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"https://www.academia.edu/login?post_login_redirect_url=https%3A%2F%2Fwww.academia.edu%2F124684311%2FSelective_reduction_in_glutaminase_activity_of_l_Asparaginase_by_asparagine_248_to_serine_mutation_A_combined_computational_and_experimental_effort_in_blood_cancer_treatment%3Fshow_translation%3Dtrue"; window.loswp.previewableAttachments = [{"id":118864596,"identifier":"Attachment_118864596","shouldShowBulkDownload":false}]; window.loswp.shouldDetectTimezone = true; window.loswp.shouldShowBulkDownload = true; window.loswp.showSignupCaptcha = false window.loswp.willEdgeCache = false; window.loswp.work = {"work":{"id":124684311,"created_at":"2024-10-13T08:30:54.241-07:00","from_world_paper_id":260119628,"updated_at":"2024-11-25T22:39:02.425-08:00","_data":{"publisher":"Elsevier BV","grobid_abstract":"Type II L-asparaginase (L-ASNase) is an FDA approved enzyme drug with extensive applications for treatment of certain blood cancers. However, the therapeutic efficiency of this enzyme is hampered by its undesirable glutaminase activity. Given the pivotal role of this enzyme against cancer, designing engineered mutants with diminished glutaminase activity would be of great therapeutic interest. To this end, N248S mutation was selected as the potential mutation with beneficial effects. Various in silico analyses including MD simulation, molecular docking and QMMM studies were performed to assess the effects of N248S mutation on the activity of the enzyme. Thereafter, this mutation along with N248A, N248V and N248T mutations as controls were exerted in L-ASNase gene. The results from in silico analyses and experimental efforts indicated that N248S mutation is associated with the suitable L-ASNase activity, while the glutaminase activity is disturbed due to impaired interactions. It has been shown that glutamine turnover was affected much more strongly than asparagine hydrolysis. The approach of exploiting in silico tools to design mutated enzymes lead to staggering time and cost reduction. Following this strategy, we have designed a mutant L-ASNase with diminished glutaminase activity, which could be of interest for improved biomedical applications.","publication_date":"2018,,","publication_name":"International Journal of Biological Macromolecules","grobid_abstract_attachment_id":"118864596"},"document_type":"paper","pre_hit_view_count_baseline":null,"quality":"high","language":"en","title":"Selective reduction in glutaminase activity of l‑Asparaginase by asparagine 248 to serine mutation: A combined computational and experimental effort in blood cancer treatment","broadcastable":false,"draft":null,"has_indexable_attachment":true,"indexable":true}}["work"]; window.loswp.workCoauthors = [26655805]; window.loswp.locale = "en"; window.loswp.countryCode = "SG"; window.loswp.cwvAbTestBucket = ""; window.loswp.designVariant = "ds_vanilla"; window.loswp.fullPageMobileSutdModalVariant = "full_page_mobile_sutd_modal"; window.loswp.useOptimizedScribd4genScript = false; window.loginModal = {}; window.loginModal.appleClientId = 'edu.academia.applesignon'; window.userInChina = "false";</script><script defer="" src="https://accounts.google.com/gsi/client"></script><div class="ds-loswp-container"><div class="ds-work-card--grid-container"><div class="ds-work-card--container js-loswp-work-card"><div class="ds-work-card--cover"><div class="ds-work-cover--wrapper"><div class="ds-work-cover--container"><button class="ds-work-cover--clickable js-swp-download-button" data-signup-modal="{"location":"swp-splash-paper-cover","attachmentId":118864596,"attachmentType":"pdf"}"><img alt="First page of “Selective reduction in glutaminase activity of l‑Asparaginase by asparagine 248 to serine mutation: A combined computational and experimental effort in blood cancer treatment”" class="ds-work-cover--cover-thumbnail" src="https://0.academia-photos.com/attachment_thumbnails/118864596/mini_magick20241013-1-88igdt.png?1728833519" /><img alt="PDF Icon" class="ds-work-cover--file-icon" src="//a.academia-assets.com/images/single_work_splash/adobe_icon.svg" /><div class="ds-work-cover--hover-container"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span><p>Download Free PDF</p></div><div class="ds-work-cover--ribbon-container">Download Free PDF</div><div class="ds-work-cover--ribbon-triangle"></div></button></div></div></div><div class="ds-work-card--work-information"><h1 class="ds-work-card--work-title">Selective reduction in glutaminase activity of l‑Asparaginase by asparagine 248 to serine mutation: A combined computational and experimental effort in blood cancer treatment</h1><div class="ds-work-card--work-authors ds-work-card--detail"><a class="ds-work-card--author js-wsj-grid-card-author ds2-5-body-md ds2-5-body-link" data-author-id="26655805" href="https://iausdj.academia.edu/SakoMirzaie"><img alt="Profile image of Sako Mirzaie" class="ds-work-card--author-avatar" src="//a.academia-assets.com/images/s65_no_pic.png" />Sako