Rhizobium etli asparaginase II: an alternative for acute lymphoblastic leukemia (ALL) treatment.
Bacterial L-asparaginase has been a universal component of therapies for childhood acute lymphoblastic leukemia since the 1970s. Two principal enzymes derived from Escherichia coli and Erwinia chrysanthemi are the only options clinically approved to date. We recently reported a study of recombinant L-asparaginase (AnsA) from Rhizobium etli and described an increasing type of AnsA family members. Sequence analysis revealed four conserved motifs with notable differences with respect to the conserved regions of amino acid sequences of type I and type II L-asparaginases, particularly in comparison with therapeutic enzymes from E. coli and E. chrysanthemi. These differences suggested a distinct immunological specificity. Here, we report an in silico analysis that revealed immunogenic determinants of AnsA. Also, we used an extensive approach to compare the crystal structures of E. coli and E. chrysantemi asparaginases with a computational model of AnsA and identified immunogenic epitopes. A three-dimensional model of AsnA revealed, as expected based on sequence dissimilarities, completely different folding and different immunogenic epitopes. This approach could be very useful in transcending the problem of immunogenicity in two major ways: by chemical modifications of epitopes to reduce drug immunogenicity, and by site-directed mutagenesis of amino acid residues to diminish immunogenicity without reduction of enzymatic activity.
Departamento de Microbiología Molecular; Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca Morelos, México. saquero@ibt.unam.mx
Alejandro
A
Huerta-Saquero
Zahaed
Z
Evangelista-Martínez
Angélica
A
Moreno-Enriquez
Ernesto
E
Perez-Rueda
D000595:Amino Acid Sequence; D001215:Asparaginase / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D016974:Dickeya chrysanthemi / Q000737:chemistry / Q000201:enzymology / Q000235:genetics; D004926:Escherichia coli / Q000737:chemistry / Q000201:enzymology / Q000235:genetics; D008969:Molecular Sequence Data; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000276:immunology; D042163:Rhizobium etli / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D016415:Sequence Alignment
D001426:Bacterial Proteins; D001215:Asparaginase