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1.
J Anal Toxicol ; 47(2): 162-174, 2023 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-35921233

RESUMO

α-Pyrrolidinohexiophenone (α-PHP) is a derivative of the class of α-pyrrolidinophenones, a subgroup of synthetic cathinones. These substances are the second most abused drugs of new psychoactive substances. Here, we report the toxicological investigation of a series of 29 authentic forensic and clinical cases with analytically confirmed intake of α-PHP including two cases of drug testing in newborns using meconium. The age range of subjects where serum samples were available was 23-51 years (median 39.5), and 90% were male. Serum α-PHP concentrations, determined by a validated LC-MS-MS method, showed a high variability ranging from 1 to 83 ng/mL (mean, 40 ng/mL; median, 36 ng/mL). Comprehensive toxicological analysis revealed co-consumption of other psychotropic drugs in almost all cases with frequent occurrence of opiates (60%), benzodiazepines (35%), cannabinoids (30%), and cocaine (20%). Hence, forensic and clinical symptoms like aggressive behavior, sweating, delayed physical response, and impaired balance could not be explained by the abuse of α-PHP alone but rather by poly-intoxications. Liquid chromatography-quadrupole time-of-flight mass spectrometry and gas chromatography-mass spectrometry were used to investigate the metabolism of α-PHP in vivo using authentic human urine samples. Altogether, 11 phase I metabolites and 5 phase II glucuronides could be identified by this approach. Apart from the parent drug, most abundant findings in urine were the metabolites dihydroxy-pyrrolidinyl-α-PHP and dihydro-α-PHP and, to a lesser extent, 2'-oxo-dihydro-α-PHP and 2'-oxo-α-PHP. Monitoring of these metabolites along with the parent drug in forensic and clinical toxicology could unambiguously prove the abuse of the novel designer drug α-PHP.


Assuntos
Pirrolidinas , Catinona Sintética , Recém-Nascido , Humanos , Masculino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Detecção do Abuso de Substâncias/métodos
2.
Drug Test Anal ; 12(9): 1320-1335, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32476242

RESUMO

Among the increasing number of new psychoactive substances, 3',4'-methylenedioxy-α-pyrrolidinohexanophenone (MDPHP) belongs to the group of synthetic cathinones, which are the derivatives of the naturally occurring compound cathinone, the main psychoactive ingredient in the khat plant. Currently, only limited data are available for MDPHP, and no information is available on its human metabolism. We describe the toxicological investigation of nine cases associated with the use of MDPHP during the period February-June 2019. Serum MDPHP concentrations showed a high variability ranging from 3.3 to 140 ng/mL (mean 30.3 ng/mL and median 16 ng/mL). Intoxication symptoms of the described cases could not be explained by the abuse of MDPHP alone because in all cases the co-consumption of other psychotropic drugs with frequent occurrence of opiates and benzodiazepines could be verified. Therefore, the patients showed different clinical symptoms, including aggressive behaviour, delayed physical response, loss of consciousness and coma. Liquid chromatography-high-resolution mass spectrometry was successfully used to investigate the human in vivo metabolism of MDPHP using authentic human urine samples. The metabolism data for MDPHP were further substantiated by the analysis of human urine using gas chromatography-mass spectrometry (GC-MS, a widely used systematic toxicological analysis method appropriate for the toxicological detection of MDPHP intake), which revealed the presence of seven phase I metabolites and three phase II metabolites as glucuronides. GC-MS spectral data for MDPHP and metabolites are provided. The identified metabolite pattern corroborates the principal metabolic pathways of α-pyrrolidinophenones in humans.


