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Article ; Online: Targeting metabolic changes in cancer: novel therapeutic approaches.

Bobrovnikova-Marjon, Ekaterina / Hurov, Jonathan B

2014 Volume 65, Page(s) 157–170

Abstract: Therapeutic strategies designed to target cancer metabolism are an area of intense research. Antimetabolites, first used to treat patients in the early twentieth century, served as an early proof of concept for such therapies. We highlight strategies ... ...

Abstract	Therapeutic strategies designed to target cancer metabolism are an area of intense research. Antimetabolites, first used to treat patients in the early twentieth century, served as an early proof of concept for such therapies. We highlight strategies that attempt to improve on the anti-metabolite approach as well as new metabolic drug targets. Some of these targets have the advantage of a strong genetic anchor to drive patient selection (isocitrate dehydrogenase 1/2, Enolase 2). Additional approaches described here derive from hypothesis-driven and systems biology efforts designed to exploit tumor cell metabolic dependencies (fatty acid oxidation, nicotinamide adenine dinucleotide synthesis, glutamine biology).
MeSH term(s)	Antimetabolites, Antineoplastic/therapeutic use ; Biomarkers, Tumor/genetics ; DNA-Binding Proteins/genetics ; Fatty Acids/metabolism ; Glutamine/metabolism ; Humans ; Isocitrate Dehydrogenase/genetics ; Methotrexate/therapeutic use ; NAD/metabolism ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Phosphopyruvate Hydratase/genetics ; Signal Transduction ; Tumor Suppressor Proteins/genetics
Chemical Substances	Antimetabolites, Antineoplastic ; Biomarkers, Tumor ; DNA-Binding Proteins ; Fatty Acids ; Tumor Suppressor Proteins ; Glutamine (0RH81L854J) ; NAD (0U46U6E8UK) ; Isocitrate Dehydrogenase (EC 1.1.1.41) ; ENO1 protein, human (EC 4.2.1.11) ; Phosphopyruvate Hydratase (EC 4.2.1.11) ; Methotrexate (YL5FZ2Y5U1)
Language	English
Publishing date	2014
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	207930-6
ISSN	1545-326X ; 0066-4219
ISSN (online)	1545-326X
ISSN	0066-4219
DOI	10.1146/annurev-med-092012-112344
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Article ; Online: The Par-1/MARK family of protein kinases: from polarity to metabolism.

Hurov, Jonathan / Piwnica-Worms, Helen

Cell cycle (Georgetown, Tex.)

2007 Volume 6, Issue 16, Page(s) 1966–1969

Abstract: The Par-1 protein kinases are conserved from yeast to man and belong to a subfamily of kinases that includes the energy sensor and metabolic regulator, AMPK. Par-1 is regulated by LKB1 and atypical PKC and has been shown in multiple organisms and cell ... ...

Abstract	The Par-1 protein kinases are conserved from yeast to man and belong to a subfamily of kinases that includes the energy sensor and metabolic regulator, AMPK. Par-1 is regulated by LKB1 and atypical PKC and has been shown in multiple organisms and cell types to be critical for regulation of cellular polarity. Recent studies using knockout mice have revealed several surprising physiological functions for Par-1b/MARK2/EMK1. Our recent study shows that Par-1b regulates metabolic rate, adiposity and insulin sensitivity. This is the first study to implicate these kinases in metabolic functions akin to those previously defined for AMPK. Conversely, another series of recent publications now implicate AMPK in regulation of polarity. Here we discuss the metabolic phenotype seen in Par-1b deficient mice and the synthesis of several findings that link Par-1 and AMPK to a degree that has not been previously appreciated.
MeSH term(s)	AMP-Activated Protein Kinases ; Amino Acid Sequence ; Animals ; Cell Polarity/genetics ; Cell Polarity/physiology ; Energy Metabolism/genetics ; Energy Metabolism/physiology ; Humans ; Multienzyme Complexes/genetics ; Multienzyme Complexes/metabolism ; Protein Kinase C/genetics ; Protein Kinase C/metabolism ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Sequence Homology, Amino Acid
Chemical Substances	Multienzyme Complexes ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Protein Kinase C (EC 2.7.11.13) ; AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2007-06-08
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.6.16.4576
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Article ; Online: Action at a distance: allostery and the development of drugs to target cancer cell metabolism.

DeLaBarre, Byron / Hurov, Jonathan / Cianchetta, Giovanni / Murray, Stuart / Dang, Lenny

Chemistry & biology

2014 Volume 21, Issue 9, Page(s) 1143–1161

Abstract: Cancer cells must carefully regulate their metabolism to maintain growth and division under varying nutrient and oxygen levels. Compelling data support the investigation of numerous enzymes as therapeutic targets to exploit metabolic vulnerabilities ... ...