Mirzaie</a></div><div class="ds-work-card--detail"><p class="ds-work-card--detail ds2-5-body-sm">2018, International Journal of Biological Macromolecules</p><div class="ds-work-card--work-metadata"><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">visibility</span><p class="ds2-5-body-sm" id="work-metadata-view-count">…</p></div><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">description</span><p class="ds2-5-body-sm">45 pages</p></div><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">link</span><p class="ds2-5-body-sm">1 file</p></div></div><script>(async () => { const workId = 124684311; const worksViewsPath = "/v0/works/views?subdomain_param=api&work_ids%5B%5D=124684311"; const getWorkViews = async (workId) => { const response = await fetch(worksViewsPath); if (!response.ok) { throw new Error('Failed to load work views'); } const data = await response.json(); return data.views[workId]; }; // Get the view count for the work - we send this immediately rather than waiting for // the DOM to load, so it can be available as soon as possible (but without holding up // the backend or other resource requests, because it's a bit expensive and not critical). const viewCount = await getWorkViews(workId); const updateViewCount = (viewCount) => { try { const viewCountNumber = parseInt(viewCount, 10); if (viewCountNumber === 0) { // Remove the whole views element if there are zero views. document.getElementById('work-metadata-view-count')?.parentNode?.remove(); return; } const commaizedViewCount = viewCountNumber.toLocaleString(); const viewCountBody = document.getElementById('work-metadata-view-count'); if (!viewCountBody) { throw new Error('Failed to find work views element'); } viewCountBody.textContent = `${commaizedViewCount} views`; } catch (error) { // Remove the whole views element if there was some issue parsing. document.getElementById('work-metadata-view-count')?.parentNode?.remove(); throw new Error(`Failed to parse view count: ${viewCount}`, error); } }; // If the DOM is still loading, wait for it to be ready before updating the view count. if (document.readyState === "loading") { document.addEventListener('DOMContentLoaded', () => { updateViewCount(viewCount); }); // Otherwise, just update it immediately. } else { updateViewCount(viewCount); } })();</script></div><p class="ds-work-card--work-abstract ds-work-card--detail ds2-5-body-md">Type II L-asparaginase (L-ASNase) is an FDA approved enzyme drug with extensive applications for treatment of certain blood cancers. However, the therapeutic efficiency of this enzyme is hampered by its undesirable glutaminase activity. Given the pivotal role of this enzyme against cancer, designing engineered mutants with diminished glutaminase activity would be of great therapeutic interest. To this end, N248S mutation was selected as the potential mutation with beneficial effects. Various in silico analyses including MD simulation, molecular docking and QMMM studies were performed to assess the effects of N248S mutation on the activity of the enzyme. Thereafter, this mutation along with N248A, N248V and N248T mutations as controls were exerted in L-ASNase gene. The results from in silico analyses and experimental efforts indicated that N248S mutation is associated with the suitable L-ASNase activity, while the glutaminase activity is disturbed due to impaired interactions. It has been shown that glutamine turnover was affected much more strongly than asparagine hydrolysis. The approach of exploiting in silico tools to design mutated enzymes lead to staggering time and cost reduction. Following this strategy, we have designed a mutant L-ASNase with diminished glutaminase activity, which could be of interest for improved biomedical applications.</p><div class="ds-work-card--button-container"><button class="ds2-5-button js-swp-download-button" data-signup-modal="{"location":"continue-reading-button--work-card","attachmentId":118864596,"attachmentType":"pdf","workUrl":"https://www.academia.edu/124684311/Selective_reduction_in_glutaminase_activity_of_l_Asparaginase_by_asparagine_248_to_serine_mutation_A_combined_computational_and_experimental_effort_in_blood_cancer_treatment"}">See full PDF</button><button class="ds2-5-button ds2-5-button--secondary js-swp-download-button" data-signup-modal="{"location":"download-pdf-button--work-card","attachmentId":118864596,"attachmentType":"pdf","workUrl":"https://www.academia.edu/124684311/Selective_reduction_in_glutaminase_activity_of_l_Asparaginase_by_asparagine_248_to_serine_mutation_A_combined_computational_and_experimental_effort_in_blood_cancer_treatment"}"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span>Download PDF</button></div><div class="ds-signup-banner-trigger-container"><div class="ds-signup-banner-trigger ds-signup-banner-trigger-control"></div></div><div class="ds-signup-banner ds-signup-banner-control"><div id="ds-signup-banner-close-button"><button class="ds2-5-button