کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5513918 1400686 2017 7 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Crystal structure of a mutant glycosylasparaginase shedding light on aspartylglycosaminuria-causing mechanism as well as on hydrolysis of non-chitobiose substrate
ترجمه فارسی عنوان
ساختار بلوری یک گلیکوزیلاسپارژیناز جهش یافته در زمینه سازگاری آسپارتیل گلیکوزامینووره و همچنین بر روی هیدرولیز بستر غیر تراشه
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
چکیده انگلیسی


- Precursor of a Canadian-AGU mutant autoproteolyzes to mature form after crystallization
- Effect of a Gly to Asp mutation on hydrolytic activity of GA enzyme
- Proposed mechanism for non-chitobiose substrate processing by wildtype GA

Glycosylasparaginase (GA) is an amidase that cleaves Asn-linked glycoproteins in lysosomes. Deficiency of this enzyme causes accumulation of glycoasparagines in lysosomes of cells, resulting in a genetic condition called aspartylglycosaminuria (AGU). To better understand the mechanism of a disease-causing mutation with a single residue change from a glycine to an aspartic acid, we generated a model mutant enzyme at the corresponding position (named G172D mutant). Here we report a 1.8 Å resolution crystal structure of mature G172D mutant and analyzed the reason behind its low hydrolase activity. Comparison of mature G172D and wildtype GA models reveals that the presence of Asp 172 near the catalytic site affects substrate catabolism in mature G172D, making it less efficient in substrate processing. Also recent studies suggest that GA is capable of processing substrates that lack a chitobiose (Glycan, N-acetylchiobios, NAcGlc) moiety, by its exo-hydrolase activity. The mechanism for this type of catalysis is not yet clear. l-Aspartic acid β-hydroxamate (β-AHA) is a non-chitobiose substrate that is known to interact with GA. To study the underlying mechanism of non-chitobiose substrate processing, we built a GA-β-AHA complex structure by comparing to a previously published G172D mutant precursor in complex with a β-AHA molecule. A hydrolysis mechanism of β-AHA by GA is proposed based on this complex model.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Molecular Genetics and Metabolism - Volume 121, Issue 2, June 2017, Pages 150-156
نویسندگان
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