Abstract	Cancer cells must carefully regulate their metabolism to maintain growth and division under varying nutrient and oxygen levels. Compelling data support the investigation of numerous enzymes as therapeutic targets to exploit metabolic vulnerabilities common to several cancer types. We discuss the rationale for developing such drugs and review three targets with central roles in metabolic pathways crucial for cancer cell growth: pyruvate kinase muscle isozyme splice variant 2 (PKM2) in glycolysis, glutaminase in glutaminolysis, and mutations in isocitrate dehydrogenase 1 and 2 isozymes (IDH1/2) in the tricarboxylic acid cycle. These targets exemplify the drugging approach to cancer metabolism, with allosteric modulation being the common theme. The first glutaminase and mutant IDH1/2 inhibitors have entered clinical testing, and early data are promising. Cancer metabolism provides a wealth of novel targets, and targeting allosteric sites promises to yield selective drugs with the potential to transform clinical outcomes across many cancer types.
MeSH term(s)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Carrier Proteins/antagonists & inhibitors ; Carrier Proteins/metabolism ; Citric Acid Cycle/drug effects ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Glutaminase/antagonists & inhibitors ; Glutaminase/metabolism ; Glycolysis/drug effects ; Humans ; Isocitrate Dehydrogenase/antagonists & inhibitors ; Isocitrate Dehydrogenase/metabolism ; Isoenzymes/antagonists & inhibitors ; Isoenzymes/metabolism ; Membrane Proteins/antagonists & inhibitors ; Membrane Proteins/metabolism ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplastic Stem Cells/cytology ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Thyroid Hormones/metabolism ; Thyroid Hormone-Binding Proteins
Chemical Substances	Antineoplastic Agents ; Carrier Proteins ; Enzyme Inhibitors ; Isoenzymes ; Membrane Proteins ; Thyroid Hormones ; Isocitrate Dehydrogenase (EC 1.1.1.41) ; Glutaminase (EC 3.5.1.2)
Language	English
Publishing date	2014-08-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	917827-2
ISSN	1879-1301 ; 1074-5521
ISSN (online)	1879-1301
ISSN	1074-5521
DOI	10.1016/j.chembiol.2014.08.007
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Article: Atypical PKC phosphorylates PAR-1 kinases to regulate localization and activity.

Hurov, Jonathan B / Watkins, Janis L / Piwnica-Worms, Helen

Current biology : CB

2004 Volume 14, Issue 8, Page(s) 736–741

Abstract: The establishment and maintenance of cellular polarity are essential biological processes that must be maintained throughout the lifetime of eukaryotic organisms. The Par-1 protein kinases are key polarity determinants that have been conserved throughout ...

Abstract	The establishment and maintenance of cellular polarity are essential biological processes that must be maintained throughout the lifetime of eukaryotic organisms. The Par-1 protein kinases are key polarity determinants that have been conserved throughout evolution. Par-1 directs anterior-posterior asymmetry in the one-cell C. elegans embryo and the Drosophila oocyte. In mammalian cells, Par-1 may regulate epithelial cell polarity. Relevant substrates of Par-1 in these pathways are just being identified, but it is not yet known how Par-1 itself is regulated. Here, we demonstrate that human Par-1b (hPar-1b) interacts with and is negatively regulated by atypical PKC. hPar-1b is phosphorylated by aPKC on threonine 595, a residue conserved in Par-1 orthologs in mammals, worms, and flies. The equivalent site in hPar-1a, T564, is phosphorylated in vivo and by aPKC in vitro. Importantly, phosphorylation of hPar-1b on T595 negatively regulates the kinase activity and plasma membrane localization of hPar-1b in vivo. This study establishes a novel functional link between two central determinants of cellular polarity, aPKC and Par-1, and suggests a model by which aPKC may regulate Par-1 in polarized cells.
MeSH term(s)	Blotting, Western ; Cell Polarity/physiology ; Electrophoresis, Polyacrylamide Gel ; Fluorescence ; HeLa Cells ; Humans ; Phosphopeptides/metabolism ; Phosphorylation ; Plasmids/genetics ; Precipitin Tests ; Protein Kinase C/metabolism ; Protein Kinase C/physiology ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/metabolism ; Protein-Serine-Threonine Kinases/physiology ; Threonine/metabolism ; Transfection
Chemical Substances	Phosphopeptides ; Threonine (2ZD004190S) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; PKC-3 protein (EC 2.7.11.13) ; Protein Kinase C (EC 2.7.11.13)
Language	English
Publishing date	2004-04-20
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2004.04.007
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Article ; Online: Roadmap for the Emerging Field of Cancer Neuroscience.