Assuntos
Cromatografia Líquida/métodos , Drogas Desenhadas/intoxicação , Espectrometria de Massas/métodos , Detecção do Abuso de Substâncias/métodos , Adulto , Drogas Desenhadas/análise , Drogas Desenhadas/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Psicotrópicos/análise , Psicotrópicos/metabolismo , Psicotrópicos/intoxicação
3.
Clin Toxicol (Phila) ; 57(9): 806-812, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30775936

RESUMO

Introduction: Fentanyl derivatives like cyclopropylfentanyl have recently appeared on the recreational drug market. Cyclopropylfentanyl is probably a highly potent opioid, but human toxicological data are not available so far. Similar to other fentanyl derivatives the most serious acute health risk due to the use of cyclopropylfentanyl is likely to be respiratory depression. In case of overdose, this may lead to apnoea, respiratory arrest and death. In this paper, we present three cases of severe intoxication with cyclopropylfentanyl. Methods: Observational case series including three intoxications treated in the Emergency Department at the University Medical Centre in 2017. In all cases, the consumption of any drugs was denied by the patients and relatives. Toxicological analyses using GC-MS, LC-QTOF-MS and LC-MS-MS of serum, urine samples and in one case of a powder sample, found in the hospital room, were performed. Medical records were reviewed to obtain clinical data. Results: Clinical effects of severe opioid intoxications comprising loss of consciousness, bradypnea, hypercapnia, arterial hypotension and miosis were recorded. In all cases, the novel fentanyl analogue cyclopropylfentanyl was detected in body fluids. In two cases further synthetic opioids (U-47700, methoxyacetylfentanyl, butyrfentanyl, 2-fluoroiso- or 4-fluoroisobutyrfentanyl) and mitragynine or desoxypipradrol were found. A discovered powder sample contained cyclopropylfentanyl, cyclopropylnorfentanyl, acetylfentanyl, 4-ANPP, U-47700 and caffeine. Except for acetylfentanyl all ingredients could be detected in the respective blood and urine sample. In two cases a cyclopropylfentanyl serum concentration of 51 and 76 ng/ml was determined. Discussion: In three cases of severe potentially life-threatening intoxication, cyclopropylfentanyl was verified using different analytical procedures. The ingested substance, as well as the excreted metabolites, were detected by application of various mass spectrometric techniques. Conclusions: In cases of intoxication without a medical history, the detailed toxicological analysis may reveal new psychoactive substances which are not detected by standard toxicological screening approaches. The high pharmacological potency of new products with unknown toxicological data and unknown synergistic effects may easily lead to a life-threatening overdose.


Assuntos
Analgésicos Opioides/toxicidade , Coma/induzido quimicamente , Overdose de Drogas/complicações , Fentanila/análogos & derivados , Insuficiência Respiratória/induzido quimicamente , Adulto , Analgésicos Opioides/sangue , Analgésicos Opioides/urina , Overdose de Drogas/sangue , Overdose de Drogas/diagnóstico , Overdose de Drogas/urina , Fentanila/sangue , Fentanila/toxicidade , Fentanila/urina , Humanos , Masculino
4.
Forensic Sci Int ; 287: 63-73, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29649771

RESUMO

Comprehensive screening procedures for psychoactive agents in body fluids are an essential task in clinical and forensic toxicology. With the continuous emergence and adaption of new psychoactive substances (NPS) keeping a screening method up to date is challenging. To meet these demands, hyphenated high-resolution mass spectrometry has gained interest as extensive and expandable screening approach. Here we present a comprehensive method for systematic toxicological analysis of serum by liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS) with data independent acquisition. The potential of this method was demonstrated by analysis of 247 authentic serum- and 12 post-mortem femoral blood samples. Thus 950 compounds, comprising 185 different drugs and metabolites could be identified. For the detected substances, including pharmaceutical substances, illicit drugs as well as NPS, serum concentrations were confirmed ranging from traces to toxic values indicating the capability for forensic toxicological requirements. Positive identification of drugs was achieved by accurate mass measurement (±5ppm for [M+H]+; ±10ppm for [M-H]-), retention time (±0.35min), isotopic pattern match (less than 10 m/z RMS [ppm]), isotope match intensity (less than 20% RMS) and the presence of at least two fragment ions. The LC-QTOF-MS procedure was shown to be superior to serum screening by GC-MS, since 240% (335 versus 141) more drugs were identified in serum samples compared to GC-MS.


