小配体高胱氨酸尿症中靶向性胱硫醚β-合成酶错误折叠:工艺现状和发展方向

Title:Targeting Cystathionine Beta-Synthase Misfolding in Homocystinuria by Small Ligands: State of the Art and Future Directions

Volume: 17 Issue: 13

Author(s): Tomas Majtan, Angel L. Pey, June Ereño-Orbea, Luis Alfonso Martínez-Cruz, Jan P. Kraus

Affiliation:

关键词: 经典的高胱氨酸尿症，胱硫醚合成酶，高通量筛选，同型半胱氨酸，药物分子伴侣蛋白的错误折叠，血红素，吡哆醛磷酸腺苷甲硫氨酸

摘要: Classical homocystinuria (HCU) is the most common loss-of-function inborn error of sulfur amino acids 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 betasynthase (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 non-functional aggregates or to undergo proteasome-dependent degradation. Thus correction of CBS misfolding represents an alternative therapeutic approach for HCU. In this review, we summarize the complex nature of CBS, its multidomain architecture, the interplay between the three cofactors required for CBS function (heme, pyridoxal-5’-phosphate (PLP) and S-adenosyl-L-methionine) as well as the intricate allosteric regulatory mechanism only recently explained thanks to advances in CBS crystallography. While roughly half of the patients responds 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 increased 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.

Cite this article as:

Tomas Majtan, Angel L. Pey, June Ereño-Orbea, Luis Alfonso Martínez-Cruz, Jan P. Kraus , Targeting Cystathionine Beta-Synthase Misfolding in Homocystinuria by Small Ligands: State of the Art and Future Directions, Current Drug Targets 2016; 17 (13) . https://dx.doi.org/10.2174/1389450117666160302094910