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Article: Long-range action of an HDAC inhibitor treats chronic pain in a spared nerve injury rat model.

Centeno, Maria Virginia / Alam, Md Suhail / Haldar, Kasturi / Apkarian, Apkar Vania

bioRxiv : the preprint server for biology

2023

Abstract: Histone deacetylase inhibitors (HDACi) that modulate epigenetic regulation and are approved for treating rare cancers have, in disease models, also been shown to mitigate neurological conditions, including chronic pain. They are of interest as non-opioid ...

Abstract	Histone deacetylase inhibitors (HDACi) that modulate epigenetic regulation and are approved for treating rare cancers have, in disease models, also been shown to mitigate neurological conditions, including chronic pain. They are of interest as non-opioid treatments, but achieving long-term efficacy with limited dosing has remained elusive. Here we utilize a triple combination formulation (TCF) comprised of a pan-HDACi vorinostat (Vo at its FDA-approved daily dose of 50mg/Kg), the caging agent 2-hydroxypropyl-β-cyclodextrin (HPBCD) and polyethylene glycol (PEG) known to boost plasma and brain exposure and efficacy of Vo in mice and rats, of various ages, spared nerve injury (SNI) model of chronic neuropathic pain. Administration of the TCF (but not HPBCD and PEG) decreased mechanical allodynia for 4 weeks without antagonizing weight, anxiety, or mobility. This was achieved at less than 1% of the total dose of Vo approved for 4 weeks of tumor treatment and associated with decreased levels of major inflammatory markers and microglia in ipsilateral (but not contralateral) spinal cord regions. A single TCF injection was sufficient for 3-4 weeks of efficacy: this was mirrored in repeat injections, specific for the injured paw and not seen on sham treatment. Pharmacodynamics in an SNI mouse model suggested pain relief was sustained for days to weeks after Vo elimination. Doubling Vo in a single TCF injection proved effectiveness was limited to male rats, where the response amplitude tripled and remained effective for > 2 months, an efficacy that outperforms all currently available chronic pain pharmacotherapies. Together, these data suggest that through pharmacological modulation of Vo, the TCF enables single-dose effectiveness with extended action, reduces long-term HDACi dosage, and presents excellent potential to develop as a non-opioid treatment option for chronic pain.
Language	English
Publishing date	2023-12-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.13.571583
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Article ; Online: Genomic analyses of glycine decarboxylase neurogenic mutations yield a large-scale prediction model for prenatal disease.

Farris, Joseph / Alam, Md Suhail / Rajashekara, Arpitha Mysore / Haldar, Kasturi

PLoS genetics

2021 Volume 17, Issue 2, Page(s) e1009307

Abstract: Hundreds of mutations in a single gene result in rare diseases, but why mutations induce severe or attenuated states remains poorly understood. Defect in glycine decarboxylase (GLDC) causes Non-ketotic Hyperglycinemia (NKH), a neurological disease ... ...

