[45] Glutamine binding sites

Pinkus, Lawrence M.

doi:10.1016/s0076-6879(77)46049-x

Cited by 79 publications

(57 citation statements)

References 34 publications

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“…For most of the 80 years since glutaminase was discovered, the only chemical inhibitor of note was DON (6-diazo-5-oxo-l -norleucine), which is a glutamine mimetic and irreversibly binds to the catalytic serine of both glutaminase isozymes ( Figure 6A) [122,123]. While other small molecules were utilized to inhibit GLS (particularly membrane-impermeable molecules for determining subcellular localization), DON was the most extensively used inhibitor until the last decade [39].…”

Section: Kidney-type Glutaminase: Drug Discoverymentioning

confidence: 99%

“…While other small molecules were utilized to inhibit GLS (particularly membrane-impermeable molecules for determining subcellular localization), DON was the most extensively used inhibitor until the last decade [39]. DON has a number of other targets, and offers little therapeutic potential due to excessive toxicity [123].…”

Section: Kidney-type Glutaminase: Drug Discoverymentioning

confidence: 99%

“…BPTES is a long, highly flexible and C 2 -symmetrical molecule which binds in a 1:2 ratio with GLS and sits at the dimer-dimer binding interface, where it stabilizes an inactive tetramer ( Figure 6B) [67,124]. It has been suggested to have approximately 1000-fold greater affinity for GLS than for LGA, however to date, the only studies showing this with purified recombinant enzymes have used mutants of GLS which resemble LGA at the BPTES binding site, rather than using full-length LGA [68,123]. BPTES has been the subject of significant research efforts since its discovery, aided by the early reports of crystal structures of the molecule in complex with GLS.…”

Section: Kidney-type Glutaminase: Drug Discoverymentioning

confidence: 99%

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A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

2017

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Many cancer cells exhibit an altered metabolic phenotype, in which glutamine consumption is upregulated relative to healthy cells. This metabolic reprogramming often depends upon mitochondrial glutaminase activity, which converts glutamine to glutamate, a key precursor for biosynthetic and bioenergetic processes. Two isozymes of glutaminase exist, a kidney-type (GLS) and a liver-type enzyme (GLS2 or LGA). While a majority of studies have focused on GLS, here we summarize key findings on both glutaminases, describing their structure and function, their roles in cancer and pharmacological approaches to inhibiting their activities.

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Section: Kidney-type Glutaminase: Drug Discoverymentioning

confidence: 99%

Section: Kidney-type Glutaminase: Drug Discoverymentioning

confidence: 99%

Section: Kidney-type Glutaminase: Drug Discoverymentioning

confidence: 99%

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A Tale of Two Glutaminases: Homologous Enzymes with Distinct Roles in Tumorigenesis

2017

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“…MSO is a GS inhibitor (8) and AZA is a glutamine analog that inhibits GOGAT (18). Conversion ofaspartate to asparagine was inhibited in soybean leaves infiltrated with either MSO or AZA during 60 and 90 min labeling periods (23).…”

mentioning

confidence: 99%

Asparagine Biosynthesis in Alfalfa (Medicago sativa L.) Root Nodules

Snapp

Vance²

1986

Plant Physiol.

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ABSTRACIRapid direct conversion of exogenously supplied I'4Claspartate to I`Cj asparagine and to tricarboxylic cycle acids was observed in alfalfa (Medicago sativa L.) nodules. Aspartate aminotransferase activity readily converted carbon from exogenously applied I'Cjaspartate into the tricarboxylic acid cycle with subsequent conversion to the orpanic acids malate, succinate, and fumarate. Aminooxyacetate, an inhibitor of aminotransferase activity, reduced the flow of carbon from I'4Claspartate into tricarboxylic cycle acids and decreased "4C02 evolution by 9%. Concurrently, demonstrated with in vivo studies utilizing metabolic inhibitors, with in vitro enzyme analysis (3, 9, 22), and has been purified from soybean (10). Recent data indicate that both NH3-and glutamine-dependent asparagine synthesis occurs in alfalfa nodules (27). However, the regulation of carbon skeletons into asparagine biosynthesis remains unclear (15,17,24,25).In alfalfa, birdsfoot trefoil (Lotus corniculatus L.) and soybean, radioactive asparagine was readily formed when excised nodules were exposed to '4CO2 (9, 16). Radiolabeled asparagine and aspartate were transported in the xylem sap of nodulated root systems of alfalfa and birdsfoot trefoil exposed to "4C02 (16,29 (14,15,17,24

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“…We attribute the latter resistance to the fact that the E. coli enzyme utilizes the NH4' ion as an amide donor (3), whereas the mammalian enzyme utilizes glutamine (10); Albizziin is believed to inhibit AS enzyme function by affecting its ability to transfer amide groups from glutamine (15). Both the animal cell and the bacterial AS enzyme appear to be inhibited by the asparagine analog P-AH.…”

Section: Resultsmentioning

confidence: 99%