Assuntos
Cromatografia Líquida/métodos , Cromatografia Gasosa-Espectrometria de Massas , Drogas Ilícitas/sangue , Espectrometria de Massas/métodos , Preparações Farmacêuticas/sangue , Toxicologia Forense/métodos , Humanos , Detecção do Abuso de Substâncias/métodos
5.
Forensic Sci Int ; 273: 1-9, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28187296

RESUMO

3,4-methylenedioxypyrovalerone (MDPV) is a synthetic cathinone belonging to the class of α-pyrrolidinophenones that become increasingly popular as a designer psychostimulant. Here, we report a comprehensive collection of MDPV exposure with quantitative serum level confirmation in Germany. During the years 2014-2016, we could proof consumption of MDPV in 23 cases where urine and blood samples were submitted to our laboratory by the police of Lower Saxony. Most of the samples underwent systematic toxicological analysis by gas chromatography-mass spectrometry (GC-MS), where MDPV could be detected in urine and/or serum samples. The determined concentrations of MDPV in serum showed a high variability, ranging from traces (<10ng/mL) up to 576ng/mL with a mean concentration of 118ng/mL and median of 47ng/mL. The majority of MDPV users were men (87%) and the age ranged from 23 to 49 years (mean 35.9, median 37 years). For most of the analytically confirmed MDPV cases we could prove co-consumption of other psychotropic drugs with frequent occurrence of opiates and cannabinoids in 22% of the cases, followed by benzodiazepines and cocaine in 17%. Analysis of urine samples by GC-MS disclosed the presence of MDPV and its metabolites 2'-oxo-MDPV, demethylenyl-MDPV, demethylenyl-methyl-MDPV, demethylenyl-oxo-MDPV, demethylenyl-methyl-oxo-MDPV and demethylenyl-methyl-N,N-bisdealkyl-MDPV. The metabolite pattern substantiates previous suggestions for principle metabolic pathways of MDPV in humans.


Assuntos
Benzodioxóis/sangue , Benzodioxóis/urina , Drogas Desenhadas/análise , Pirrolidinas/sangue , Pirrolidinas/urina , Adulto , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Pessoa de Meia-Idade , Psicotrópicos/sangue , Psicotrópicos/urina , Detecção do Abuso de Substâncias , Transtornos Relacionados ao Uso de Substâncias/sangue , Transtornos Relacionados ao Uso de Substâncias/urina , Adulto Jovem , Catinona Sintética
6.
Forensic Sci Int ; 259: e14-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26775198

RESUMO

α-Pyrrolidinovalerophenone (α-PVP) is a synthetic cathinone belonging to the group of "second generation" pyrrolidinophenones that becomes more and more popular as a designer psychostimulant. Here we provide toxicological analytical support for a severe poisoning with α-PVP. Serum and urine samples that were sent to our laboratory were subjected to a general unknown screening procedure. The procedure includes immunoassay-based screening of drugs of abuse in serum and systematic toxicological analysis of urine and serum after neutral and basic liquid-liquid extraction followed by gas chromatography-mass spectrometry (GC-MS). Whereas the immunoassay delivered negative results, analyzing the urine sample by GC-MS in full scan mode disclosed the presence of α-PVP and its metabolites α-(2″-oxo-pyrrolidino)valerophenone (2″-oxo-α-PVP) and 1-phenyl-2-(pyrrolidin-1-yl)pentan-1-ol (OH-α-PVP). In the acetylated urine sample we found additionally N,N-bis-dealkyl-PVP. In serum, α-PVP could be detected after solid phase extraction and a concentration of 29ng/mL was determined. Other forensic relevant substances were not detected. The presented data can explain the psychotic symptoms and behavioural pattern of the subject after abuse of α-PVP, leading to a clinical condition similar to excited delirium syndrome.


