预约演示

更新于：2025-01-23

HADHB

更新于：2025-01-23

基本信息

别名

3-ketoacyl-CoA thiolase、Acetyl-CoA acyltransferase、Beta-ketothiolase

+ [5]

简介

Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway (PubMed:8135828, PubMed:29915090, PubMed:30850536). The mitochondrial beta-oxidation pathway is the major energy-producing process in tissues and is performed through four consecutive reactions breaking down fatty acids into acetyl-CoA (PubMed:29915090). Among the enzymes involved in this pathway, the trifunctional enzyme exhibits specificity for long-chain fatty acids (PubMed:30850536). Mitochondrial trifunctional enzyme is a heterotetrameric complex composed of two proteins, the trifunctional enzyme subunit alpha/HADHA carries the 2,3-enoyl-CoA hydratase and the 3-hydroxyacyl-CoA dehydrogenase activities, while the trifunctional enzyme subunit beta/HADHB described here bears the 3-ketoacyl-CoA thiolase activity (PubMed:8135828, PubMed:29915090, PubMed:30850536).

关联

项与 HADHB 相关的药物

Ninerafaxstat

靶点

HADHB

作用机制

HADHB inhibitors [+1]

在研机构

Imbria Pharmaceuticals, Inc.初创企业

原研机构

Imbria Pharmaceuticals, Inc.初创企业

在研适应症

非梗阻性肥厚型心肌病 [+6]

非在研适应症

难治性心绞痛

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 HADHB 相关的临床试验

NCT04306237

/ Suspended临床2期

A Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of IMB-1018972 in Patients With Refractory Angina

The objectives of the study are to assess the safety, tolerability, and potential efficacy of IMB-1018972 on patients with refractory angina. Study will assess functional capacity employing a modified Bruce Protocol treadmill ETT, patient reports of angina symptoms via an electronic diary, and activity using an accelerometer.

开始日期2023-11-01

申办/合作机构

Imbria Pharmaceuticals, Inc.初创企业

NCT04826185

/ Completed临床2期

A Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of IMB-1018972 in Patients With Non-obstructive Hypertrophic Cardiomyopathy

The purpose of this study is to assess the safety, tolerability, and potential efficacy of IMB-1018972 in patients with non-obstructive HCM.

开始日期2021-06-14

申办/合作机构

Imbria Pharmaceuticals, Inc.初创企业

NCT04826172

/ Completed临床2期

A Randomized, Double-Blind, Placebo-Controlled, Exploratory Study on the Safety, Tolerability, and Pharmacodynamics of IMB-1018972 in Subjects With Angina Due to Obstructive Coronary Artery Disease

The purpose of this study is to assess the safety and tolerability of IMB-1018972 in subjects with obstructive CAD and inducible ischemia.

开始日期2021-04-23

申办/合作机构

Imbria Pharmaceuticals, Inc.初创企业

100 项与 HADHB 相关的临床结果

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100 项与 HADHB 相关的转化医学

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0 项与 HADHB 相关的专利（医药）

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199

项与 HADHB 相关的文献（医药）

2025-02-01·Toxicology

Effective analysis of thyroid toxicity and mechanisms of acetyltributyl citrate using network toxicology, molecular docking, and machine learning strategies

Article

作者: Peng, Qingping ; Liu, Huan ; Fu, Bowen ; Lan, Yujian

The growing prevalence of environmental pollutants has raised concerns about their potential role in thyroid dysfunction and related disorders. Previous research suggests that various chemicals, including plasticizers like acetyl tributyl citrate (ATBC), may adversely affect thyroid health, yet the precise mechanisms remain poorly understood. The objective of this study was to elucidate the complex effects of acetyl tributyl citrate (ATBC) on the thyroid gland and to clarify the potential molecular mechanisms by which environmental pollutants influence the disease process. Through an exhaustive exploration of databases such as ChEMBL, STITCH, and GEO, we identified a comprehensive list of 19 potential targets closely associated with ATBC and the thyroid gland. After rigorous screening using the STRING platform and Cytoscape software, we narrowed this list to 15 candidate targets, ultimately identifying five core targets: CBX5, HADHB, TRIM33, TP53, and CUL4A, utilizing three well-established machine learning methods. In-depth Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses conducted in the DAVID database revealed that the primary pathways through which ATBC affects the thyroid gland involve key signaling cascades, including the FoxO signaling pathway and metabolic pathways such as fatty acid metabolism. Furthermore, molecular docking simulations using Molecular Operating Environment software confirmed strong binding interactions between ATBC and these core targets, enhancing our understanding of their interactions. Overall, our findings provide a theoretical framework for comprehending the intricate molecular mechanisms underlying ATBC's effects on thyroid damage and pave the way for the development of preventive and therapeutic strategies against thyroid disorders caused by exposure to ATBC-containing plastics or overexposure to ATBC.