ds2-5-button--secondary ds2-5-button--inverse"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">close</span></button></div><div class="ds-signup-banner-ctas"><img src="//a.academia-assets.com/images/academia-logo-capital-white.svg" /><h4 class="ds2-5-heading-serif-sm">Sign up for access to the world's latest research</h4><button class="ds2-5-button ds2-5-button--inverse ds2-5-button--full-width js-swp-download-button" data-signup-modal="{"location":"signup-banner"}">Sign up for free<span class="material-symbols-outlined" style="font-size: 20px" translate="no">arrow_forward</span></button></div><div class="ds-signup-banner-divider"></div><div class="ds-signup-banner-reasons"><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Get notified about relevant papers</span></div><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Save papers to use in your research</span></div><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Join the discussion with peers</span></div><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Track your impact</span></div></div></div><script>(() => { // Set up signup banner show/hide behavior: // 1. 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We have previously reported that the therapeutic antileukemic protein macromolecule Escherichia coli L-asparaginase is degraded by leukemic lysosomal cysteine proteases. In the present study, we successfully engineered L-asparaginaseto resist proteolytic cleavage and at the same time improve activity. We employed a novel combination of mutant sampling using a genetic algorithm in tandem with flexibility studies using molecular dynamics to investigate the impact of lid-loop and mutations on drug activity. Applying these methods, we successfully predicted the more active L-asparaginase mutants N24T and N24A. For the latter, a unique hydrogen bond network contributes to higher activity. Furthermore, interface mutations controlling secondary glutaminase activity demonstrated the importance of this enzymatic activity for drug cytotoxicity. All selected mutants were expressed, ...</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Rational engineering of L-asparaginase reveals importance of dual activity for cancer cell toxicity","attachmentId":109356129,"attachmentType":"pdf","work_url":"https://www.academia.edu/111983150/Rational_engineering_of_L_asparaginase_reveals_importance_of_dual_activity_for_cancer_cell_toxicity","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/111983150/Rational_engineering_of_L_asparaginase_reveals_importance_of_dual_activity_for_cancer_cell_toxicity"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="1" data-entity-id="125439489" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/125439489/Novel_mutant_of_Escherichia_coli_asparaginase_II_to_reduction_of_the_glutaminase_activity_in_treatment_of_acute_lymphocytic_leukemia_by_molecular_dynamics_simulations_and_QM_MM_studies">Novel mutant of Escherichia coli asparaginase II to reduction of the glutaminase activity in treatment of acute lymphocytic leukemia by molecular dynamics simulations and QM-MM studies</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="19567919" href="https://independent.academia.edu/RamazanAliKhavariNejad">Ramazan Ali Khavari-Nejad</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Medical Hypotheses, 2018</p><p class="ds-related-work--abstract ds2-5-body-sm">L-Asparaginases (ASNase) belong to a family of amidohydrolases, have both asparaginase and glutaminase activity. Acute lymphocytic leukemia (ALL) is an outrageous disease worldwide. Bacterial ASNase has been used for the treatment of ALL. Glutaminase activity of enzyme causes some side effect and it is not essential for anticancer activity. The aim of this study was engineering of Escherichia coli asparaginase II to find a mutant with reduced glutaminase activity by molecular docking, molecular dynamics (MD) and QM-MM (Quantum mechanics molecular dynamics) simulations. Residues with low free energy of binding to Asn and high free binding energy to Gln were chosen for mutagenesis. Then, a mutant with higher glutaminase free binding energy was selected for further studies. Additionally, the MD simulation and QM-MM computation of wild type (WT) were employed and the selected mutated ASNase were analyzed and discussed. Our data showed that V27T is a good candidate to reduction the glutaminase activity, while has no remarkable effect on asparaginase activity of the enzyme. The simulation analysis revealed that V27T mutant is more stable than WT and mutant simulation was successful completely. QM-MM results confirmed the successfulness of our mutagenesis.