Potential pharmacological chaperones for cystathionine beta-synthase-deficient homocystinuria

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F18%3A10390309" target="_blank" >RIV/00216208:11110/18:10390309 - isvavai.cz</a>

Alternative codes found

RIV/00064165:_____/18:10390309

Result on the web

<a href="http://dx.doi.org/10.1007/164_2017_72" target="_blank" >http://dx.doi.org/10.1007/164_2017_72</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1007/164_2017_72" target="_blank" >10.1007/164_2017_72</a>

Result language

angličtina

Original language name

Potential pharmacological chaperones for cystathionine beta-synthase-deficient homocystinuria

Original language description

Classical homocystinuria (HCU) is the most common loss-of-function inborn error of sulfur amino acid metabolism. HCU is caused by a deficiency in enzymatic degradation of homocysteine, a toxic intermediate of methionine transformation to cysteine, chiefly due to missense mutations in the cystathionine beta-synthase (CBS) gene. As with many other inherited disorders, the pathogenic mutations do not target key catalytic residues, but rather introduce structural perturbations leading to an enhanced tendency of the mutant CBS to misfold and either to form nonfunctional aggregates or to undergo proteasome-dependent degradation. Correction of CBS misfolding would represent an alternative therapeutic approach for HCU. In this review, we summarize the complex nature of CBS, its multi-domain architecture, the interplay between the three cofactors required for CBS function [heme, pyridoxal-5&apos;-phosphate (PLP), and S-adenosylmethionine (SAM)], as well as the intricate allosteric regulatory mechanism only recently understood, thanks to advances in CBS crystallography. While roughly half of the patients respond to treatment with a PLP precursor pyridoxine, many studies suggested usefulness of small chemicals, such as chemical and pharmacological chaperones or proteasome inhibitors, rescuing mutant CBS activity in cellular and animal models of HCU. Non-specific chemical chaperones and proteasome inhibitors assist in mutant CBS folding process and/or prevent its rapid degradation, thus resulting in increased steady-state levels of the enzyme and CBS activity. Recent interest in the field and available structural information will hopefully yield CBS-specific compounds, by using high-throughput screening and computational modeling of novel ligands, improving folding, stability, and activity of CBS mutants.

Czech name

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Czech description

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Type

C - Chapter in a specialist book

CEP classification

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OECD FORD branch

30202 - Endocrinology and metabolism (including diabetes, hormones)

Project

<a href="/en/project/NV16-30384A" target="_blank" >NV16-30384A: Metabolism of organic and inorganic sulfur compounds in selected human diseases</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2018

Confidentiality

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

Book/collection name

Targeting Trafficking in Drug Development

ISBN

978-3-319-74163-5

Number of pages of the result

39

Pages from-to

345-383

Number of pages of the book

425

Publisher name

Springer

Place of publication

Cham

UT code for WoS chapter

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