Effect of Cysteamine on Mutant ASL Proteins with Cysteine for Arginine Substitutions

Inauen, Corinne; Rüfenacht, Véronique; Pandey, Amit V.; Hu, Liyan; Blom, Henk J.; Nuoffer, Jean-Marc; Häberle, Johannes

doi:10.1007/s40291-015-0182-z

Cited by 4 publications

(9 citation statements)

References 32 publications

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“…Both in vitro and in vivo studies suggest that cysteamine can restore the function of some Arg to Cys mutated proteins (Table 2, see below). Next, we focus on describing the earliest reports on cysteamine use to target human proteins back in the 1980's, comprising studies with ApoE3 and Factor VIII proteins (Gahl et al 1985, Weisgraber et al 1981), as well as recent molecular targeting studies addressing argininosuccinate lyase (ASL) and CBS (Mendes et al 2015; Inauen et al 2016). …”

Section: Molecular Targeting Of Arg To Cys Mutationsmentioning

confidence: 99%

“…The high number of arginine to cysteine mutations in ASLD has triggered the interest of exploiting aminothiol therapy as a potential approach in ASLD patients. Cysteamine treatment has recently been studied in all known Arg to Cys mutations in ASLD (p.Arg94Cys; p.Arg95Cys; p.Arg168Cys; p.Arg379Cys and p.Arg385Cys) (Inauen et al 2016). Mutants were overexpressed in 293T cells and incubated with cysteamine from 0.05 to 0.1 mM.…”

Section: Molecular Targeting Of Arg To Cys Mutationsmentioning

confidence: 99%

“…Interestingly, the effect of direct incubation of cell lysates with cysteamine (0-0.1 mM at 37°C for 1h) was dependent on the location of the mutation in the recombinant ASL proteins. Increased ASL activities after cysteamine incubation (0.05 and 0.1 mM) were reported in cells lysates carrying p.Arg94Cys; p.Arg379Cys and p.Arg385Cys mutations (Inauen et al 2016). Notably, cell lysates carrying p.Arg385Cys incubated with cysteamine recovered similar activities to the untreated cell lysate carrying the p.Arg385Lys mutation, which is in line with the expected cysteamine-induced change of the cysteine residue to mimic a lysine analogue (Inauen et al 2016).…”

Section: Molecular Targeting Of Arg To Cys Mutationsmentioning

confidence: 99%

“…Both of these cysteines could react with cysteamine, being Cys264 the preferred spot for docking. Analysis of the Cys264Lys mutant, which represents a structural analog of the cysteamine-cysteine-264 disulfide, showed that all the crucial bonding interactions in the ASL wild-type structure were preserved (Inauen et al 2016). Ex vivo and in vitro , modification of either of these cysteines was found not to impact the ASL tetramer structure or enzymatic function in the wild-type protein.…”

Section: Molecular Targeting Of Arg To Cys Mutationsmentioning

confidence: 99%

“…The reactivity of Cys residues in proteins has been a matter of intense research, and excellent reviews are available on the topic (see for example (Go and Jones 2013, Jones and Go 2011, Marino and Gladyshev 2012, Rebrin et al 2004)). Work has emerged on the use of the endogenous aminothiols as cysteamine for the targeted reconstitution of function in proteins harboring Arg to Cys mutations (Inauen et al 2016). …”

Section: Introductionmentioning

confidence: 99%

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Cysteamine revisited: repair of arginine to cysteine mutations