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Novel mutant of Escherichia coli asparaginase II to reduction of the glutaminase activity in treatment of acute lymphocytic leukemia by molecular dynamics simulations and QM-MM studies","attachmentId":119482288,"attachmentType":"pdf","work_url":"https://www.academia.edu/125439489/Novel_mutant_of_Escherichia_coli_asparaginase_II_to_reduction_of_the_glutaminase_activity_in_treatment_of_acute_lymphocytic_leukemia_by_molecular_dynamics_simulations_and_QM_MM_studies","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/125439489/Novel_mutant_of_Escherichia_coli_asparaginase_II_to_reduction_of_the_glutaminase_activity_in_treatment_of_acute_lymphocytic_leukemia_by_molecular_dynamics_simulations_and_QM_MM_studies"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="2" data-entity-id="96285374" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/96285374/Catalytic_Role_of_the_Substrate_Defines_Specificity_of_Therapeutic_l_Asparaginase">Catalytic Role of the Substrate Defines Specificity of Therapeutic l-Asparaginase</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="32819717" href="https://umd.academia.edu/SergeiSukharev">Sergei Sukharev</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Molecular Biology, 2015</p><p class="ds-related-work--abstract ds2-5-body-sm">Type II bacterial L-asparaginases (L-ASP) have played an important therapeutic role in cancer treatment for over four decades, yet their exact reaction mechanism remains elusive. L-ASP from E. coli deamidates asparagine (Asn) and glutamine, with a ~10 4 higher specificity (k cat /K m) for asparagine despite only one methylene difference in length. Through a sensitive kinetic approach, we quantify competition among the substrates and interpret its clinical role. To understand specificity, we use molecular simulations characterize enzyme interactions with substrates and a product (aspartate). We present evidence that the aspartate product in the crystal structure of L-ASP exists in an unusual -COOH protonation state. Consequently, the set of enzyme-product interactions found in the crystal structure, which guided prior mechanistic interpretations, differs from those observed in dynamic simulations of the enzyme with the substrates. Finally, we probe the initial nucleophilic attack with ab initio simulations. The unusual protonation state reappears, suggesting that crystal structures (wild-type and a T89V mutant) represent intermediate steps rather than initial binding. Also, a proton transfers spontaneously to Asn, advancing a new hypothesis that the substrate"s -carboxyl serves as a proton acceptor and activates one of the catalytic threonines during L-ASP"s nucleophilic attack on the amide carbon. That hypothesis explains for the first time why proximity of the substrate -COOgroup to the carboxamide is absolutely required for catalysis. The substrate"s catalytic role is likely the determining factor in enzyme specificity as it constrains the allowed distance between the backbone carboxyl and the amide carbon of any L-ASP substrate.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Catalytic Role of the Substrate Defines Specificity of Therapeutic l-Asparaginase","attachmentId":98226753,"attachmentType":"pdf","work_url":"https://www.academia.edu/96285374/Catalytic_Role_of_the_Substrate_Defines_Specificity_of_Therapeutic_l_Asparaginase","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/96285374/Catalytic_Role_of_the_Substrate_Defines_Specificity_of_Therapeutic_l_Asparaginase"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="3" data-entity-id="21574938" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/21574938/Catalytic_role_of_the_substrate_defines_specificity_of_therapeutic_L_asparaginase_L_ASP_">Catalytic role of the substrate defines specificity of therapeutic L-asparaginase (L-ASP)</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="32880372" href="https://umcp.academia.edu/AndriyAnishkin">Andriy Anishkin</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Molecular Biology, 2015</p><p class="ds-related-work--abstract ds2-5-body-sm">Type II bacterial L-asparaginases (L-ASP) have played an important therapeutic role in cancer treatment for over four decades, yet their exact reaction mechanism remains elusive. L-ASP from E. coli deamidates asparagine (Asn) and glutamine, with a ~10 4 higher specificity (k cat /K m ) for asparagine despite only one methylene difference in length. Through a sensitive kinetic approach, we quantify competition among the substrates and interpret its clinical role. To understand specificity, we use molecular simulations characterize enzyme interactions with substrates and a product (aspartate). We present evidence that the aspartate product in the crystal structure of L-ASP exists in an unusual -COOH protonation state. Consequently, the set of enzyme-product interactions found in the crystal structure, which guided prior mechanistic interpretations, differs from those observed in dynamic simulations of the enzyme with the substrates. Finally, we probe the initial nucleophilic attack with ab initio simulations. The unusual protonation state reappears, suggesting that crystal structures (wild-type and a T89V mutant) represent intermediate steps rather than initial binding. Also, a proton transfers spontaneously to Asn, advancing a new hypothesis that the substrate's -carboxyl serves as a proton acceptor and activates one of the catalytic threonines during L-ASP's nucleophilic attack on the amide carbon. That hypothesis explains for the first time why proximity of the substrate -COOgroup to the carboxamide is absolutely required for catalysis. The substrate's catalytic role is likely the determining factor in enzyme specificity as it constrains the allowed distance between the backbone carboxyl and the amide carbon of any L-ASP substrate.