摘要
经典的高胱氨酸尿症(HCU)是最常见的与生俱来的含硫氨基酸代谢功能损失。它由在同型半胱氨酸酶降解不足引起的,一种有毒的蛋氨酸转化为半胱氨酸中间体,主要由于胱硫醚β-合成(CBS)基因错义突变。与许多其他遗传性疾病相比,致病突变目标关键不是催化残基,而是引入结构扰动导致增强的趋势突变胱硫醚β-合成错误折叠,形成无功能的聚集体或接受蛋白酶依赖的降解。因此,错误校正的胱硫醚β-合成代表高胱氨酸尿症的替代治疗方法。在这篇综述中,我们总结了胱硫醚β-合成的复杂性,其多畴结构,胱硫醚β-合成功能要求的3个辅因子之间的相互作用(血红素,磷酸吡哆醛(PLP)和S-腺苷甲硫氨酸)以及近段才解释说由于在胱硫醚β-合成的晶体学研究进展复杂的变构调节机制。在大约一半的患者对磷酸吡哆醛前驱吡哆醇治疗响应,许多研究表明小分子化合物的有用性,如化学和药物分子伴侣或蛋白酶体抑制剂,在高胱氨酸尿症的细胞和动物模型修复突变胱硫醚β-合成活性。非特定的化学分子伴侣和蛋白酶体抑制剂协助突变胱硫醚β-合成折叠过程和/或防止其快速降解,从而提高稳态水平的活性酶和胱硫醚β-合成。最近在该领域的关注度增加和可用的结构信息,将采用通过提高折叠的新型配体的高通量筛选和计算模型的特定化合物的胱硫醚β-合成,使胱硫醚β-合成具有稳定性和活性。
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
图形摘要
Current Drug Targets
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.
Export Options
About this article
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
DOI https://dx.doi.org/10.2174/1389450117666160302094910 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
Related Journals
Related Books
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Neurophysiological Mechanisms Related to Pain Management in Bone Tumors
Current Neuropharmacology Beyond the "Lock and Key" Paradigm: Targeting Lipid Rafts to Induce the Selective Apoptosis of Cancer Cells
Current Medicinal Chemistry Apoptosis Induction by Thalidomide: Critical for Limb Teratogenicity but Therapeutic Potential in Idiopathic Pulmonary Fibrosis?
Current Molecular Pharmacology Metabolite Quantification in Tumours by Magnetic Resonance Spectroscopy: Objectives, Results and Perspectives
Current Medical Imaging Current Development of ROS-Modulating Agents as Novel Antitumor Therapy
Current Cancer Drug Targets Natural Products: A Rich Source of Antiviral Drug Lead Candidates for the Management of COVID-19
Current Pharmaceutical Design Kinetic Measurement Techniques in the Evaluation of Lipid Metabolism
Current Drug Discovery Technologies Omega-3 Fatty Acid Treatment Combined with Chemotherapy to Prevent Toxicity, Drug Resistance, and Metastasis in Cancer
Current Drug Targets Target Sites for the Design of Anti-trypanosomatid Drugs Based on the Structure of Dihydroorotate Dehydrogenase
Current Pharmaceutical Design Anti-Cancer Approach with NK4: Bivalent Action and Mechanisms
Anti-Cancer Agents in Medicinal Chemistry Direct Evidence on the Immune-Mediated Spontaneous Regression of Human Cancer: An Incentive for Pharmaceutical Companies to Develop a Novel Anti-Cancer Vaccine
Current Pharmaceutical Design Molecular Targeted Therapy in Melanoma: A Way to Reverse Resistance to Conventional Drugs
Current Drug Delivery The Prevention of Oral Mucositis in Patients with Blood Cancers: Current Concepts and Emerging Landscapes
Cardiovascular & Hematological Agents in Medicinal Chemistry GSK-3 Inhibitors in the Regulation and Control of Colon Carcinoma
Current Drug Targets Osteoprotegerin and Diabetes-Associated Pathologies
Current Molecular Medicine Role of Serum and Glucocorticoid-Inducible Kinase (SGK)-1 in Senescence: A Novel Molecular Target Against Age-Related Diseases
Current Medicinal Chemistry Bisphosphonate Therapy for Patients with Breast Cancer
Current Cancer Therapy Reviews Molecular and Genetic Mechanisms of Osteoporosis: Implication for Treatment
Current Molecular Medicine 1,2,4-Triazine Analogs as Novel Class of Therapeutic Agents
Mini-Reviews in Medicinal Chemistry A Novel 99mTc-labeled Diphosphonic Acid as Potential Bone Seeking Agent: Synthesis and Biological Evaluation
Current Radiopharmaceuticals