Assuntos
Delírio/induzido quimicamente , Drogas Desenhadas/análise , Cromatografia Gasosa-Espectrometria de Massas , Pirrolidinas/sangue , Pirrolidinas/urina , Doença Aguda , Adulto , Delírio/sangue , Delírio/urina , Humanos , Masculino , Pirrolidinas/intoxicação
7.
Drug Test Anal ; 8(8): 816-25, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26333204

RESUMO

Non-targeted screening of body fluids for psychoactive agents is an essential task for forensic toxicology. The challenge is the identification of xenobiotics of interest from background noise and endogenous matrix components. The aim of the present work was to evaluate the use of an Automated Mass Spectral Deconvolution and Identification System (AMDIS) for gas chromatography-mass spectrometry (GC-MS) based toxicological serum screening. One hundred fifty serum samples submitted to the authors´ laboratory for systematic forensic toxicological analysis underwent GC-MS screening after neutral and basic liquid-liquid extraction. Recorded datasets were routinely evaluated both by experienced personnel and automatically using the AMDIS software combined with the Maurer/Pfleger/Weber GC-MS library MPW_2011. The results from manual and automated data evaluation were then systematically compared. AMDIS parameters for data deconvolution and substance identification had been successfully adapted to the GC-MS screening procedure in serum. The number of false positive hits could substantially be reduced without increasing the risk of overlooking relevant compounds. With AMDIS-based data evaluation, additional drugs were identified in 25 samples (17%) that had not been detected by manual data evaluation. Importantly, among these drugs, there were frequently prescribed and toxicologically relevant antidepressants and antipsychotic drugs such as citalopram, mirtazapine, quetiapine, or venlafaxine. For most of the identified drugs, their serum concentrations were in the therapeutic or subtherapeutic range. Thus, our study indicated that automated data evaluation by AMDIS provided reliable screening results. Copyright © 2015 John Wiley & Sons, Ltd.


Assuntos
Toxicologia Forense/métodos , Cromatografia Gasosa-Espectrometria de Massas/métodos , Psicotrópicos/sangue , Antidepressivos/sangue , Antipsicóticos/sangue , Humanos , Extração Líquido-Líquido/métodos
8.
Nat Commun ; 4: 2123, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23828504

RESUMO

Loss of folate receptor-α function is associated with cerebral folate transport deficiency and childhood-onset neurodegeneration. To clarify the mechanism of cerebral folate transport at the blood-cerebrospinal fluid barrier, we investigate the transport of 5-methyltetrahydrofolate in polarized cells. Here we identify folate receptor-α-positive intralumenal vesicles within multivesicular bodies and demonstrate the directional cotransport of human folate receptor-α, and labelled folate from the basolateral to the apical membrane in rat choroid plexus cells. Both the apical medium of folate receptor-α-transfected rat choroid plexus cells and human cerebrospinal fluid contain folate receptor-α-positive exosomes. Loss of folate receptor-α-expressing cerebrospinal fluid exosomes correlates with severely reduced 5-methyltetrahydrofolate concentration, corroborating the importance of the folate receptor-α-mediated folate transport in the cerebrospinal fluid. Intraventricular injections of folate receptor-α-positive and -negative exosomes into mouse brains demonstrate folate receptor-α-dependent delivery of exosomes into the brain parenchyma. Our results unravel a new pathway of folate receptor-α-dependent exosome-mediated folate delivery into the brain parenchyma and opens new avenues for cerebral drug targeting.


Assuntos
Plexo Corióideo/citologia , Plexo Corióideo/metabolismo , Exossomos/metabolismo , Ácido Fólico/metabolismo , Transcitose , Adolescente , Adulto , Animais , Polaridade Celular/efeitos dos fármacos , Criança , Plexo Corióideo/ultraestrutura , Vesículas Citoplasmáticas/efeitos dos fármacos , Vesículas Citoplasmáticas/metabolismo , Cães , Exossomos/efeitos dos fármacos , Exossomos/ultraestrutura , Feminino , Receptor 1 de Folato/metabolismo , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos , Modelos Biológicos , Monensin/farmacologia , Transporte Proteico/efeitos dos fármacos , Transportador de Folato Acoplado a Próton/metabolismo , Ratos , Tetra-Hidrofolatos/metabolismo , Transcitose/efeitos dos fármacos , Transferrina/farmacologia , Adulto Jovem
9.
Nucleic Acids Res ; 40(17): 8733-42, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22735700

