A Yeast Genetic Assay for Caspase Cleavage of the Amyloid-beta Precursor Protein

Pl, Gunyuzlu; Wh, White; Gl, Davis; Gf, Hollis; Toyn, Jeremy H.

doi:10.1385/mb:15:1:29

Cited by 11 publications

(6 citation statements)

References 39 publications

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“…Discrepant IC50 values may arise when using reporter assays for γ-secretase activity that rely on translocation of endogenous or transcription factor tagged intracellular domains of a given substrate. In these assays, γ-secretase cleavage liberates the intracellular domain and enables it to translocate to the nucleus where it activates a reporter gene [121-122]. It is not clear that these reporter assays accurately reflect effects on cleavage, as there are often large differnces between inhibitor IC50s in the reporter assays versus direct cleavage assays.…”

Section: Avoiding Gsi Toxicity Substrate Selective Gsis and Othermentioning

confidence: 99%

γ-Secretase inhibitors and modulators

Golde

Koo

Felsenstein

et al. 2013

Biochimica et Biophysica Acta (BBA) - Biomembranes

259

231

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γ-Secretase is a fascinating, multi-subunit, intramembrane-cleaving protease that is now being considered as a therapeutic target for a number of diseases. Potent, orally bioavailable γ-secretase inhibitors (GSIs) have been developed and tested in humans with Alzheimer's disease (AD) and cancer. Preclinical studies also suggest the therapeutic potential for GSIs in other disease conditions. However, due to inherent mechanism based-toxicity of non-selective inhibition of γ-secretase, clinical development of GSIs will require empirical testing with careful evaluation of benefit versus risk. In addition to GSIs, compounds referred to as γ-secretase modulators (GSMs) remain in development as AD therapeutics. GSMs do not inhibit γ-secretase, but modulate γ-secretase processivity and thereby shift the profile of the secreted amyloid β peptides (Aβ) peptides produced. Although GSMs are thought to have an inherently safe mechanism of action, their effects on substrates other than the amyloid β protein precursor (APP) have not been extensively investigated. Herein, we will review the current state of development of GSIs and GSMs and explore pertinent biological and pharmacological questions pertaining to the use of these agents for select indications.

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Section: Avoiding Gsi Toxicity Substrate Selective Gsis and Othermentioning

confidence: 99%

γ-Secretase inhibitors and modulators

Golde

Koo

Felsenstein

et al. 2013

Biochimica et Biophysica Acta (BBA) - Biomembranes

259

231

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“…Yeast DNA isolation for recovery of plasmids in E. coli was carried out using the Yeast Plasmid Isolation kit (Bio 101, Carlsbad, CA). The FMS1 coding sequence was amplified by polymerase chain reaction using oligonucleotide primers Fms1For-Xho (5Ј-ccctcgagatgaatacagtttcaccag-3Ј) and Fms1Rev-Bam (5Ј-ttggatccctatttcagtaagtcag-3Ј) and ligated into the SalI and BamHI sites of YEp195AC (25) to create the ADH1-FMS1 overexpression vector. The E39Q substitution was made using QuikChange (Stratagene, La Jolla, CA) and mutagenic primers FmsE39Qupper (5Ј-gtcttgttcttcaggccagagatc-3Ј) and FmsE39Qlower (5Ј-gatctctggcctgaagaacaagac-3Ј).…”

Section: ϫ4mentioning

confidence: 99%

Saccharomyces cerevisiae Is Capable of de Novo Pantothenic Acid Biosynthesis Involving a Novel Pathway of β-Alanine Production from Spermine

White

Gunyuzlu

Toyn

2001

Journal of Biological Chemistry

Self Cite

150

136

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Pantothenic acid and ␤-alanine are metabolic intermediates in coenzyme A biosynthesis. Using a functional screen in the yeast Saccharomyces cerevisiae, a putative amine oxidase, encoded by FMS1, was found to be ratelimiting for ␤-alanine and pantothenic acid biosynthesis. Overexpression of FMS1 caused excess pantothenic acid to be excreted into the medium, whereas deletion mutants required ␤-alanine or pantothenic acid for growth. Furthermore, yeast genes ECM31 and YIL145c, which both have structural homology to genes of the bacterial pantothenic acid pathway, were also required for pantothenic acid biosynthesis. The homology of FMS1 to FAD-containing amine oxidases and its role in ␤-alanine biosynthesis suggested that its substrates are polyamines. Indeed, we found that all the enzymes of the polyamine pathway in yeast are necessary for ␤-alanine biosynthesis; spe1⌬ , spe2⌬ , spe3⌬ , and spe4⌬ are all ␤-alanine auxotrophs. Thus, contrary to previous reports, yeast is naturally capable of pantothenic acid biosynthesis, and the ␤-alanine is derived from methionine via a pathway involving spermine. These findings should facilitate the identification of further enzymes and biochemical pathways involved in polyamine degradation and pantothenic acid biosynthesis in S. cerevisiae and raise questions about these pathways in other organisms.Pantothenic acid (vitamin B 5 ) is a metabolic precursor to coenzyme A (CoA) and acyl carrier protein, which are cofactors required by a large number of metabolic enzymes. Biosynthesis of pantothenic acid occurs in microbes and plants only, whereas animals obtain it in their diet. In bacteria, it is synthesized by the condensation of pantoate, derived from 2-oxoisovalerate, an intermediate in valine biosynthesis, and ␤-alanine, produced by the decarboxylation of L-aspartate (1, 2). In Escherichia coli, four genes, panB, panC, panD, and panE, encode the four enzymes required for pantothenic acid biosynthesis, as illustrated in Fig.

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“…In T2DM the dephosphorylated BAD upregulates BCl2 and causes cell death. Similarly in AD, dephosphorylated BAD protein causes mitochondrial dysfunction 20 thereby inducing apoptosis through Apoptosis regulator Bcl-2 (BCL2) mediated proteins such as CASP3 21 22 , CASP8 23 24 , PSEN1 25 26 , PIN1 27 28 , TP53BP2 29 30 , ITM2B 31 32 and results in APP formation that contributes in the pathogenesis of Alzheimer’s disease in the early stage.…”

Section: Resultsmentioning

confidence: 99%

Type 3 Diabetes: Cross Talk between Differentially Regulated Proteins of Type 2 Diabetes Mellitus and Alzheimer’s Disease

Mittal

Mani

Katare

2016

Sci Rep

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Type 3 Diabetes (T3D) is a neuroendocrine disorder that represents the progression of Type 2 Diabetes Mellitus (T2DM) to Alzheimer’s disease (AD). T3D contributes in the increase of the total load of Alzheimer’s patients worldwide. The protein network based strategies were used for the analysis of protein interactions and hypothesis was derived describing the possible routes of communications among proteins. The hypothesis provides the insight on the probable mechanism of the disease progression for T3D. The current study also suggests that insulin degrading enzyme (IDE) could be the major player which holds the capacity to shift T2DM to T3D by altering metabolic pathways like regulation of beta-cell development, negative regulation of PI3K/AKT pathways and amyloid beta degradation.

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A Yeast Genetic Assay for Caspase Cleavage of the Amyloid-beta Precursor Protein

Cited by 11 publications

References 39 publications

γ-Secretase inhibitors and modulators

γ-Secretase inhibitors and modulators

Saccharomyces cerevisiae Is Capable of de Novo Pantothenic Acid Biosynthesis Involving a Novel Pathway of β-Alanine Production from Spermine

Type 3 Diabetes: Cross Talk between Differentially Regulated Proteins of Type 2 Diabetes Mellitus and Alzheimer’s Disease

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