2025-01-02·Cancer Research

TCTN1 Induces Fatty Acid Oxidation to Promote Melanoma Metastasis

Article

作者: Gu, Jianying ; Li, Jianrui ; Wei, Chuanyuan ; Gao, Zixu ; Yang, Yang ; Luo, Zucheng ; Yang, Yanwen ; Wang, Lu ; Zheng, Shaoluan ; Zhang, Tianyi ; Zhu, Yu ; Wei, Chenlu ; Ming, Ren ; Ding, Yiteng ; Li, Yinlam ; Xuan, Jiangying ; Hu, Qianrong ; Shen, Kangjie

AbstractMetabolic reprogramming promotes and sustains multiple steps of melanoma metastasis. Identification of key regulators of metabolic reprogramming could lead to the development of treatments for preventing and treating metastatic melanoma. In this study, we identified that tectonic family member 1 (TCTN1) promotes melanoma metastasis by increasing fatty acid oxidation (FAO). In clinical melanoma samples, high expression of TCTN1 correlated with increased metastasis and shorter patient survival. Functionally, TCTN1 promoted melanoma invasion and migration in vitro and distant metastasis in vivo and induced a mesenchymal-like phenotype switch. Mechanistically, TCTN1 acted as a protein scaffold to promote the binding of HADHA and HADHB, subunits of the mitochondrial trifunctional protein complex, thus leading to FAO activation. TCTN1-mediated FAO activated the p38/MAPK signaling pathway in melanoma cells, promoting tumor epithelial–mesenchymal transition and stemness. Molecular docking indicated that the prostaglandin F receptor agonist fluprostenol can block HADHA/HADHB binding, which was confirmed experimentally. Treatment with fluprostenol was able to inhibit TCTN1-induced melanoma invasion and metastasis. Taken together, these findings elucidate the mechanism of TCTN1-mediated promotion of melanoma metastasis and support the potential application of fluprostenol for targeted therapy of metastatic melanoma.Significance: TCTN1 activates fatty acid oxidation to induce melanoma mesenchymal phenotype switching and invasion by promoting the binding of the subunits of MTP, which can be targeted with fluprostenol to inhibit melanoma metastasis.

2025-01-02·Epigenomics

Multi-omics insights into the pathogenesis of diabetic cardiomyopathy: epigenetic and metabolic profiles

Article

作者: Yan, Jiangtao ; Chen, Chen ; Ma, Xiaozhu ; Cai, Ziyang ; Ding, Hu ; Wuyun, Qidamugai ; Mei, Shuai ; Zhou, Li

AIMDiabetic cardiomyopathy (DbCM), a complex metabolic disease, greatly threatens human health due to therapeutic limitations. Multi-omics approaches facilitate the elucidation of its intrinsic pathological changes.METHODSMetabolomics, RNA-seq, proteomics, and assay of transposase-accessible chromatin (ATAC-seq) were utilized to elucidate multidimensional molecular alterations in DbCM.RESULTSIn the heart and plasma of mice with DbCM, metabolomic analysis demonstrated significant differences in branched-chain amino acids (BCAAs) and lipids. Subsequent RNA-seq and proteomics showed that the key genes, including BCKDHB, PPM1K, Cpt1b, Fabp4, Acadm, Acadl, Acadvl, HADH, HADHA, HADHB, Eci1, Eci2, PDK4, and HMGCS2, were aberrantly regulated, contributing to the disorder of BCAAs and fatty acids. ATAC-seq analysis underscored the pivotal role of epigenetic regulation by revealing dynamic shifts in chromatin accessibility and a robust positive correlation with gene expression patterns in diabetic cardiomyopathy mice. Furthermore, motif analysis identified that KLF15 as a critical transcription factor in DbCM, regulating the core genes implicated with BCAAs metabolism.CONCLUSIONOur research delved into the metabolic alterations and epigenetic landscape and revealed that KLF15 may be a promising candidate for therapeutic intervention in DbCM.

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