RESUMO

Mutations in the gene of human RNase T2 are associated with white matter disease of the human brain. Although brain abnormalities (bilateral temporal lobe cysts and multifocal white matter lesions) and clinical symptoms (psychomotor impairments, spasticity and epilepsy) are well characterized, the pathomechanism of RNase T2 deficiency remains unclear. RNase T2 is the only member of the Rh/T2/S family of acidic hydrolases in humans. In recent years, new functions such as tumor suppressing properties of RNase T2 have been reported that are independent of its catalytic activity. We determined the X-ray structure of human RNase T2 at 1.6 Å resolution. The α+ß core fold shows high similarity to those of known T2 RNase structures from plants, while, in contrast, the external loop regions show distinct structural differences. The catalytic features of RNase T2 in presence of bivalent cations were analyzed and the structural consequences of known clinical mutations were investigated. Our data provide further insight into the function of human RNase T2 and may prove useful in understanding its mode of action independent of its enzymatic activity.


Assuntos
Endorribonucleases/química , Sequência de Aminoácidos , Sítios de Ligação , Cobre/farmacologia , Cristalografia por Raios X , Endorribonucleases/genética , Endorribonucleases/metabolismo , Glicosilação , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Dobramento de Proteína , Homologia Estrutural de Proteína , Zinco/química , Zinco/farmacologia
10.
J Bacteriol ; 192(3): 674-8, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19948802

RESUMO

Reduced ferredoxin is an intermediate in the methylotrophic and aceticlastic pathway of methanogenesis and donates electrons to membrane-integral proteins, which transfer electrons to the heterodisulfide reductase. A ferredoxin interaction has been observed previously for the Ech hydrogenase. Here we present a detailed analysis of a Methanosarcina mazei Delta ech mutant which shows decreased ferredoxin-dependent membrane-bound electron transport activity, a lower growth rate, and faster substrate consumption. Evidence is presented that a second protein whose identity is unknown oxidizes reduced ferredoxin, indicating an involvement in methanogenesis from methylated C(1) compounds.


Assuntos
Proteínas Arqueais/metabolismo , Ferredoxinas/metabolismo , Membranas/metabolismo , Methanosarcina/enzimologia , Methanosarcina/metabolismo , Oxirredutases/metabolismo , Proteínas Arqueais/genética , Transporte de Elétrons/fisiologia , Methanosarcina/genética , Modelos Biológicos , Mutação , Oxirredutases/genética
11.
Am J Hum Genet ; 85(3): 354-63, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19732866

RESUMO

Sufficient folate supplementation is essential for a multitude of biological processes and diverse organ systems. At least five distinct inherited disorders of folate transport and metabolism are presently known, all of which cause systemic folate deficiency. We identified an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 (FOLR1) gene coding for folate receptor alpha (FRalpha). Three patients carrying FOLR1 mutations developed progressive movement disturbance, psychomotor decline, and epilepsy and showed severely reduced folate concentrations in the cerebrospinal fluid (CSF). Brain magnetic resonance imaging (MRI) demonstrated profound hypomyelination, and MR-based in vivo metabolite analysis indicated a combined depletion of white-matter choline and inositol. Retroviral transfection of patient cells with either FRalpha or FRbeta could rescue folate binding. Furthermore, CSF folate concentrations, as well as glial choline and inositol depletion, were restored by folinic acid therapy and preceded clinical improvements. Our studies not only characterize a previously unknown and treatable disorder of early childhood, but also provide new insights into the folate metabolic pathways involved in postnatal myelination and brain development.


