Chaperone therapy for homocystinuria: the rescue of CBS mutations by heme arginate

Kód výsledku v IS VaVaI

RIV/00216208:11110/15:10294808 - isvavai.cz

Nalezeny alternativní kódy

RIV/00064165:_____/15:10294808

Výsledek na webu

http://dx.doi.org/10.1007/s10545-014-9781-9

DOI - Digital Object Identifier

10.1007/s10545-014-9781-9

Jazyk výsledku

angličtina

Název v původním jazyce

Chaperone therapy for homocystinuria: the rescue of CBS mutations by heme arginate

Popis výsledku v původním jazyce

Classical homocystinuria is caused by mutations in the cystathionine beta-synthase (CBS) gene. Previous experiments in bacterial and yeast cells showed that many mutant CBS enzymes misfold and that chemical chaperones enable proper folding of a number ofmutations. In the present study, we tested the extent of misfolding of 27 CBS mutations previously tested in E. coli under the more folding-permissive conditions of mammalian CHO-K1 cells and the ability of chaperones to rescue the conformation of thesemutations. Expression of mutations in mammalian cells increased the median activity 16-fold and the amount of tetramers 3.2-fold compared with expression in bacteria. Subsequently, we tested the responses of seven selected mutations to three compounds with chaperone-like activity. Aminooxyacetic acid and 4-phenylbutyric acid exhibited only a weak effect. In contrast, heme arginate substantially increased the formation of mutant CBS protein tetramers (up to sixfold) and rescued catalytic

Název v anglickém jazyce

Chaperone therapy for homocystinuria: the rescue of CBS mutations by heme arginate

Popis výsledku anglicky

Classical homocystinuria is caused by mutations in the cystathionine beta-synthase (CBS) gene. Previous experiments in bacterial and yeast cells showed that many mutant CBS enzymes misfold and that chemical chaperones enable proper folding of a number ofmutations. In the present study, we tested the extent of misfolding of 27 CBS mutations previously tested in E. coli under the more folding-permissive conditions of mammalian CHO-K1 cells and the ability of chaperones to rescue the conformation of thesemutations. Expression of mutations in mammalian cells increased the median activity 16-fold and the amount of tetramers 3.2-fold compared with expression in bacteria. Subsequently, we tested the responses of seven selected mutations to three compounds with chaperone-like activity. Aminooxyacetic acid and 4-phenylbutyric acid exhibited only a weak effect. In contrast, heme arginate substantially increased the formation of mutant CBS protein tetramers (up to sixfold) and rescued catalytic

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

EB - Genetika a molekulární biologie

OECD FORD obor

—

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2015

Kód důvěrnosti údajů

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

Název periodika

Journal of Inherited Metabolic Disease

ISSN

0141-8955

e-ISSN

—

Svazek periodika

38

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

8

Strana od-do

287-294

Kód UT WoS článku

000350360200010

EID výsledku v databázi Scopus

2-s2.0-84925504823