Monje, Michelle / Borniger, Jeremy C / D'Silva, Nisha J / Deneen, Benjamin / Dirks, Peter B / Fattahi, Faranak / Frenette, Paul S / Garzia, Livia / Gutmann, David H / Hanahan, Douglas / Hervey-Jumper, Shawn L / Hondermarck, Hubert / Hurov, Jonathan B / Kepecs, Adam / Knox, Sarah M / Lloyd, Alison C / Magnon, Claire / Saloman, Jami L / Segal, Rosalind A /

Sloan, Erica K / Sun, Xin / Taylor, Michael D / Tracey, Kevin J / Trotman, Lloyd C / Tuveson, David A / Wang, Timothy C / White, Ruth A / Winkler, Frank

Cell

2020 Volume 181, Issue 2, Page(s) 219–222

Abstract: Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary seeks to describe the burgeoning field of "cancer ... ...

Abstract	Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary seeks to describe the burgeoning field of "cancer neuroscience" and encourage multidisciplinary collaboration for the study of cancer-nervous system interactions.
MeSH term(s)	Humans ; Neoplasms/metabolism ; Nervous System/metabolism ; Neurosciences
Language	English
Publishing date	2020-04-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2020.03.034
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Article ; Online: Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase.

McDonald, Gabrielle / Chubukov, Victor / Coco, John / Truskowski, Kevin / Narayanaswamy, Rohini / Choe, Sung / Steadman, Mya / Artin, Erin / Padyana, Anil K / Jin, Lei / Ronseaux, Sebastien / Locuson, Charles / Fan, Zi-Peng / Erdmann, Tabea / Mann, Alan / Hayes, Sebastian / Fletcher, Mark / Nellore, Kavitha / Rao, Siva Sanjeeva /

Subramanya, Hosahalli / Reddy, K Satish / Panigrahi, Sunil K / Antony, Thomas / Gopinath, Sreevalsam / Sui, Zhihua / Nagaraja, Nelamangala / Dang, Lenny / Lenz, Georg / Hurov, Jonathan / Biller, Scott A / Murtie, Josh / Marks, Kevin M / Ulanet, Danielle B

Molecular cancer therapeutics

2020 Volume 19, Issue 12, Page(s) 2502–2515

Abstract: Agents targeting metabolic pathways form the backbone of standard oncology treatments, though a better understanding of differential metabolic dependencies could instruct more rationale-based therapeutic approaches. We performed a chemical biology screen ...

Abstract	Agents targeting metabolic pathways form the backbone of standard oncology treatments, though a better understanding of differential metabolic dependencies could instruct more rationale-based therapeutic approaches. We performed a chemical biology screen that revealed a strong enrichment in sensitivity to a novel dihydroorotate dehydrogenase (DHODH) inhibitor, AG-636, in cancer cell lines of hematologic versus solid tumor origin. Differential AG-636 activity translated to the
MeSH term(s)	Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; DNA Damage/drug effects ; Enzyme Inhibitors/pharmacology ; Genomics/methods ; Hematologic Neoplasms/drug therapy ; Hematologic Neoplasms/etiology ; Hematologic Neoplasms/metabolism ; Hematologic Neoplasms/pathology ; Humans ; Neoplasm Staging ; Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors ; Proteomics/methods ; Pyrimidines/metabolism
Chemical Substances	Antineoplastic Agents ; Enzyme Inhibitors ; Pyrimidines ; Oxidoreductases Acting on CH-CH Group Donors (EC 1.3.-) ; dihydroorotate dehydrogenase (EC 1.3.5.2) ; pyrimidine (K8CXK5Q32L)
Language	English
Publishing date	2020-10-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-20-0550
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Article ; Online: Mesenchymal phenotype predisposes lung cancer cells to impaired proliferation and redox stress in response to glutaminase inhibition.

Ulanet, Danielle B / Couto, Kiley / Jha, Abhishek / Choe, Sung / Wang, Amanda / Woo, Hin-Koon / Steadman, Mya / DeLaBarre, Byron / Gross, Stefan / Driggers, Edward / Dorsch, Marion / Hurov, Jonathan B

PloS one

2014 Volume 9, Issue 12, Page(s) e115144

Abstract: Recent work has highlighted glutaminase (GLS) as a key player in cancer cell metabolism, providing glutamine-derived carbon and nitrogen to pathways that support proliferation. There is significant interest in targeting GLS for cancer therapy, although ... ...