Assuntos
Encéfalo/metabolismo , Encéfalo/patologia , Proteínas de Transporte/genética , Ácido Fólico/metabolismo , Bainha de Mielina/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/terapia , Receptores de Superfície Celular/genética , Sequência de Aminoácidos , Transporte Biológico , Mapeamento Encefálico , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Pré-Escolar , Análise Mutacional de DNA , Feminino , Receptor 1 de Folato , Receptores de Folato com Âncoras de GPI , Perfilação da Expressão Gênica , Humanos , Lactente , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Modelos Biológicos , Dados de Sequência Molecular , Proteínas Mutantes/metabolismo , Mutação/genética , Especificidade de Órgãos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/química , Receptores de Superfície Celular/metabolismo
12.
Biochim Biophys Acta ; 1789(5): 403-12, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19217949

RESUMO

The transcription factor PAX6 plays an important role in transcriptional regulation of the peptide hormone glucagon from pancreatic alpha-cells. PAX6 contains two DNA binding domains, the paired domain (PD) and the homeodomain (HD). While the interaction of the PD with the PAX6 responsive elements G1 and G3 in the rat glucagon gene promoter is well understood, the role of the PAX6 HD for PAX6 binding and function on G1 and G3 remains unclear. In EMSA studies the PAX6 HD was found to be mandatory for PAX6 binding to G1 but not to G3. Transient transfections with luciferase reporter gene constructs revealed the HD to be critical for proper function of PAX6 on both, G1 and G3. Transfection data with variant promoter constructs and limited proteolysis assays demonstrated that the DNA sequence located 5' to the PD binding site plays an important role for PAX6 function and its conformation on the elements G1 and G3. Taken together, our data indicate a PH0-like binding of PAX6 to the glucagon promoter elements G1 and G3 where the HD binding site is abutted directly to the PD binding motif. The data suggest that the PH0-like binding induces a transcriptionally active conformation of PAX6.


Assuntos
Proteínas do Olho/genética , Glucagon/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição Box Pareados/genética , Proteínas Repressoras/genética , Ativação Transcricional , Animais , Sequência de Bases , Linhagem Celular , Interpretação Estatística de Dados , Proteínas do Olho/metabolismo , Glucagon/metabolismo , Células Secretoras de Glucagon/fisiologia , Proteínas de Homeodomínio/metabolismo , Dados de Sequência Molecular , Mutação , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/metabolismo , Fragmentos de Peptídeos/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Conformação Proteica , Ratos , Proteínas Repressoras/metabolismo , Elementos de Resposta , Alinhamento de Sequência , Tripsina/metabolismo
13.
J Biol Chem ; 284(6): 3976-84, 2009 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-19038966

RESUMO

Late infantile neuronal ceroid lipofuscinosis, a fatal neurodegenerative disease of childhood, is caused by mutations in the TPP1 gene that encodes tripeptidyl-peptidase I. We show that purified TPP1 requires at least partial glycosylation for in vitro autoprocessing and proteolytic activity. We crystallized the fully glycosylated TPP1 precursor under conditions that implied partial autocatalytic cleavage between the prosegment and the catalytic domain. X-ray crystallographic analysis at 2.35 angstroms resolution reveals a globular structure with a subtilisin-like fold, a Ser475-Glu272-Asp360 catalytic triad, and an octahedrally coordinated Ca2+-binding site that are characteristic features of the S53 sedolisin family of peptidases. In contrast to other S53 peptidases, the TPP1 structure revealed steric constraints on the P4 substrate pocket explaining its preferential cleavage of tripeptides from the unsubstituted N terminus of proteins. Two alternative conformations of the catalytic Asp276 are associated with the activation status of TPP1. 28 disease-causing missense mutations are analyzed in the light of the TPP1 structure providing insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis.


Assuntos
Endopeptidases/química , Lipofuscinoses Ceroides Neuronais/enzimologia , Dobramento de Proteína , Aminopeptidases , Linhagem Celular , Cristalografia por Raios X , Dipeptidil Peptidases e Tripeptidil Peptidases , Endopeptidases/genética , Glicosilação , Humanos , Mutação , Lipofuscinoses Ceroides Neuronais/genética , Estrutura Terciária de Proteína/genética , Serina Proteases , Homologia Estrutural de Proteína , Relação Estrutura-Atividade , Tripeptidil-Peptidase 1
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