Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of renin inhibitors containing the dipeptide transition state mimics (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-7-methyloctanoic acid (Leu (OH)/Val) and (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexylhexanoic acid (CHa /(OH)/Val) was prepared. A structure-activity study with Boc-Phe-His-Leu (OH)/Val-Ile-His-NH2 (8a) as starting material led to N-[(2S)-2-[(tert-butylsulfonyl)methyl]-3-phenylpropionyl]-His-Cha (OH)/ Val- NHC4H9-n (8i) which has the length of a tetrapeptide and contains only one natural amino acid. Compound 8i had an IC50 of 2 x 10(-9) M against human renin and showed high enzyme specificity; IC50 values against the related aspartic proteinases pepsin and cathepsin D were (8 x 10(-6) and 3 x 10(-6) M, respectively). In salt-depleted marmosets, 8i inhibited plasma renin activity PRA and lowered blood pressure for up to 2 h after oral administration of a dose of 10 mg/kg.
 ...
PMID:Synthesis and biological activity of some transition-state inhibitors of human renin. 313 45

Progesterone receptor isoforms A and B exert different biological effects in breast cancer cells. Alteration of PRA/PRB ratio is often observed during breast cancer progression. High PRA/PRB ratios in breast cancer patients are associated with resistance to chemotherapy and poor prognosis. While it is well accepted that PRA and PRB regulate different sets of genes, how the expression of PRA and PRB alters breast cancer proteomes has not been fully investigated. To directly investigate the effects of PR isoform expression on the breast cancer proteome, both in the presence and absence of progestin, PRA and PRB were independently stably expressed in T47DC42 PR-null breast cancer cells using a doxycycline (Dox)-regulated promoter. Dox induction dose-dependently increased PRA and PRB expression. Dox-induced PRA and PRB showed normal receptor localization and were transcriptionally active. Differential quantitative proteomic analysis by stable isotope dimethyl labeling was performed to quantitatively examine how PR isoforms altered global breast cancer proteomes. Cells expressing PRA in the absence of progestin were enriched in proteins involved in the TCA cycle and enriched in proteins involved in glycolysis in the presence of progestin, whilst cells expressing PRB in the absence and presence progestin were significantly enriched in proteins involved in the cell cycle and cell apoptosis pathways. This proteomic data revealed a link between PR isoform expression and alteration in cell metabolism, cell proliferation, and apoptosis. The enrichment of proteins involved in the glycolytic pathway in breast cancer cells expressing PRA is consistent with stem cell-like properties, previously reported in PRA-rich breast cancer cells. Moreover, compared to liganded PRB, liganded PRA differentially upregulated proteins involved in chromatin remodeling, such as linker histone H1.2. Silencing H1.2 gene expression suppressed PRA-mediated cell proliferation and promoted G2/M and S phase entry of the cell cycle. Additionally, liganded PRA upregulated the expression of cathepsin D (CTSD) protease, whose expression is associated with poor prognosis in breast cancer patients. Together, our data demonstrated that the expression of PRA or PRB dramatically and differentially altered breast cancer cell proteomes. These isoform-specific changes in the breast cancer proteome will help to explain the distinct phenotypic properties of breast cancer cells expressing different levels of PRA and PRB.
 ...
PMID:Differential quantitative proteomics reveals key proteins related to phenotypic changes of breast cancer cells expressing progesterone receptor A. 3180 70