Abstract	Hundreds of mutations in a single gene result in rare diseases, but why mutations induce severe or attenuated states remains poorly understood. Defect in glycine decarboxylase (GLDC) causes Non-ketotic Hyperglycinemia (NKH), a neurological disease associated with elevation of plasma glycine. We unified a human multiparametric NKH mutation scale that separates severe from attenuated neurological disease with new in silico tools for murine and human genome level-analyses, gathered in vivo evidence from mice engineered with top-ranking attenuated and a highly pathogenic mutation, and integrated the data in a model of pre- and post-natal disease outcomes, relevant for over a hundred major and minor neurogenic mutations. Our findings suggest that highly severe neurogenic mutations predict fatal, prenatal disease that can be remedied by metabolic supplementation of dams, without amelioration of persistent plasma glycine. The work also provides a systems approach to identify functional consequences of mutations across hundreds of genetic diseases. Our studies provide a new framework for a large scale understanding of mutation functions and the prediction that severity of a neurogenic mutation is a direct measure of pre-natal disease in neurometabolic NKH mouse models. This framework can be extended to analyses of hundreds of monogenetic rare disorders where the underlying genes are known but understanding of the vast majority of mutations and why and how they cause disease, has yet to be realized.
MeSH term(s)	Animals ; Disease Models, Animal ; Female ; Genomics ; Genotype ; Glycine/genetics ; Glycine/metabolism ; Glycine Dehydrogenase (Decarboxylating)/chemistry ; Glycine Dehydrogenase (Decarboxylating)/genetics ; Humans ; Hyperglycinemia, Nonketotic/genetics ; Hyperglycinemia, Nonketotic/metabolism ; Hyperglycinemia, Nonketotic/pathology ; Male ; Mass Spectrometry ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mutation ; Mutation, Missense ; Phenotype
Chemical Substances	Glycine Dehydrogenase (Decarboxylating) (EC 1.4.4.2) ; Glycine (TE7660XO1C)
Language	English
Publishing date	2021-02-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1009307
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Article ; Online: Generation of three induced pluripotent stem cell lines from a patient with Kabuki syndrome carrying the KMT2D p.R4198X mutation.

Lager, Tyson W / Zuo, Junjun / Alam, Md Suhail / Calhoun, Barbara / Haldar, Kasturi / Panopoulos, Athanasia D

Stem cell research

2022 Volume 62, Page(s) 102799

Abstract: Kabuki syndrome (KS) is a rare genetic disorder typically characterized by facial abnormalities, developmental delay, cognitive dysfunction, and organ impairment. In this report, fibroblast cells obtained from a KS patient containing a heterozygous KMT2D ...

Abstract	Kabuki syndrome (KS) is a rare genetic disorder typically characterized by facial abnormalities, developmental delay, cognitive dysfunction, and organ impairment. In this report, fibroblast cells obtained from a KS patient containing a heterozygous KMT2D c.12592 C>T mutation (p.R4198X) were reprogrammed using non-integrative Sendai virus to generate three induced pluripotent stem cell (iPSC) clones. The iPSC lines retained the KS patient mutation, and displayed normal karyotypes, pluripotency marker expression, and the ability to differentiate into the three germ layers.
MeSH term(s)	Abnormalities, Multiple ; Face/abnormalities ; Hematologic Diseases/genetics ; Humans ; Induced Pluripotent Stem Cells ; Mutation/genetics ; Vestibular Diseases/genetics
Language	English
Publishing date	2022-05-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2393143-7
ISSN	1876-7753 ; 1873-5061
ISSN (online)	1876-7753
ISSN	1873-5061
DOI	10.1016/j.scr.2022.102799
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Article ; Online: Large scale analyses of genotype-phenotype relationships of glycine decarboxylase mutations and neurological disease severity.

Farris, Joseph / Calhoun, Barbara / Alam, Md Suhail / Lee, Shaun / Haldar, Kasturi

PLoS computational biology

2020 Volume 16, Issue 5, Page(s) e1007871

Abstract: Monogenetic diseases provide unique opportunity for studying complex, clinical states that underlie neurological severity. Loss of glycine decarboxylase (GLDC) can severely impact neurological development as seen in non-ketotic hyperglycinemia (NKH). NKH ...

