170322
[Lr] Data última revisão:
170322
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140107
[St] Status:MEDLINE
[do] DOI:10.1111/pcmr.12209


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[PMID]:24139804
[Au] Autor:Wawrzyniak JA; Bianchi-Smiraglia A; Bshara W; Mannava S; Ackroyd J; Bagati A; Omilian AR; Im M; Fedtsova N; Miecznikowski JC; Moparthy KC; Zucker SN; Zhu Q; Kozlova NI; Berman AE; Hoek KS; Gudkov AV; Shewach DS; Morrison CD; Nikiforov MA
[Ad] Endereço:Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
[Ti] Título:A purine nucleotide biosynthesis enzyme guanosine monophosphate reductase is a suppressor of melanoma invasion.
[So] Source:Cell Rep;5(2):493-507, 2013 Oct 31.
[Is] ISSN:2211-1247
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Melanoma is one of the most aggressive types of human cancers, and the mechanisms underlying melanoma invasive phenotype are not completely understood. Here, we report that expression of guanosine monophosphate reductase (GMPR), an enzyme involved in de novo biosynthesis of purine nucleotides, was downregulated in the invasive stages of human melanoma. Loss- and gain-of-function experiments revealed that GMPR downregulates the amounts of several GTP-bound (active) Rho-GTPases and suppresses the ability of melanoma cells to form invadopodia, degrade extracellular matrix, invade in vitro, and grow as tumor xenografts in vivo. Mechanistically, we demonstrated that GMPR partially depletes intracellular GTP pools. Pharmacological inhibition of de novo GTP biosynthesis suppressed whereas addition of exogenous guanosine increased invasion of melanoma cells as well as cells from other cancer types. Our data identify GMPR as a melanoma invasion suppressor and establish a link between guanosine metabolism and Rho-GTPase-dependent melanoma cell invasion.
[Mh] Termos MeSH primário: GMP Redutase/metabolismo
Melanoma/enzimologia
Nucleosídeos de Purina/biossíntese
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Movimento Celular
Matriz Extracelular/metabolismo
GMP Redutase/antagonistas & inibidores
GMP Redutase/genética
Guanosina Trifosfato/metabolismo
Células HCT116
Seres Humanos
IMP Desidrogenase/metabolismo
Melanoma/metabolismo
Melanoma/patologia
Camundongos
Fenótipo
Interferência de RNA
RNA Interferente Pequeno/metabolismo
Transplante Heterólogo
Proteínas rac1 de Ligação ao GTP/genética
Proteínas rac1 de Ligação ao GTP/metabolismo
Proteínas rho de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Purine Nucleosides); 0 (RNA, Small Interfering); 86-01-1 (Guanosine Triphosphate); EC 1.1.1.205 (IMP Dehydrogenase); EC 1.1.1.205 (IMPDH2 protein, human); EC 1.7.1.7 (GMP Reductase); EC 3.6.5.2 (rac1 GTP-Binding Protein); EC 3.6.5.2 (rho GTP-Binding Proteins)
[Em] Mês de entrada:1501
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131022
[St] Status:MEDLINE


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[PMID]:23208589
[Au] Autor:Baker BG; Ball GR; Rakha EA; Nolan CC; Caldas C; Ellis IO; Green AR
[Ad] Endereço:School of Molecular Medical Sciences and Cellular Pathology, Nottingham University Hospitals and University of Nottingham, Nottingham, UK.
[Ti] Título:Lack of expression of the proteins GMPR2 and PPARα are associated with the basal phenotype and patient outcome in breast cancer.
[So] Source:Breast Cancer Res Treat;137(1):127-37, 2013 Jan.
[Is] ISSN:1573-7217
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: Basal-like tumours (BP) are a poor prognostic class of breast cancer but remain a biologically and clinically heterogeneous group. We have previously identified two novel genes PPARα (positive) and GMPR2 (negative) whose expression was significantly associated with BP at the transcriptome level. In this study, using a large and well-characterised series of operable invasive breast carcinomas (1,043 cases) prepared as TMAs, we assessed these targets at the protein level using immunohistochemistry and investigated associations with clinicopathological variables and patient outcome. RESULTS: Lack of PPARα and GMPR2 protein expression was associated with BP, as defined by the expression of cytokeratin (CK) 5/6 and/or CK14, (p = 0.023, p = 0.001, respectively) or as triple-negative (ER-, PR-, HER2-) phenotype (p < 0.001 for both proteins). Positive expression of both markers was associated ER and PR positive status (p < 0.05) and with the good Nottingham Prognostic Index group (p = 0.012, p < 0.001, respectively). Univariate survival analysis showed an association between lack of expression of PPARα and GMPR2 and poor outcome in terms of shorter disease-free survival and shorter breast cancer-specific survival, respectively. However, multivariate analysis showed that these associations were not independent of other prognostic variables, namely tumour size, grade, and nodal stage. In conclusion, this study demonstrates that loss of expression of GMPR2 and PPARα is associated with BP at the protein level; indicating that they may play a role in carcinogenesis of this molecularly complex and clinically important subtype. Further studies into their relevance in further classification of BP are warranted.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/metabolismo
Neoplasias da Mama/metabolismo
Carcinoma Ductal de Mama/metabolismo
GMP Redutase/metabolismo
Neoplasia de Células Basais/metabolismo
PPAR alfa/metabolismo
[Mh] Termos MeSH secundário: Biomarcadores Tumorais/genética
Neoplasias da Mama/mortalidade
Neoplasias da Mama/patologia
Carcinoma Ductal de Mama/mortalidade
Carcinoma Ductal de Mama/secundário
Intervalo Livre de Doença
Feminino
GMP Redutase/genética
Expressão Gênica
Seres Humanos
Estimativa de Kaplan-Meier
Metástase Linfática
Meia-Idade
Análise Multivariada
Neoplasia de Células Basais/mortalidade
Neoplasia de Células Basais/secundário
PPAR alfa/genética
Fenótipo
Modelos de Riscos Proporcionais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (PPAR alpha); EC 1.7.1.7 (GMP Reductase); EC 1.7.1.7 (GMPR2 protein, human)
[Em] Mês de entrada:1305
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:121205
[St] Status:MEDLINE
[do] DOI:10.1007/s10549-012-2302-3


