Scholarlink

<p>L-asparaginase (L-asparagine amidohydrolase, EC 3.5.1.1) is an enzyme that focusses on Acute Lymphoblastic Leukemia (ALL) treatment and in the food industry as alleviation of acrylamide contamination. In the past ten years, structural biology, enzyme engineering, and drug delivery have made giant strides to change the perception of its structural diversity, catalytic mechanism, and therapeutic potential. The expanded classification of L-asparaginases has been done into Type-II, <i>Rhizobium etli</i>-type, and putative new families based on comparative structural analyses that have a different oligomeric state, active site, and immunogenic profile compared to classical bacterial Type I and Type II enzymes. High-resolution techniques such as X-ray crystallography, cryo-electron microscopy (cryo-EM), quantum mechanics/molecular mechanics (QM/MM) simulations, and single-molecule studies have refined the catalytic model of L-asparaginase that have elucidated the molecular basis of the enzyme’s dual L-asparaginase and L-glutaminase activities, clarifying their roles in both therapeutic efficacy and off-target toxicity. They have also identified key structural regions suitable for deimmunization and modulation of substrate specificity. Protein engineering strategies—including rational design, directed evolution, deep mutational scanning, and machine learning guided modeling—have generated improved “biobetter” variants with enhanced stability, prolonged half-life, and optimized glutaminase activity. Advanced delivery systems, including polyethylene glycol modification (PEGylation), fusion proteins, nanoparticles, liposomes, and injectable hydrogels, are significantly improving the enzyme’s pharmacokinetics and reducing its toxicity. In parallel, microbial and fungal L-asparaginases are being engineered for enhanced pH and thermal stability to enable efficient immobilization and reuse in industrial applications. This review summarizes the emerging knowledge on the structural and mechanistic picture of L-asparaginases and sets the focus on the state-of-the-art therapeutic and industrial innovations, focusing on the prospects of next generation precision biotherapeutics and sustainable bioprocesses.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Emerging Insights and Advances in L-asparaginase: Structural Diversity, Mechanistic Understanding, and Therapeutic Innovations

  • 期刊论文

  • 发表日期：

    2026年7月31日

查看全文
  • Vijaya Kumar Talari,
  • Revanth Yenisetty,
  • Anup Ashok

摘要

L-asparaginase (L-asparagine amidohydrolase, EC 3.5.1.1) is an enzyme that focusses on Acute Lymphoblastic Leukemia (ALL) treatment and in the food industry as alleviation of acrylamide contamination. In the past ten years, structural biology, enzyme engineering, and drug delivery have made giant strides to change the perception of its structural diversity, catalytic mechanism, and therapeutic potential. The expanded classification of L-asparaginases has been done into Type-II, Rhizobium etli-type, and putative new families based on comparative structural analyses that have a different oligomeric state, active site, and immunogenic profile compared to classical bacterial Type I and Type II enzymes. High-resolution techniques such as X-ray crystallography, cryo-electron microscopy (cryo-EM), quantum mechanics/molecular mechanics (QM/MM) simulations, and single-molecule studies have refined the catalytic model of L-asparaginase that have elucidated the molecular basis of the enzyme’s dual L-asparaginase and L-glutaminase activities, clarifying their roles in both therapeutic efficacy and off-target toxicity. They have also identified key structural regions suitable for deimmunization and modulation of substrate specificity. Protein engineering strategies—including rational design, directed evolution, deep mutational scanning, and machine learning guided modeling—have generated improved “biobetter” variants with enhanced stability, prolonged half-life, and optimized glutaminase activity. Advanced delivery systems, including polyethylene glycol modification (PEGylation), fusion proteins, nanoparticles, liposomes, and injectable hydrogels, are significantly improving the enzyme’s pharmacokinetics and reducing its toxicity. In parallel, microbial and fungal L-asparaginases are being engineered for enhanced pH and thermal stability to enable efficient immobilization and reuse in industrial applications. This review summarizes the emerging knowledge on the structural and mechanistic picture of L-asparaginases and sets the focus on the state-of-the-art therapeutic and industrial innovations, focusing on the prospects of next generation precision biotherapeutics and sustainable bioprocesses.