Abstract	Monogenetic diseases provide unique opportunity for studying complex, clinical states that underlie neurological severity. Loss of glycine decarboxylase (GLDC) can severely impact neurological development as seen in non-ketotic hyperglycinemia (NKH). NKH is a neuro-metabolic disorder lacking quantitative predictors of disease states. It is characterized by elevation of glycine, seizures and failure to thrive, but glycine reduction often fails to confer neurological benefit, suggesting need for alternate tools to distinguish severe from attenuated disease. A major challenge has been that there are 255 unique disease-causing missense mutations in GLDC, of which 206 remain entirely uncharacterized. Here we report a Multiparametric Mutation Score (MMS) developed by combining in silico predictions of stability, evolutionary conservation and protein interaction models and suitable to assess 251 of 255 mutations. In addition, we created a quantitative scale of clinical disease severity comprising of four major disease domains (seizure, cognitive failure, muscular and motor control and brain-malformation) to comprehensively score patient symptoms identified in 131 clinical reports published over the last 15 years. The resulting patient Clinical Outcomes Scores (COS) were used to optimize the MMS for biological and clinical relevance and yield a patient Weighted Multiparametric Mutation Score (WMMS) that separates severe from attenuated neurological disease (p = 1.2 e-5). Our study provides understanding for developing quantitative tools to predict clinical severity of neurological disease and a clinical scale that advances monitoring disease progression needed to evaluate new treatments for NKH.
MeSH term(s)	Gene Expression Regulation, Enzymologic ; Genotype ; Glycine Dehydrogenase (Decarboxylating)/genetics ; Humans ; Hyperglycinemia, Nonketotic/diagnosis ; Hyperglycinemia, Nonketotic/genetics ; Hyperglycinemia, Nonketotic/pathology ; Mutation, Missense ; Phenotype ; Severity of Illness Index
Chemical Substances	Glycine Dehydrogenase (Decarboxylating) (EC 1.4.4.2)
Language	English
Publishing date	2020-05-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1007871
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Article ; Online: Tolerance of chronic HDACi treatment for neurological, visceral and lung Niemann-Pick Type C disease in mice.

Alam, Md Suhail / Cooper, Bruce / Farris, Joseph D / Haldar, Kasturi

Scientific reports

2018 Volume 8, Issue 1, Page(s) 3875

Abstract: Histone deacetylase (HDAC) inhibitors are of significant interest as drugs. However, their use to treat neurological disorders has raised concern because HDACs are required for brain function. We have previously shown that a triple combination ... ...

Abstract	Histone deacetylase (HDAC) inhibitors are of significant interest as drugs. However, their use to treat neurological disorders has raised concern because HDACs are required for brain function. We have previously shown that a triple combination formulation (TCF) of the pan HDACi vorinostat (Vo), 2-hydroxypropyl-beta-cyclodextrin (HPBCD) and polyethylene glycol (PEG) 400 improves pharmacokinetic exposure and entry of Vo into the brain. TCF treatment significantly delayed both neurodegeneration and death in the Npc1
MeSH term(s)	2-Hydroxypropyl-beta-cyclodextrin/pharmacology ; Animals ; Brain/drug effects ; Brain/pathology ; Disease Models, Animal ; Disease Progression ; Drug Combinations ; Drug Tolerance ; Female ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/metabolism ; Immune Tolerance ; Lung/drug effects ; Lung/pathology ; Lung Diseases/pathology ; Male ; Mice ; Mice, Inbred BALB C ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/metabolism ; Niemann-Pick Disease, Type C/drug therapy ; Niemann-Pick Disease, Type C/metabolism ; Niemann-Pick Disease, Type C/physiopathology ; Polyethylene Glycols/pharmacology ; Proteins/metabolism ; Purkinje Cells/drug effects ; Purkinje Cells/metabolism ; Vorinostat/metabolism ; Vorinostat/pharmacology
Chemical Substances	Drug Combinations ; Histone Deacetylase Inhibitors ; Npc1 protein, mouse ; Proteins ; 2-Hydroxypropyl-beta-cyclodextrin (1I96OHX6EK) ; Polyethylene Glycols (3WJQ0SDW1A) ; Vorinostat (58IFB293JI) ; polyethylene glycol 400 (B697894SGQ) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2018-03-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-22162-7
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Article ; Online: Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model.

Alam, Md Suhail / Getz, Michelle / Haldar, Kasturi

Science translational medicine

2016 Volume 8, Issue 326, Page(s) 326ra23

Abstract: Histone deacetylase inhibitors (HDACi) are approved for treating rare cancers and are of interest as potential therapies for neurodegenerative disorders. We evaluated a triple combination formulation (TCF) comprising the pan-HDACi vorinostat, the caging ... ...