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[PMID]:22332716
[Au] Autor:Hedstrom L
[Ad] Endereço:Departments of Biology and Chemistry, Brandeis University, Waltham, MA 02454, USA. hedstrom@brandeis.edu
[Ti] Título:The dynamic determinants of reaction specificity in the IMPDH/GMPR family of (ß/α)(8) barrel enzymes.
[So] Source:Crit Rev Biochem Mol Biol;47(3):250-63, 2012 May-Jun.
[Is] ISSN:1549-7798
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The inosine monophosphate dehydrogenase (IMPDH)/guanosine monophosphate reductase (GMPR) family of (ß/α)(8) enzymes presents an excellent opportunity to investigate how subtle changes in enzyme structure change reaction specificity. IMPDH and GMPR bind the same ligands with similar affinities and share a common set of catalytic residues. Both enzymes catalyze a hydride transfer reaction involving a nicotinamide cofactor hydride, and both reactions proceed via the same covalent intermediate. In the case of IMPDH, this intermediate reacts with water, while in GMPR it reacts with ammonia. In both cases, the two chemical transformations are separated by a conformational change. In IMPDH, the conformational change involves a mobile protein flap while in GMPR, the cofactor moves. Thus reaction specificity is controlled by differences in dynamics, which in turn are controlled by residues outside the active site. These findings have some intriguing implications for the evolution of the IMPDH/GMPR family.
[Mh] Termos MeSH primário: GMP Redutase/química
Guanosina Monofosfato/química
IMP Desidrogenase/química
[Mh] Termos MeSH secundário: Amônia/química
Domínio Catalítico
Cátions Monovalentes/química
Seres Humanos
Cinética
Ligantes
Ligação Proteica
Dobramento de Proteína
Estrutura Secundária de Proteína
Estrutura Terciária de Proteína
Especificidade por Substrato
Água/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; REVIEW
[Nm] Nome de substância:
0 (Cations, Monovalent); 0 (Ligands); 059QF0KO0R (Water); 7664-41-7 (Ammonia); 85-32-5 (Guanosine Monophosphate); EC 1.1.1.205 (IMP Dehydrogenase); EC 1.1.1.205 (IMPDH2 protein, human); EC 1.7.1.7 (GMP Reductase); EC 1.7.1.7 (GMPR2 protein, human)
[Em] Mês de entrada:1208
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120216
[St] Status:MEDLINE
[do] DOI:10.3109/10409238.2012.656843


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[PMID]:22037469
[Au] Autor:Patton GC; Stenmark P; Gollapalli DR; Sevastik R; Kursula P; Flodin S; Schuler H; Swales CT; Eklund H; Himo F; Nordlund P; Hedstrom L
[Ad] Endereço:Department of Biology, Brandeis University, Waltham, Massachusetts, USA.
[Ti] Título:Cofactor mobility determines reaction outcome in the IMPDH and GMPR (ß-α)8 barrel enzymes.
[So] Source:Nat Chem Biol;7(12):950-8, 2011 Oct 30.
[Is] ISSN:1552-4469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Inosine monophosphate dehydrogenase (IMPDH) and guanosine monophosphate reductase (GMPR) belong to the same structural family, share a common set of catalytic residues and bind the same ligands. The structural and mechanistic features that determine reaction outcome in the IMPDH and GMPR family have not been identified. Here we show that the GMPR reaction uses the same intermediate E-XMP* as IMPDH, but in this reaction the intermediate reacts with ammonia instead of water. A single crystal structure of human GMPR type 2 with IMP and NADPH fortuitously captures three different states, each of which mimics a distinct step in the catalytic cycle of GMPR. The cofactor is found in two conformations: an 'in' conformation poised for hydride transfer and an 'out' conformation in which the cofactor is 6 Å from IMP. Mutagenesis along with substrate and cofactor analog experiments demonstrate that the out conformation is required for the deamination of GMP. Remarkably, the cofactor is part of the catalytic machinery that activates ammonia.
[Mh] Termos MeSH primário: GMP Redutase/metabolismo
IMP Desidrogenase/metabolismo
[Mh] Termos MeSH secundário: Biocatálise
Cristalografia por Raios X
GMP Redutase/química
Guanosina Monofosfato/biossíntese
Guanosina Monofosfato/química
Guanosina Monofosfato/metabolismo
Seres Humanos
IMP Desidrogenase/química
Inosina Monofosfato/química
Inosina Monofosfato/metabolismo
Cinética
Modelos Moleculares
Estrutura Molecular
NADP/química
NADP/metabolismo
Teoria Quântica
Compostos de Sulfidrila/química
Compostos de Sulfidrila/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Sulfhydryl Compounds); 131-99-7 (Inosine Monophosphate); 53-59-8 (NADP); 85-32-5 (Guanosine Monophosphate); EC 1.1.1.205 (IMP Dehydrogenase); EC 1.7.1.7 (GMP Reductase); EC 1.7.1.7 (GMPR2 protein, human)
[Em] Mês de entrada:1201
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:111101
[St] Status:MEDLINE
[do] DOI:10.1038/nchembio.693



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