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Catalytic role of the substrate defines specificity of therapeutic L-asparaginase (L-ASP)","attachmentId":42114034,"attachmentType":"pdf","work_url":"https://www.academia.edu/21574938/Catalytic_role_of_the_substrate_defines_specificity_of_therapeutic_L_asparaginase_L_ASP_","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/21574938/Catalytic_role_of_the_substrate_defines_specificity_of_therapeutic_L_asparaginase_L_ASP_"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="4" data-entity-id="123589069" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/123589069/The_glutaminase_activity_of_l_asparaginase_is_not_required_for_anticancer_activity_against_ASNS_negative_cells">The glutaminase activity of l-asparaginase is not required for anticancer activity against ASNS-negative cells</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="32819717" href="https://umd.academia.edu/SergeiSukharev">Sergei Sukharev</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Blood, 2014</p><p class="ds-related-work--abstract ds2-5-body-sm">• We used molecular dynamics, saturation mutagenesis, and enzymologic screening to develop a glutaminase-free mutant (Q59L) L-ASP. • We then used Q59L to show that glutaminase activity is not required for L-ASP activity against ASNS-negative cancer cells. L-Asparaginase (L-ASP) is a key component of therapy for acute lymphoblastic leukemia. Its mechanism of action, however, is still poorly understood, in part because of its dual asparaginase and glutaminase activities. Here, we show that L-ASP's glutaminase activity is not always required for the enzyme's anticancer effect. We first used molecular dynamics simulations of the clinically standard Escherichia coli L-ASP to predict what mutated forms could be engineered to retain activity against asparagine but not glutamine. Dynamic mapping of enzyme substrate contacts identified Q59 as a promising mutagenesis target for that purpose. Saturation mutagenesis followed by enzymatic screening identified Q59L as a variant that retains asparaginase activity but shows undetectable glutaminase activity. Unlike wild-type L-ASP, Q59L is inactive against cancer cells that express measurable asparagine synthetase (ASNS). Q59L is potently active, however, against ASNS-negative cells. Those observations indicate that the glutaminase activity of L-ASP is necessary for anticancer activity against ASNS-positive cell types but not ASNS-negative cell types. Because the clinical toxicity of L-ASP is thought to stem from its glutaminase activity, these findings suggest the hypothesis that glutaminase-negative variants of L-ASP would provide larger therapeutic indices than wild-type</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"The glutaminase activity of l-asparaginase is not required for anticancer activity against ASNS-negative cells","attachmentId":117986228,"attachmentType":"pdf","work_url":"https://www.academia.edu/123589069/The_glutaminase_activity_of_l_asparaginase_is_not_required_for_anticancer_activity_against_ASNS_negative_cells","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/123589069/The_glutaminase_activity_of_l_asparaginase_is_not_required_for_anticancer_activity_against_ASNS_negative_cells"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="5" data-entity-id="112458865" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/112458865/Engineering_the_substrate_specificity_of_i_Escherichia_coli_i_asparaginase_II_Selective_reduction_of_glutaminase_activity_by_amino_acid_replacements_at_position_248">Engineering the substrate specificity of<i>Escherichia coli</i>asparaginase II. Selective reduction of glutaminase activity by amino acid replacements at position 248</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="213672677" href="https://independent.academia.edu/KlausHeinrichR%C3%B6hm">Klaus-Heinrich Röhm</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Protein Science, 2000</p><p class="ds-related-work--abstract ds2-5-body-sm">The use of Escherichia coli asparaginase II as a drug for the treatment of acute lymphoblastic leukemia is complicated by the significant glutaminase side activity of the enzyme. To develop enzyme forms with reduced glutaminase activity, a number of variants with amino acid replacements in the vicinity of the substrate binding site were constructed and assayed for their kinetic and stability properties. We found that replacements of Asp248 affected glutamine turnover much more strongly than asparagine hydrolysis. In the wild-type enzyme, N248 modulates substrate binding to a neighboring subunit by hydrogen bonding to side chains that directly interact with the substrate. In variant N248A, the loss of transition state stabilization caused by the mutation was 15 kJ mol Ϫ1 for l-glutamine compared to 4 kJ mol Ϫ1 for l-aspartic b-hydroxamate and 7 kJ mol Ϫ1 for l-asparagine. Smaller differences were seen with other N248 variants. Modeling studies suggested that the selective reduction of glutaminase activity is the result of small conformational changes that affect active-site residues and catalytically relevant water molecules.