Abstract	Histone deacetylase inhibitors (HDACi) are approved for treating rare cancers and are of interest as potential therapies for neurodegenerative disorders. We evaluated a triple combination formulation (TCF) comprising the pan-HDACi vorinostat, the caging agent 2-hydroxypropyl-β-cyclodextrin (HPBCD), and polyethylene glycol (PEG) for treating a mouse model (the Npc1(nmf164) mouse) of Niemann-Pick type C (NPC) disease, a difficult-to-treat cerebellar disorder. Vorinostat alone showed activity in cultured primary cells derived from Npc1(nmf164) mice but did not improve animal survival. However, low-dose, once-weekly intraperitoneal injections of the TCF containing vorinostat increased histone acetylation in the mouse brain, preserved neurites and Purkinje cells, delayed symptoms of neurodegeneration, and extended mouse life span from 4 to almost 9 months. We demonstrate that the TCF boosted the ability of HDACi to cross the blood-brain barrier and was not toxic even when used long term. Further, the TCF enabled dose reduction, which has been a major challenge in HDACi therapy. TCF simultaneously treats neurodegenerative and systemic symptoms of Niemann-Pick type C disease in a mouse model.
MeSH term(s)	2-Hydroxypropyl-beta-cyclodextrin ; Animals ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Blood-Brain Barrier/pathology ; Disease Models, Animal ; Disease Progression ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Histone Deacetylase Inhibitors/administration & dosage ; Histone Deacetylase Inhibitors/blood ; Histone Deacetylase Inhibitors/therapeutic use ; Hydroxamic Acids/administration & dosage ; Hydroxamic Acids/blood ; Hydroxamic Acids/therapeutic use ; Inflammation/blood ; Inflammation/complications ; Inflammation/pathology ; Liver/drug effects ; Liver/pathology ; Mice ; Mutation/genetics ; Nerve Degeneration/blood ; Nerve Degeneration/complications ; Nerve Degeneration/drug therapy ; Nerve Degeneration/pathology ; Niemann-Pick Disease, Type C/blood ; Niemann-Pick Disease, Type C/complications ; Niemann-Pick Disease, Type C/drug therapy ; Niemann-Pick Disease, Type C/pathology ; Polyethylene Glycols/chemistry ; Purkinje Cells/drug effects ; Purkinje Cells/metabolism ; Purkinje Cells/pathology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Spleen/drug effects ; Spleen/pathology ; Survival Analysis ; beta-Cyclodextrins/chemistry
Chemical Substances	Histone Deacetylase Inhibitors ; Hydroxamic Acids ; RNA, Messenger ; beta-Cyclodextrins ; 2-Hydroxypropyl-beta-cyclodextrin (1I96OHX6EK) ; Polyethylene Glycols (30IQX730WE) ; vorinostat (58IFB293JI)
Language	English
Publishing date	2016-02-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.aad9407
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Article ; Online: Case report: a synonymous VHL mutation (c.414A > G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing.

Liu, Fang / Calhoun, Barbara / Alam, Md Suhail / Sun, Miaomiao / Wang, Xuechun / Zhang, Chao / Haldar, Kasturi / Lu, Xin

BMC medical genetics

2020 Volume 21, Issue 1, Page(s) 42

Abstract: Background: von Hippel-Lindau (VHL) disease is a familial neoplasia syndrome that results from the germline mutation of VHL. Pathogenic VHL mutations include deletion, frameshift, nonsense and missense mutations. Synonymous mutations are expected to be ... ...

