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

    5 Citations (Scopus)

    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

    Fingerprint

    Cystathionine beta-Synthase
    Homocystinuria
    Pharmacology
    Proteasome Inhibitors
    Pyridoxal Phosphate
    Degradation
    Inborn Errors Amino Acid Metabolism
    Sulfur Amino Acids
    S-Adenosylmethionine
    Pyridoxine
    Crystallography
    Poisons
    Homocysteine
    Missense Mutation
    Proteasome Endopeptidase Complex
    Heme
    Metabolism
    Methionine
    Cysteine
    Screening

    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

    Potential pharmacological chaperones for cystathionine beta-synthase-deficient homocystinuria. / Majtan, Tomas; Pey, Angel L.; Gimenez-Mascarell, Paula; Martínez-Cruz, Luis Alfonso; Szabo, Csaba; Kožich, Viktor; Kraus, Jan P.

    Handbook of Experimental Pharmacology. Springer New York LLC, 2018. p. 345-383 (Handbook of Experimental Pharmacology; Vol. 245).

    Research output: Chapter in Book/Report/Conference proceedingChapter

    Majtan, T, Pey, AL, Gimenez-Mascarell, P, Martínez-Cruz, LA, Szabo, C, Kožich, V & Kraus, JP 2018, Potential pharmacological chaperones for cystathionine beta-synthase-deficient homocystinuria. in Handbook of Experimental Pharmacology. Handbook of Experimental Pharmacology, vol. 245, Springer New York LLC, pp. 345-383. https://doi.org/10.1007/164_2017_72
    Majtan T, Pey AL, Gimenez-Mascarell P, Martínez-Cruz LA, Szabo C, Kožich V et al. Potential pharmacological chaperones for cystathionine beta-synthase-deficient homocystinuria. In Handbook of Experimental Pharmacology. Springer New York LLC. 2018. p. 345-383. (Handbook of Experimental Pharmacology). https://doi.org/10.1007/164_2017_72
    Majtan, Tomas ; Pey, Angel L. ; Gimenez-Mascarell, Paula ; Martínez-Cruz, Luis Alfonso ; Szabo, Csaba ; Kožich, Viktor ; Kraus, Jan P. / Potential pharmacological chaperones for cystathionine beta-synthase-deficient homocystinuria. Handbook of Experimental Pharmacology. Springer New York LLC, 2018. pp. 345-383 (Handbook of Experimental Pharmacology).
    @inbook{d447bb2f90434f01ba117eb291478711,
    title = "Potential pharmacological chaperones for cystathionine beta-synthase-deficient homocystinuria",
    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.",
    keywords = "Heme, High-throughput screening, Homocysteine, Protein misfolding, Pyridoxal-5′-phosphate, S-adenosylmethionine",
    author = "Tomas Majtan and Pey, {Angel L.} and Paula Gimenez-Mascarell and Mart{\'i}nez-Cruz, {Luis Alfonso} and Csaba Szabo and Viktor Kožich and Kraus, {Jan P.}",
    year = "2018",
    month = "1",
    day = "1",
    doi = "10.1007/164_2017_72",
    language = "English (US)",
    series = "Handbook of Experimental Pharmacology",
    publisher = "Springer New York LLC",
    pages = "345--383",
    booktitle = "Handbook of Experimental Pharmacology",

    }

    TY - CHAP

    T1 - Potential pharmacological chaperones for cystathionine beta-synthase-deficient homocystinuria

    AU - Majtan, Tomas

    AU - Pey, Angel L.

    AU - Gimenez-Mascarell, Paula

    AU - Martínez-Cruz, Luis Alfonso

    AU - Szabo, Csaba

    AU - Kožich, Viktor

    AU - Kraus, Jan P.

    PY - 2018/1/1

    Y1 - 2018/1/1

    N2 - 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.

    AB - 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.

    KW - Heme

    KW - High-throughput screening

    KW - Homocysteine

    KW - Protein misfolding

    KW - Pyridoxal-5′-phosphate

    KW - S-adenosylmethionine

    UR - http://www.scopus.com/inward/record.url?scp=85045846749&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=85045846749&partnerID=8YFLogxK

    U2 - 10.1007/164_2017_72

    DO - 10.1007/164_2017_72

    M3 - Chapter

    C2 - 29119254

    AN - SCOPUS:85045846749

    T3 - Handbook of Experimental Pharmacology

    SP - 345

    EP - 383

    BT - Handbook of Experimental Pharmacology

    PB - Springer New York LLC

    ER -