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Engineering the substrate specificity of\u003ci\u003eEscherichia coli\u003c/i\u003easparaginase II. Selective reduction of glutaminase activity by amino acid replacements at position 248","attachmentId":109683108,"attachmentType":"pdf","work_url":"https://www.academia.edu/112458865/Engineering_the_substrate_specificity_of_i_Escherichia_coli_i_asparaginase_II_Selective_reduction_of_glutaminase_activity_by_amino_acid_replacements_at_position_248","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/112458865/Engineering_the_substrate_specificity_of_i_Escherichia_coli_i_asparaginase_II_Selective_reduction_of_glutaminase_activity_by_amino_acid_replacements_at_position_248"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="6" data-entity-id="98269579" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/98269579/In_Silico_Design_of_a_Chimeric_Humanized_L_Asparaginase">In Silico Design of a Chimeric Humanized L-Asparaginase</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="73448288" href="https://ufro.academia.edu/LisandraHerreraBel%C3%A9n">Lisandra Herrera Belén</a></div><p class="ds-related-work--abstract ds2-5-body-sm">Acute lymphoblastic leukemia (ALL) is the most common cancer among children worldwide, characterized by an overproduction of undifferentiated lymphoblasts in the bone marrow. The treatment of choice for this disease is the enzyme L-asparaginase (ASNase) from bacterial sources. ASNase hydrolyzes circulating L-asparagine in plasma, leading to starvation of leukemic cells. The ASNase formulations of E. coli and E. chrysanthemi present notorious adverse effects, especially the immunogenicity they generate, which undermines both their effectiveness as drugs and patient safety. In this study, we developed a humanized chimeric enzyme from E. coli L-asparaginase, which would reduce the immunological problems associated with current L-asparaginase therapy. For these, the immunogenic epitopes of E. coli L-asparaginase (PDB: 3ECA) were determined and replaced with those of the less immunogenic Homo sapiens asparaginase (PDB:4O0H). The structures were modeled using the Pymol software and the ch...</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"In Silico Design of a Chimeric Humanized L-Asparaginase","attachmentId":99667731,"attachmentType":"pdf","work_url":"https://www.academia.edu/98269579/In_Silico_Design_of_a_Chimeric_Humanized_L_Asparaginase","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/98269579/In_Silico_Design_of_a_Chimeric_Humanized_L_Asparaginase"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="7" data-entity-id="61500524" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/61500524/Molecular_dynamic_simulations_of_Escherichia_coli_l_asparaginase_to_illuminate_its_role_in_deamination_of_asparagine_and_glutamine_residues">Molecular dynamic simulations of Escherichia coli l-asparaginase to illuminate its role in deamination of asparagine and glutamine residues</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="23627598" href="https://rgpv.academia.edu/MayuriBhatia">Mayuri Bhatia</a></div><p class="ds-related-work--metadata ds2-5-body-xs">3 Biotech, 2015</p><p class="ds-related-work--abstract ds2-5-body-sm">Acute lymphocytic leukemia (ALL) is an outrageous disease worldwide. L-Asparagine (L-Asn) and L-Glutamine (L-Gln) deamination play a crucial role in ALL treatment. Role of Elspar Ò (L-asparaginase from Escherichia coli) in regulation of L-Asn and L-Gln has been confirmed by the other researchers through experimental studies. Therapeutic research against ALL remained elusive with the lack of information on molecular interactions of Elspar Ò with amino acid substrates. In the present study, using different docking tools binding cavities, key residues in binding and ligand binding mechanisms were identified. For the apo state enzyme and ligand bound state complexes, MD simulations were performed. Trajectory analysis for 30 ns run confirmed the kinship of L-Asn with Lasparaginase enzyme in the dynamic system with less stability in comparison to L-Gln docked complex. Overall findings strongly supported the bi-functional nature of the enzyme drug. A good number of conformational changes were