Abstract	Background: von Hippel-Lindau (VHL) disease is a familial neoplasia syndrome that results from the germline mutation of VHL. Pathogenic VHL mutations include deletion, frameshift, nonsense and missense mutations. Synonymous mutations are expected to be phenotypically silent and their role in VHL disease remains poorly understood. Case presentation: We report a Caucasian male with a family history of pheochromocytoma and the synonymous VHL mutation c.414A > G (p.Pro138Pro). At 47-years, MRI revealed pheochromocytoma in the left adrenal gland and hemangioblastomas in the spine and brain. Pheochromocytoma was treated by adrenalectomy. Radiotherapy, followed by craniotomy and resection were needed to reduce hemangioblastomas to residual lesions. Two of three of the proband's children inherited the mutation and both presented with retinal hemangioblastomas without pheochromocytoma at age 7: one twin needed four laser treatments. Primary skin fibroblasts carrying the heterozygous mutation or wild type VHL were established from the family. Mutant fibroblasts downregulated full-length VHL mRNA and protein, and upregulated the short VHL mRNA isoform (a result of exon 2 skipping in splicing) at the mRNA level but not at the protein level. Conclusions: Our study shows that the synonymous VHL mutation c.414A > G can within 7 years induce pediatric retinal hemangioblastoma in absence of pheochromocytoma. This highlights the need to include splicing-altering synonymous mutations into the screening for VHL disease. This is also the first report on detecting and validating a synonymous VHL mutation using patient-derived fibroblasts. The mutation c.414A > G translates to p.Pro138Pro, yet it is not functionally silent, because it causes aberrant splicing by skipping exon 2. The reduced but not completely abolished pVHL protein in a loss-of-heterozygosity genetic backdrop may underlie the etiology of VHL disease.
MeSH term(s)	Adrenal Gland Neoplasms/complications ; Adrenal Gland Neoplasms/diagnosis ; Adrenal Gland Neoplasms/genetics ; Cerebellar Neoplasms/complications ; Cerebellar Neoplasms/diagnosis ; Cerebellar Neoplasms/genetics ; Child ; Child, Preschool ; Family ; Female ; Frameshift Mutation/genetics ; Germ-Line Mutation ; Hemangioblastoma/complications ; Hemangioblastoma/diagnosis ; Hemangioblastoma/genetics ; Humans ; Male ; Middle Aged ; Neoplasms, Multiple Primary/diagnosis ; Neoplasms, Multiple Primary/genetics ; Pedigree ; Pheochromocytoma/complications ; Pheochromocytoma/diagnosis ; Pheochromocytoma/genetics ; Proline/genetics ; RNA Splicing/genetics ; Retinal Neoplasms/complications ; Retinal Neoplasms/diagnosis ; Retinal Neoplasms/genetics ; Silent Mutation ; Spinal Neoplasms/complications ; Spinal Neoplasms/diagnosis ; Spinal Neoplasms/genetics ; Von Hippel-Lindau Tumor Suppressor Protein/genetics ; von Hippel-Lindau Disease/complications ; von Hippel-Lindau Disease/genetics
Chemical Substances	Proline (9DLQ4CIU6V) ; Von Hippel-Lindau Tumor Suppressor Protein (EC 2.3.2.27) ; VHL protein, human (EC 6.3.2.-)
Language	English
Publishing date	2020-02-27
Publishing country	England
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1471-2350
ISSN (online)	1471-2350
DOI	10.1186/s12881-020-0976-7
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Article ; Online: Pluronic based β-cyclodextrin polyrotaxanes for treatment of Niemann-Pick Type C disease.

Collins, Christopher J / Loren, Bradley P / Alam, Md Suhail / Mondjinou, Yawo / Skulsky, Joseph L / Chaplain, Cheyenne R / Haldar, Kasturi / Thompson, David H

Scientific reports

2017 Volume 7, Page(s) 46737

Abstract: Niemann-Pick Type C disease (NPC) is a rare metabolic disorder characterized by disruption of normal cholesterol trafficking within the cells of the body. There are no FDA approved treatments available for NPC patients. Recently, the cycloheptaglucoside ... ...

