Is glutamine depletion needed in ALL disease?

Avramis, Vassilios I.

doi:10.1182/blood-2014-04-565523

Cited by 9 publications

(10 citation statements)

References 8 publications

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“…It is, however, important to indicate that particular interest with the glutaminolytic activity of ASNases was evident even in the early reports, when the relationship between this activity and deleterious therapeutic effects was first suggested [2,103]. This conclusion, however, was based on limited data and its rationale is still debated [31,33,34,125,126]. Unfortunately, many recent structural reports tout novel ASNases as promising therapeutics due to their absent or negligible glutaminolytic activity [112,[127][128][129].…”

Section: Substrate Specificitymentioning

confidence: 99%

“…For all other ASNases, however, the glutaminolytic activity is nearly universally quite minor (i.e., below several percent), compared to asparaginolytic activity. As indicated earlier, there is no consensus whether glutaminolytic activity is therapeutically deleterious or, conversely, necessary [33,34,124,125], and if so, what is its optimal level (that can be different for each patient). In vivo, L-Asn is mostly synthesized from L-Gln with an aid of asparagine synthetase [129], thus therapeutic suppression of L-Asn levels without controlling levels of L-Gln may be insufficient for starvation of cancer cells [124].…”

Section: Substrate Specificitymentioning

confidence: 99%

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Structural and biochemical properties of L‐asparaginase

Łubkowski

Wlodawer

2021

The FEBS Journal

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L-asparaginase (a hydrolase converting L-asparagine to L-aspartic acid) was the first enzyme to be used in clinical practice as an anticancer agent after its approval in 1978 as a component of a treatment protocol for childhood acute lymphoblastic leukemia (ALL). Structural and biochemical properties of L-asparaginases have been extensively investigated during the last half century, providing an accurate structural description of the enzyme isolated from a variety of sources, as well as clarifying the mechanism of its activity. This review provides a critical assessment of the current state of knowledge of primarily structural, but also selected biochemical properties of "bacterial-type" L-asparaginases from different organisms. The most extensively studied members of this enzyme family are L-asparaginases highly homologous to one of the two enzymes from Escherichia coli (usually referred to as EcAI and EcAII). Members of this enzyme family, although often called bacterial-type L-asparaginases, have been also identified in such divergent organisms as archaea or eukarya. Over 100 structural models of L-asparaginases have been deposited in the Protein Data Bank during the last 30 years. One of the prime achievements of structure-centered approaches was the elucidation of the details of the mechanism of enzymatic action of this unique hydrolase that utilizes a side chain of threonine as the primary nucleophile. The molecular basis of other important properties of these enzymes, such as their substrate specificity, are still being evaluated. Results of structural and mechanistic studies of L-asparaginases are being utilized in efforts to improve the clinical properties of this important anticancer drug.

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Section: Substrate Specificitymentioning

confidence: 99%

Section: Substrate Specificitymentioning

confidence: 99%

Structural and biochemical properties of L‐asparaginase

Łubkowski

Wlodawer

2021

The FEBS Journal

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“…ASNase inhibits synthesis of proteins in vitro ( 16 ) and in vivo ( 17 , 18 ) by a mechanism consistent with reduced ribosomal translocation at Asn codons. In humans, ASNase treatment protocols cause depletion of plasma Asn and modest reductions of plasma Gln levels accompanied by mild transient hyperglycemia and occasional ketoacidosis ( 11 , 19 , 20 ). In mice, administration of ASNase causes Asn depletion in plasma and some tissues, e.g., skeletal muscle ( 21 , 22 ), indicating, importantly, that intracellular Asn can also be depleted.…”

Section: Foundation Of the Hypothesismentioning

confidence: 99%

Asparaginase treatment side-effects may be due to genes with homopolymeric Asn codons (Review-Hypothesis)

Banerji¹

2015

International Journal of Molecular Medicine

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The present treatment of childhood T-cell leukemias involves the systemic administration of prokary-otic L-asparaginase (ASNase), which depletes plasma Asparagine (Asn) and inhibits protein synthesis. The mechanism of therapeutic action of ASNase is poorly understood, as are the etiologies of the side-effects incurred by treatment. Protein expression from genes bearing Asn homopolymeric coding regions (N-hCR) may be particularly susceptible to Asn level fluctuation. In mammals, N-hCR are rare, short and conserved. In humans, misfunctions of genes encoding N-hCR are associated with a cluster of disorders that mimic ASNase therapy side-effects which include impaired glycemic control, dislipidemia, pancreatitis, compromised vascular integrity, and neurological dysfunction. This paper proposes that dysregulation of Asn homeostasis, potentially even by ASNase produced by the microbiome, may contribute to several clinically important syndromes by altering expression of N-hCR bearing genes. By altering amino acid abundance and modulating ribosome translocation rates at codon repeats, the microbiomic environment may contribute to genome decoding and to shaping the proteome. We suggest that impaired translation at poly Asn codons elevates diabetes risk and severity.

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“…For over 4 decades Echerichia coli and Erwinia chrysantemi type II L-ASNases (EcAII and ErA, respectively) have been used in the treatment of acute lymphoblastic leukaemia (ALL), above all in childhood [ 3 , 4 , 5 , 6 ]. Their therapeutic efficacy can be primarily attributed to the reduction of serum L-ASN, which is essential for survival of L-asparagine synthetase (ASNS) knock-out (or down regulated) lymphoblastic tumoral cells [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Engineering of Helicobacter pylori L-Asparaginase: Characterization of Two Functionally Distinct Groups of Mutants

et al. 2015

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Bacterial L-asparaginases have been used as anti-cancer drugs for over 4 decades though presenting, along with their therapeutic efficacy, several side effects due to their bacterial origin and, seemingly, to their secondary glutaminase activity. Helicobacter pylori type II L-asparaginase possesses interesting features, among which a reduced catalytic efficiency for L-GLN, compared to the drugs presently used in therapy. In the present study, we describe some enzyme variants with catalytic and in vitro cytotoxic activities different from the wild type enzyme. Particularly, replacements on catalytic threonines (T16D and T95E) deplete the enzyme of both its catalytic activities, once more underlining the essential role of such residues. One serendipitous mutant, M121C/T169M, had a preserved efficiency vs L-asparagine but was completely unable to carry out L-glutamine hydrolysis. Interestingly, this variant did not exert any cytotoxic effect on HL-60 cells. The M121C and T169M single mutants had reduced catalytic activities (nearly 2.5- to 4-fold vs wild type enzyme, respectively). Mutant Q63E, endowed with a similar catalytic efficiency versus asparagine and halved glutaminase efficiency with respect to the wild type enzyme, was able to exert a cytotoxic effect comparable to, or higher than, the one of the wild type enzyme when similar asparaginase units were used. These findings may be relevant to determine the role of glutaminase activity of L-asparaginase in the anti-proliferative effect of the drug and to shed light on how to engineer the best asparaginase/glutaminase combination for an ever improved, patients-tailored therapy.

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Is glutamine depletion needed in ALL disease?

Cited by 9 publications

References 8 publications

Structural and biochemical properties of L‐asparaginase

Structural and biochemical properties of L‐asparaginase

Asparaginase treatment side-effects may be due to genes with homopolymeric Asn codons (Review-Hypothesis)

Engineering of Helicobacter pylori L-Asparaginase: Characterization of Two Functionally Distinct Groups of Mutants

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