Abstract	Recent work has highlighted glutaminase (GLS) as a key player in cancer cell metabolism, providing glutamine-derived carbon and nitrogen to pathways that support proliferation. There is significant interest in targeting GLS for cancer therapy, although the gene is not known to be mutated or amplified in tumors. As a result, identification of tractable markers that predict GLS dependence is needed for translation of GLS inhibitors to the clinic. Herein we validate a small molecule inhibitor of GLS and show that non-small cell lung cancer cells marked by low E-cadherin and high vimentin expression, hallmarks of a mesenchymal phenotype, are particularly sensitive to inhibition of the enzyme. Furthermore, lung cancer cells induced to undergo epithelial to mesenchymal transition (EMT) acquire sensitivity to the GLS inhibitor. Metabolic studies suggest that the mesenchymal cells have a reduced capacity for oxidative phosphorylation and increased susceptibility to oxidative stress, rendering them unable to cope with the perturbations induced by GLS inhibition. These findings elucidate selective metabolic dependencies of mesenchymal lung cancer cells and suggest novel pathways as potential targets in this aggressive cancer type.
MeSH term(s)	Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Enzyme Inhibitors/pharmacology ; Epithelial-Mesenchymal Transition ; Genetic Association Studies ; Glutaminase/antagonists & inhibitors ; Glutaminase/metabolism ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Molecular Targeted Therapy ; Oxidative Stress/drug effects ; Sulfides/pharmacology ; Thiadiazoles/pharmacology
Chemical Substances	Enzyme Inhibitors ; Sulfides ; Thiadiazoles ; bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide ; GLS protein, human (EC 3.5.1.2) ; Glutaminase (EC 3.5.1.2)
Language	English
Publishing date	2014-12-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0115144
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Article ; Online: GPAT3 and GPAT4 are regulated by insulin-stimulated phosphorylation and play distinct roles in adipogenesis.

Shan, Dandan / Li, Jian-liang / Wu, Leeying / Li, Dongmei / Hurov, Jonathan / Tobin, James F / Gimeno, Ruth E / Cao, Jingsong

Journal of lipid research

2010 Volume 51, Issue 7, Page(s) 1971–1981

Abstract: Acyl-CoA:glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first step during de novo synthesis of glycerolipids. Mammals have at least four GPAT isoforms. Here we report the further characterization of the two recently identified microsomal GPAT3 ...

Abstract	Acyl-CoA:glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first step during de novo synthesis of glycerolipids. Mammals have at least four GPAT isoforms. Here we report the further characterization of the two recently identified microsomal GPAT3 and GPAT4. Both enzymes are highly expressed in adipose tissues. However, while GPAT3 is highly (approximately 60-fold) induced during adipocyte differentiation, GPAT4 induction is only modest (approximately 5-fold), leading to a lower abundance of GPAT4 mRNA in adipocytes. While overexpression of GPAT3 and GPAT4 in either insect or mammalian cells results in a comparable increase of GPAT activity, shRNA-mediated knockdown of GPAT3, but not GPAT4, in 3T3-L1 adipocytes led to a significant decrease in GPAT activity, a profound inhibition of lipid accumulation, and a lack of expression of several adipogenic markers during adipocyte differentiation. These data suggest that GPAT3 may encode the major GPAT isoform in adipocytes and play an important role in adipogenesis. Furthermore, we have shown that both GPAT3 and GPAT4 are phosphorylated by insulin at Ser and Thr residues, leading to increased GPAT activity that is sensitive to wortmannin. Our results reveal a link between the lipogenic effects of insulin and microsomal GPAT3 and GPAT4, implying their importance in glycerolipid biosynthesis.
MeSH term(s)	1-Acylglycerol-3-Phosphate O-Acyltransferase/classification ; 1-Acylglycerol-3-Phosphate O-Acyltransferase/genetics ; 1-Acylglycerol-3-Phosphate O-Acyltransferase/metabolism ; 3T3-L1 Cells ; Adipogenesis/physiology ; Amino Acid Sequence ; Animals ; Glycerol-3-Phosphate O-Acyltransferase/classification ; Glycerol-3-Phosphate O-Acyltransferase/genetics ; Glycerol-3-Phosphate O-Acyltransferase/metabolism ; Hep G2 Cells ; Humans ; Insulin/metabolism ; Isoenzymes/classification ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Mice ; Molecular Sequence Data ; Phosphorylation ; Phylogeny ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Rats ; Sequence Alignment ; Tissue Distribution
Chemical Substances	Insulin ; Isoenzymes ; RNA, Messenger ; GPAT4 protein, human (EC 2.3.1.15) ; Glycerol-3-Phosphate O-Acyltransferase (EC 2.3.1.15) ; 1-Acylglycerol-3-Phosphate O-Acyltransferase (EC 2.3.1.51) ; GPAT3 protein, human (EC 2.3.1.51)
Language	English
Publishing date	2010-02-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1194/jlr.M006304
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Article ; Online: Mesenchymal phenotype predisposes lung cancer cells to impaired proliferation and redox stress in response to glutaminase inhibition.

