Design of a stable human acid-β-glucosidase: towards improved Gaucher disease therapy and mutation classification

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388955%3A_____%2F23%3A00570872" target="_blank" >RIV/61388955:_____/23:00570872 - isvavai.cz</a>

Result on the web

<a href="https://hdl.handle.net/11104/0342198" target="_blank" >https://hdl.handle.net/11104/0342198</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1111/febs.16758" target="_blank" >10.1111/febs.16758</a>

Result language

angličtina

Original language name

Design of a stable human acid-β-glucosidase: towards improved Gaucher disease therapy and mutation classification

Original language description

Acid-β-glucosidase (GCase, EC3.2.1.45), the lysosomal enzyme which hydrolyzes the simple glycosphingolipid, glucosylceramide (GlcCer), is encoded by the GBA1 gene. Biallelic mutations in GBA1 cause the human inherited metabolic disorder, Gaucher disease (GD), in which GlcCer accumulates, while heterozygous GBA1 mutations are the highest genetic risk factor for Parkinson's disease (PD). Recombinant GCase (e.g., Cerezyme®) is produced for use in enzyme replacement therapy for GD and is largely successful in relieving disease symptoms, except for the neurological symptoms observed in a subset of patients. As a first step toward developing an alternative to the recombinant human enzymes used to treat GD, we applied the PROSS stability-design algorithm to generate GCase variants with enhanced stability. One of the designs, containing 55 mutations compared to wild-type human GCase, exhibits improved secretion and thermal stability. Furthermore, the design has higher enzymatic activity than the clinically used human enzyme when incorporated into an AAV vector, resulting in a larger decrease in the accumulation of lipid substrates in cultured cells. Based on stability-design calculations, we also developed a machine learning-based approach to distinguish benign from deleterious (i.e., disease-causing) GBA1 mutations. This approach gave remarkably accurate predictions of the enzymatic activity of single-nucleotide polymorphisms in the GBA1 gene that are not currently associated with GD or PD. This latter approach could be applied to other diseases to determine risk factors in patients carrying rare mutations.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10403 - Physical chemistry

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

FEBS Journal

ISSN

1742-464X

e-ISSN

1742-4658

Volume of the periodical

290

Issue of the periodical within the volume

13

Country of publishing house

GB - UNITED KINGDOM

Number of pages

17

Pages from-to

3383-3399

UT code for WoS article

000955057500001

EID of the result in the Scopus database

2-s2.0-85150990685