observed with 1NNS structure due to ligand binding. Results of present study give much more information on structural and functional aspects of E. coli L-asparaginase upon the interaction with its ligands which may be useful in designing effective therapeutics for ALL. Keywords L-asparaginase Á Molecular docking Á Molecular dynamic simulations Á Acute lymphocytic leukemia Electronic supplementary material The online version of this article (</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Molecular dynamic simulations of Escherichia coli l-asparaginase to illuminate its role in deamination of asparagine and glutamine residues","attachmentId":74514073,"attachmentType":"pdf","work_url":"https://www.academia.edu/61500524/Molecular_dynamic_simulations_of_Escherichia_coli_l_asparaginase_to_illuminate_its_role_in_deamination_of_asparagine_and_glutamine_residues","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/61500524/Molecular_dynamic_simulations_of_Escherichia_coli_l_asparaginase_to_illuminate_its_role_in_deamination_of_asparagine_and_glutamine_residues"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="8" data-entity-id="82635929" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/82635929/Engineering_the_substrate_specificity_ofEscherichia_coliasparaginase_II_Selective_reduction_of_glutaminase_activity_by_amino_acid_replacements_at_position_248">Engineering the substrate specificity ofEscherichia coliasparaginase II. Selective reduction of glutaminase activity by amino acid replacements at position 248</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="213672677" href="https://independent.academia.edu/KlausHeinrichR%C3%B6hm">Klaus-Heinrich Röhm</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Protein Science, 2000</p><p class="ds-related-work--abstract ds2-5-body-sm">The use of Escherichia coli asparaginase II as a drug for the treatment of acute lymphoblastic leukemia is complicated by the significant glutaminase side activity of the enzyme. To develop enzyme forms with reduced glutaminase activity, a number of variants with amino acid replacements in the vicinity of the substrate binding site were constructed and assayed for their kinetic and stability properties. We found that replacements of Asp248 affected glutamine turnover much more strongly than asparagine hydrolysis. In the wild-type enzyme, N248 modulates substrate binding to a neighboring subunit by hydrogen bonding to side chains that directly interact with the substrate. In variant N248A, the loss of transition state stabilization caused by the mutation was 15 kJ mol Ϫ1 for l-glutamine compared to 4 kJ mol Ϫ1 for l-aspartic b-hydroxamate and 7 kJ mol Ϫ1 for l-asparagine. Smaller differences were seen with other N248 variants. Modeling studies suggested that the selective reduction of glutaminase activity is the result of small conformational changes that affect active-site residues and catalytically relevant water molecules.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Engineering the substrate specificity ofEscherichia coliasparaginase II. Selective reduction of glutaminase activity by amino acid replacements at position 248","attachmentId":88277713,"attachmentType":"pdf","work_url":"https://www.academia.edu/82635929/Engineering_the_substrate_specificity_ofEscherichia_coliasparaginase_II_Selective_reduction_of_glutaminase_activity_by_amino_acid_replacements_at_position_248","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/82635929/Engineering_the_substrate_specificity_ofEscherichia_coliasparaginase_II_Selective_reduction_of_glutaminase_activity_by_amino_acid_replacements_at_position_248"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="9" data-entity-id="48443995" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/48443995/Glutaminase_activity_of_L_asparaginase_contributes_to_durable_preclinical_activity_against_acute_lymphoblastic_leukemia">Glutaminase activity of L-asparaginase contributes to durable preclinical activity against acute lymphoblastic leukemia</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="14213758" href="https://rice.academia.edu/DiDu">Di Du</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Molecular Cancer Therapeutics</p><p class="ds-related-work--abstract ds2-5-body-sm">We and others have reported that the anticancer activity of L-asparaginase (ASNase) against asparagine synthetase (ASNS)-positive cell types requires ASNase glutaminase activity, whereas anticancer activity against ASNS-negative cell types does not. Here, we attempted to disentangle the relationship between asparagine metabolism, glutamine metabolism, and downstream pathways that modulate cell viability by testing the hypothesis that ASNase anticancer activity is based on asparagine depletion rather than glutamine depletion per se. We tested ASNase wild-type (ASNase WT) and its glutaminase-deficient Q59L mutant (ASNase Q59L) and found that ASNase glutaminase activity contributed to durable anticancer activity against xenografts of the ASNS-negative Sup-B15 leukemia cell line in NOD/SCID gamma mice, whereas asparaginase activity alone yielded a mere growth delay. Our findings suggest that ASNase glutaminase activity is necessary for durable, single-agent anticancer activity in vivo, even against ASNS-negative cancer types.