Abstract	Niemann-Pick Type C disease (NPC) is a rare metabolic disorder characterized by disruption of normal cholesterol trafficking within the cells of the body. There are no FDA approved treatments available for NPC patients. Recently, the cycloheptaglucoside 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) has shown efficacy as a potential NPC therapeutic by extending lifetime in NPC mice, delaying neurodegeneration, and decreasing visceral and neurological cholesterol burden. Although promising, systemic HP-β-CD treatment is limited by a pharmacokinetic profile characterized by rapid loss through renal filtration. To address these shortcomings, we sought to design a family of HP-β-CD pro-drug delivery vehicles, known as polyrotaxanes (PR), capable of increasing the efficacy of a given injected dose by improving both pharmacokinetic profile and bioavailability of the HP-β-CD agent. PR can effectively diminish the cholesterol pool within the liver, spleen, and kidney at molar concentrations 10-to-100-fold lower than monomeric HP-β-CD. In addition to this proof-of-concept, use of PR scaffolds with differing physiochemical properties reveal structure-activity relationships in which PR characteristics, including hydrophobicity, threading efficiency and surface charge, were found to both decisively and subtly effect therapeutic efficacy. PR scaffolds exhibit absorption, pharmacokinetics, and biodistribution patterns that are significantly altered from monomeric HP-β-CD. In all, PR scaffolds hold great promise as potential treatments for visceral disease in NPC patients.
MeSH term(s)	2-Hydroxypropyl-beta-cyclodextrin/chemistry ; 2-Hydroxypropyl-beta-cyclodextrin/pharmacokinetics ; 2-Hydroxypropyl-beta-cyclodextrin/pharmacology ; Animals ; Biological Availability ; Cholesterol/metabolism ; Excipients/chemistry ; Excipients/pharmacokinetics ; Excipients/pharmacology ; Mice, Inbred BALB C ; Niemann-Pick Disease, Type C/drug therapy ; Niemann-Pick Disease, Type C/metabolism ; Poloxamer/chemistry ; Prodrugs/chemistry ; Prodrugs/pharmacokinetics ; Prodrugs/pharmacology ; Rotaxanes/chemistry ; Tissue Distribution ; Treatment Outcome
Chemical Substances	Excipients ; Prodrugs ; Rotaxanes ; Poloxamer (106392-12-5) ; 2-Hydroxypropyl-beta-cyclodextrin (1I96OHX6EK) ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2017-04-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep46737
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Article ; Online: WhiB2/Rv3260c, a cell division-associated protein of Mycobacterium tuberculosis H37Rv, has properties of a chaperone.

Konar, Monica / Alam, Md Suhail / Arora, Chandni / Agrawal, Pushpa

The FEBS journal

2012 Volume 279, Issue 15, Page(s) 2781–2792

Abstract: whiB-like genes have been found in all actinomycetes sequenced so far. The amino-acid sequences of WhiB proteins of Mycobacterium tuberculosis H37Rv are highly conserved and participate in several cellular functions. Unlike other WhiB proteins of M. ... ...

