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Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.
- F. Kaiser, Morad Ansari, +80 authors M. Deardorff
- Biology, Medicine
- Human molecular genetics
- 1 June 2014
It is demonstrated that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS. Expand
The Presence of a Transporter-Induced Protein Binding Shift: A New Explanation for Protein-Facilitated Uptake and Improvement for In Vitro-In Vivo Extrapolation
Low unbound Km values and increased intrinsic clearance values were seen in the plasma incubations for the highly bound compounds, supporting the new hypothesis and mitigating the IVIVE underprediction previously seen for highly bound transporter substrates. Expand
General Base-General Acid Catalysis in Human Histone Deacetylase 8.
Enzymological and structural studies strongly suggest that H143 functions as a single general base-general acid catalyst, while H142 remains positively charged and serves as an electrostatic catalyst for transition state stabilization. Expand
An examination of protein binding and protein‐facilitated uptake relating to in vitro‐in vivo extrapolation
This review explores the evolution of fu terms included when implementing IVIVE, the concept of protein‐facilitated uptake, and the mechanisms that have been proposed to account for facilitated uptake. Expand
Hepatic Clearance Predictions from In Vitro–In Vivo Extrapolation and the Biopharmaceutics Drug Disposition Classification System
The results of this study emphasize the need for improved in vitro to in vivo extrapolation experimental methods, as using physiologically based scaling is still not accurate, and BDDCS cannot currently help predict accurate results. Expand
In Vitro-In Vivo Extrapolation and Hepatic Clearance-Dependent Underprediction.
Accurately predicting the hepatic clearance of compounds using in vitro to in vivo extrapolation (IVIVE) is crucial within the pharmaceutical industry. However, several groups have recently… Expand
Changes in Organic Anion Transporting Polypeptide Uptake in HEK293 Overexpressing Cells in the Presence and Absence of Human Plasma
- C. Bowman, E. Chen, +5 authors J. Mao
- Chemistry, Medicine
- Drug Metabolism and Disposition
- 7 November 2019
Shifts in the presence and absence of human plasma suggest that plasma proteins may play a role in both the active uptake and passive diffusion processes, and supports the idea of a transporter-induced protein-binding shift, where high protein binding may not limit the uptake of compounds that have high affinity for transporters. Expand
In Vitro–In Vivo Inaccuracy: The CYP3A4 Anomaly
For CYP3A4 substrates, microsomes give markedly higher predictive in vitro to in vivo extrapolation than for other metabolic enzymes, which is not found for hepatocytes, and it is hypothesized that this may be due to interplay between CYP 3A4 and the efflux transporter P-glycoprotein, as they have been shown to exhibit coordinated regulation. Expand
Antimetabolites of coenzyme Q. 16. New alkylmercaptoquinones having antimalarial curative activity.
Compromised Structure and Function of HDAC8 Mutants Identified in Cornelia de Lange Syndrome Spectrum Disorders
- C. Decroos, C. Bowman, J.-A.S. Moser, K. E. Christianson, M. Deardorff, D. Christianson
- Biology, Medicine
- ACS chemical biology
- 30 July 2014
Full characterized structure and function of five HDAC8 mutants reveal that each mutation causes local structural changes that compromise catalysis and/or thermostability, and catalytic activity of these mutants can be partially or fully rescued in vitro by theHDAC8 activator N-(phenylcarbamothioyl)benzamide. Expand