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Glutaminase activity of L-asparaginase contributes to durable preclinical activity against acute lymphoblastic leukemia","attachmentId":67052344,"attachmentType":"pdf","work_url":"https://www.academia.edu/48443995/Glutaminase_activity_of_L_asparaginase_contributes_to_durable_preclinical_activity_against_acute_lymphoblastic_leukemia","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/48443995/Glutaminase_activity_of_L_asparaginase_contributes_to_durable_preclinical_activity_against_acute_lymphoblastic_leukemia"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div></div></div><div class="ds-sticky-ctas--wrapper js-loswp-sticky-ctas hidden"><div class="ds-sticky-ctas--grid-container"><div class="ds-sticky-ctas--container"><button class="ds2-5-button js-swp-download-button" data-signup-modal="{"location":"continue-reading-button--sticky-ctas","attachmentId":118864596,"attachmentType":"pdf","workUrl":null}">See full PDF</button><button class="ds2-5-button ds2-5-button--secondary js-swp-download-button" data-signup-modal="{"location":"download-pdf-button--sticky-ctas","attachmentId":118864596,"attachmentType":"pdf","workUrl":null}"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span>Download PDF</button></div></div></div><div class="ds-below-fold--grid-container"><div class="ds-work--container js-loswp-embedded-document"><div class="attachment_preview" data-attachment="Attachment_118864596" style="display: none"><div class="js-scribd-document-container"><div class="scribd--document-loading js-scribd-document-loader" style="display: block;"><img alt="Loading..." src="//a.academia-assets.com/images/loaders/paper-load.gif" /><p>Loading Preview</p></div></div><div style="text-align: center;"><div class="scribd--no-preview-alert js-preview-unavailable"><p>Sorry, preview is currently unavailable. You can download the paper by clicking the button above.</p></div></div></div></div><div class="ds-sidebar--container js-work-sidebar"><div class="ds-related-content--container"><h2 class="ds-related-content--heading">Related papers</h2><div class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="0" data-entity-id="123589062" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/123589062/Glutaminase_Activity_of_scp_L_scp_Asparaginase_Contributes_to_Durable_Preclinical_Activity_against_Acute_Lymphoblastic_Leukemia">Glutaminase Activity of <scp>L</scp>-Asparaginase Contributes to Durable Preclinical Activity against Acute Lymphoblastic Leukemia</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="32819717" href="https://umd.academia.edu/SergeiSukharev">Sergei 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href="https://www.academia.edu/123589062/Glutaminase_Activity_of_scp_L_scp_Asparaginase_Contributes_to_Durable_Preclinical_Activity_against_Acute_Lymphoblastic_Leukemia"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="1" data-entity-id="57265628" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/57265628/A_novel_L_asparaginase_with_low_L_glutaminase_coactivity_is_highly_efficacious_against_both_T_and_B_cell_acute_lymphoblastic_leukemias_in_vivo">A novel L-asparaginase with low L-glutaminase coactivity is highly efficacious against both T and B cell acute lymphoblastic leukemias in vivo</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="49011277" href="https://independent.academia.edu/AmandaSchalk">Amanda Schalk</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Cancer research, 2018</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"A novel L-asparaginase with low L-glutaminase coactivity is highly efficacious against both T and B cell acute lymphoblastic leukemias in vivo","attachmentId":72248616,"attachmentType":"pdf","work_url":"https://www.academia.edu/57265628/A_novel_L_asparaginase_with_low_L_glutaminase_coactivity_is_highly_efficacious_against_both_T_and_B_cell_acute_lymphoblastic_leukemias_in_vivo","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-related-work-grid-card-view-pdf" href="https://www.academia.edu/57265628/A_novel_L_asparaginase_with_low_L_glutaminase_coactivity_is_highly_efficacious_against_both_T_and_B_cell_acute_lymphoblastic_leukemias_in_vivo"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="2" data-entity-id="77998706" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/77998706/Development_of_L_Asparaginase_Biobetters_Current_Research_Status_and_Review_of_the_Desirable_Quality_Profiles">Development of L-Asparaginase Biobetters: Current Research Status and Review of the Desirable Quality Profiles</a><div class="ds-related-work--metadata"><a 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