Danielle B Ulanet / Kiley Couto / Abhishek Jha / Sung Choe / Amanda Wang / Hin-Koon Woo / Mya Steadman / Byron DeLaBarre / Stefan Gross / Edward Driggers / Marion Dorsch / Jonathan B Hurov

PLoS ONE, Vol 9, Iss 12, p e

2014 Volume 115144

Abstract	Recent work has highlighted glutaminase (GLS) as a key player in cancer cell metabolism, providing glutamine-derived carbon and nitrogen to pathways that support proliferation. There is significant interest in targeting GLS for cancer therapy, although the gene is not known to be mutated or amplified in tumors. As a result, identification of tractable markers that predict GLS dependence is needed for translation of GLS inhibitors to the clinic. Herein we validate a small molecule inhibitor of GLS and show that non-small cell lung cancer cells marked by low E-cadherin and high vimentin expression, hallmarks of a mesenchymal phenotype, are particularly sensitive to inhibition of the enzyme. Furthermore, lung cancer cells induced to undergo epithelial to mesenchymal transition (EMT) acquire sensitivity to the GLS inhibitor. Metabolic studies suggest that the mesenchymal cells have a reduced capacity for oxidative phosphorylation and increased susceptibility to oxidative stress, rendering them unable to cope with the perturbations induced by GLS inhibition. These findings elucidate selective metabolic dependencies of mesenchymal lung cancer cells and suggest novel pathways as potential targets in this aggressive cancer type.
Keywords	Medicine ; R ; Science ; Q
Subject code	570 ; 610
Language	English
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Full-length human glutaminase in complex with an allosteric inhibitor.

DeLaBarre, Byron / Gross, Stefan / Fang, Cheng / Gao, Yi / Jha, Abhishek / Jiang, Fan / Song J, Juanhua / Wei, Wentao / Hurov, Jonathan B

Biochemistry

2011 Volume 50, Issue 50, Page(s) 10764–10770

Abstract: Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. The level of a splice variant of GLS1 (GAC) is elevated in certain cancers, and GAC is specifically inhibited by bis-2-(5-phenylacetimido-1,2,4,thiadiazol-2-yl)ethyl ...

Abstract	Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. The level of a splice variant of GLS1 (GAC) is elevated in certain cancers, and GAC is specifically inhibited by bis-2-(5-phenylacetimido-1,2,4,thiadiazol-2-yl)ethyl sulfide (BPTES). We report here the first full-length crystal structure of GAC in the presence and absence of BPTES molecules. Two BPTES molecules bind at an interface region of the GAC tetramer in a manner that appears to lock the GAC tetramer into a nonproductive conformation. The importance of these loops with regard to overall enzymatic activity of the tetramer was revealed by a series of GAC point mutants designed to create a BPTES resistant GAC.
MeSH term(s)	Allosteric Site ; Amino Acid Sequence ; Amino Acid Substitution ; Biocatalysis ; Databases, Protein ; Dimerization ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Glutaminase/antagonists & inhibitors ; Glutaminase/chemistry ; Glutaminase/genetics ; Glutaminase/metabolism ; Humans ; Isoenzymes/antagonists & inhibitors ; Isoenzymes/chemistry ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Kinetics ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Mutant Proteins/antagonists & inhibitors ; Mutant Proteins/chemistry ; Mutant Proteins/metabolism ; Point Mutation ; Protein Conformation ; Recombinant Proteins/antagonists & inhibitors ; Recombinant Proteins/chemistry ; Recombinant Proteins/metabolism ; Sequence Alignment ; Sulfides/chemistry ; Sulfides/metabolism ; Thiadiazoles/chemistry ; Thiadiazoles/metabolism
Chemical Substances	Enzyme Inhibitors ; Isoenzymes ; Mutant Proteins ; Recombinant Proteins ; Sulfides ; Thiadiazoles ; bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide ; Glutaminase (EC 3.5.1.2)
Language	English
Publishing date	2011-12-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/bi201613d
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