Abstract	whiB-like genes have been found in all actinomycetes sequenced so far. The amino-acid sequences of WhiB proteins of Mycobacterium tuberculosis H37Rv are highly conserved and participate in several cellular functions. Unlike other WhiB proteins of M. tuberculosis that have properties of protein disulfide reductases, WhiB2 showed properties like a chaperone as it suppressed the aggregation of several model substrates (e.g. citrate synthase, rhodanese and luciferase). Suppression of aggregation of the model substrates did not require ATP. Four cysteine residues of WhiB2 form two intramolecular disulfide bonds; however, chaperone function was unaffected by the redox state of the cysteines. WhiB2 also restored the activity of chemically denatured citrate synthase and did not require either ATP or a co-chaperone for refolding. The results indicate that WhiB2, which has been shown to be associated with cell division in mycobacteria and streptomyces, has evolved independently of other WhiBs, although it retains basic properties of this group of proteins. This is the first report to show that a WhiB protein has chaperone-like function; therefore, this report will have major implications in attempts to understand the role of WhiB proteins in mycobacteria, particularly in cell division.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/physiology ; Base Sequence ; Cell Division/genetics ; Cell Division/physiology ; Chemical Precipitation ; Citrate (si)-Synthase/chemistry ; Citrate (si)-Synthase/metabolism ; Cysteine/chemistry ; DNA, Bacterial/genetics ; Genes, Bacterial ; Insulin/chemistry ; Insulin/metabolism ; Molecular Chaperones/chemistry ; Molecular Chaperones/genetics ; Molecular Chaperones/physiology ; Mutagenesis, Site-Directed ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/physiology ; Oxidation-Reduction ; Protein Denaturation ; Serine/chemistry
Chemical Substances	Bacterial Proteins ; DNA, Bacterial ; Insulin ; Molecular Chaperones ; Serine (452VLY9402) ; Adenosine Triphosphate (8L70Q75FXE) ; Citrate (si)-Synthase (EC 2.3.3.1) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2012-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/j.1742-4658.2012.08662.x
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Article ; Online: Studies on structural and functional divergence among seven WhiB proteins of Mycobacterium tuberculosis H37Rv.

Alam, Md Suhail / Garg, Saurabh K / Agrawal, Pushpa

The FEBS journal

2009 Volume 276, Issue 1, Page(s) 76–93

Abstract: The whiB-like genes (1-7) of Mycobacterium tuberculosis are involved in cell division, nutrient starvation, pathogenesis, antibiotic resistance and stress sensing. Although the biochemical properties of WhiB1, WhiB3 and WhiB4 are known, there is no ... ...

Abstract	The whiB-like genes (1-7) of Mycobacterium tuberculosis are involved in cell division, nutrient starvation, pathogenesis, antibiotic resistance and stress sensing. Although the biochemical properties of WhiB1, WhiB3 and WhiB4 are known, there is no information about the other proteins. Here, we elucidate in detail the biochemical and biophysical properties of WhiB2, WhiB5, WhiB6 and WhiB7 of M. tuberculosis and present a comprehensive comparative study on the molecular properties of all WhiB proteins. UV-Vis spectroscopy has suggested the presence of a redox-sensitive [2Fe-2S] cluster in each of the WhiB proteins, which remains stably bound to the proteins in the presence of 8 m urea. The [2Fe-2S] cluster of each protein was oxidation labile but the rate of cluster loss decreased under reducing environments. The [2Fe-2S] cluster of each WhiB protein responded differently to the oxidative effect of air and oxidized glutathione. In all cases, disassembly of the [2Fe-2S] cluster was coupled with the oxidation of cysteine-thiols and the formation of two intramolecular disulfide bonds. Both CD and fluorescence spectroscopy revealed that WhiB proteins are structurally divergent members of the same family. Similar to WhiB1, WhiB3 and WhiB4, apo WhiB5, WhiB6 and WhiB7 also reduced the disulfide of insulin, a model substrate. However, the reduction efficiency varied significantly. Surprisingly, WhiB2 did not reduce the insulin disulfide, even though its basic properties were similar to those of others. The structural and functional divergence among WhiB proteins indicated that each WhiB protein is a distinguished member of the same family and together they may represent a novel redox system for M. tuberculosis.
MeSH term(s)	Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Cell Division ; Conserved Sequence ; Genetic Variation ; Iron-Sulfur Proteins/chemistry ; Iron-Sulfur Proteins/genetics ; Iron-Sulfur Proteins/metabolism ; Kinetics ; Mycobacterium tuberculosis/cytology ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/metabolism ; Mycobacterium tuberculosis/pathogenicity ; Protein Disulfide Reductase (Glutathione)/metabolism ; Spectrophotometry ; Transcription Factors/chemistry ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Bacterial Proteins ; Iron-Sulfur Proteins ; Transcription Factors ; Protein Disulfide Reductase (Glutathione) (EC 1.8.4.2)
Language	English
Publishing date	2009-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/j.1742-4658.2008.06755.x
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