Gallego

Hannibal

Häberle

et al. 2017

J of Inher Metab Disea

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Cysteamine is a small aminothiol endogenously derived from coenzyme A degradation. For some decades, synthetic cysteamine has been employed for the treatment of cystinosis, and new uses of the drug continue to emerge. In this review, we discuss the role of cysteamine in cellular and extracellular homeostasis and focus on the potential use of aminothiols to reconstitute the function of proteins harboring arginine (Arg) to cysteine (Cys) mutations, via repair of the Cys residue into a moiety that introduces an amino group, as seen in basic amino acid residues Lys and Arg. Cysteamine has been utilized in vitro and ex vivo in four different genetic disorders, and thus provides “proof of principle” that aminothiols can modify Cys residues. Other aminothiols such as mercaptoethylguanidine (MEG) with closer structural resemblance to the guanidinium moiety of Arg are under examination for their predicted enhanced capacity to reconstitute loss of function. Although the use of aminothiols holds clinical potential, more studies are required to refine specificity and treatment design. The efficacy of aminothiols to target proteins may vary substantially depending on their specific extracellular and intracellular locations. Redox potential, pH and specific aminothiol abundance in each physiological compartment are expected to influence the reactivity and turnover of cysteamine and analogous drugs. Upcoming research will require the use of suitable cell and animal models featuring Arg to Cys mutations. Since Arg to Cys changes comprise in general about 8% of missense mutations, repair of this specific mutation may provide promising avenues for many genetic diseases.

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Section: Molecular Targeting Of Arg To Cys Mutationsmentioning

confidence: 99%

Section: Molecular Targeting Of Arg To Cys Mutationsmentioning

confidence: 99%

Section: Molecular Targeting Of Arg To Cys Mutationsmentioning

confidence: 99%

Section: Molecular Targeting Of Arg To Cys Mutationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cysteamine revisited: repair of arginine to cysteine mutations

Gallego

Hannibal

Häberle

et al. 2017

J of Inher Metab Disea

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Thiolatocobalamins repair the activity of pathogenic variants of the human cobalamin processing enzyme CblC

et al. 2021

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P450 Oxidoreductase deficiency: Analysis of mutations and polymorphisms

Burkhard

Parween

Udhane

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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Cytochrome P450 oxidoreductase (POR) is required for metabolic reactions of steroid and drug metabolizing cytochrome P450 proteins located in endoplasmic reticulum. Mutations in POR cause a complex set of disorders resembling combined deficiencies of multiple steroid metabolizing enzymes. The P450 oxidoreductase deficiency (PORD) was first reported in patients with symptoms of defects in steroidogenic cytochrome P450 enzymes and ambiguous genitalia, and bone malformation features resembling Antley-Bixler syndrome. POR is now classified as a separate and rare form of congenital adrenal hyperplasia (CAH), which may cause disorder of sexual development (DSD). Since the initial description of PORD in 2004, a large number of POR mutations and polymorphisms have been described. In this report we have performed computational analysis of mutations and polymorphisms in POR linked to metabolism of steroids and xenobiotics and pathology of PORD from the reported cases. The mutations in POR that were identified in patients with disruption of steroidogenesis also have severe effects on cytochrome P450 proteins involved in metabolism of drugs. Different variations in POR show a range of diverse effects on different partner proteins that are often linked to the location of the particular variants. The variations in POR that cause defective binding of co-factors always have damaging effects on all partner proteins, while the mutations causing subtle structural changes may lead to altered interaction with partner proteins and the overall effect may be different for each individual partner. Computational analysis of available sequencing data and mutation analysis shows that Japanese (R457H), Caucasian (A287P) and Turkish (399-401) populations can be linked to unique founder mutations. Other mutations identified so far were identified as rare alleles or in single isolated reports. The common polymorphism of POR is the variant A503V which can be found in about 27% of alleles in general population but there are remarkable differences among different sub populations.

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Effect of Cysteamine on Mutant ASL Proteins with Cysteine for Arginine Substitutions

Abstract: Since 12 % of all known genotypes in ASL deficiency are affected by a cysteine for arginine mutation, we conclude that the potential of cysteamine or of related substances as remedy for this disease should be investigated further.

Cited by 4 publications

References 32 publications

Cysteamine revisited: repair of arginine to cysteine mutations

Cysteamine revisited: repair of arginine to cysteine mutations

Thiolatocobalamins repair the activity of pathogenic variants of the human cobalamin processing enzyme CblC

P450 Oxidoreductase deficiency: Analysis of mutations and polymorphisms

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