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.
N1 - Funding Information:
This study was supported by the American Heart Association Scientist Development Grant 16SDG3004000 (to TM), Junta de Andalucia (P11-CTS-07187 to ALP), Basque Foundation for Health and Research (BIOEF and EITB Maratoia 2015 to LAMC) by grants from the Spanish Ministry of Economy, Industry and Competitiveness (BFU2010-17857 and BFU2013-47531-R to LAMC) and from the Czech Health Research Council (16-30384A to VK). TM and JPK would like to thank Orphan Technologies Ltd. for support of their research. ALP would also like to acknowledge support from Prof. Jose Manuel Sanchez-Ruiz (University of Granada) through the Spanish Ministry of Economy, Industry and Competitiveness grant (BIO2015-66426-R) and FEDER funds. LAMC would also like to thank the Spanish Ministry of Economy, Industry and Competitiveness for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644). In addition, VK received an institutional support from projects RVO-VFN 64165 and Progres Q26.
Funding Information:
Acknowledgment This study was supported by the American Heart Association Scientist Development Grant 16SDG3004000 (to TM), Junta de Andalucia (P11-CTS-07187 to ALP), Basque Foundation for Health and Research (BIOEF and EITB Maratoia 2015 to LAMC) by grants from the Spanish Ministry of Economy, Industry and Competitiveness (BFU2010-17857 and BFU2013-47531-R to LAMC) and from the Czech Health Research Council (16-30384A to VK). TM and JPK would like to thank Orphan Technologies Ltd. for support of their research. ALP would also like to acknowledge support from Prof. Jose Manuel Sanchez-Ruiz (University of Granada) through the Spanish Ministry of Economy, Industry and Competitiveness grant (BIO2015-66426-R) and FEDER funds. LAMC would also like to thank the Spanish Ministry of Economy, Industry and Competitiveness for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644). In addition, VK received an institutional support from projects RVO-VFN 64165 and Progres Q26.
Publisher Copyright:
© Springer International Publishing AG 2017.
PY - 2018
Y1 - 2018
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 -