Potential pharmacological chaperones for cystathionine beta-synthase-deficient homocystinuria

Tomas Majtan, Angel L. Pey, Paula Gimenez-Mascarell, Luis Alfonso Martínez-Cruz, Csaba Szabo, Viktor Kožich, Jan P. Kraus

    Research output: Chapter in Book/Report/Conference proceedingChapter

    7 Scopus citations

    Abstract

    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′-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.

    Original languageEnglish (US)
    Title of host publicationHandbook of Experimental Pharmacology
    PublisherSpringer New York LLC
    Pages345-383
    Number of pages39
    DOIs
    StatePublished - Jan 1 2018

    Publication series

    NameHandbook of Experimental Pharmacology
    Volume245
    ISSN (Print)0171-2004
    ISSN (Electronic)1865-0325

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    Keywords

    • Heme
    • High-throughput screening
    • Homocysteine
    • Protein misfolding
    • Pyridoxal-5′-phosphate
    • S-adenosylmethionine

    ASJC Scopus subject areas

    • Biochemistry
    • Pharmacology, Toxicology and Pharmaceutics(all)

    Cite this

    Majtan, T., Pey, A. L., Gimenez-Mascarell, P., Martínez-Cruz, L. A., Szabo, C., Kožich, V., & Kraus, J. P. (2018). Potential pharmacological chaperones for cystathionine beta-synthase-deficient homocystinuria. In Handbook of Experimental Pharmacology (pp. 345-383). (Handbook of Experimental Pharmacology; Vol. 245). Springer New York LLC. https://doi.org/10.1007/164_2017_72