更新于：2024-11-01

HADHB

更新于：2024-11-01

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 [+7]

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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191

项与 HADHB 相关的文献（医药）

2024-09-10·JCI Insight

Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency

Article

作者: Koppes, Erik ; Mohsen, Al-Walid ; Vieira Neto, Eduardo ; Szuminsky, Austin J ; Van't Land, Clinton ; Tyurina, Yulia Y ; Anthonymuthu, Tamil S ; El-Gharbawy, Areeg H ; Bayır, Hülya ; Wang, Meicheng ; Ferraro, Lethicia ; Kagan, Valerian ; Wang, Yudong ; Zanatta, Geancarlo ; Vockley, Jerry ; Tyurin, Vladimir A

Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder leading to a block in long-chain fatty acid β-oxidation. Mutations in HADHA and HADHB, which encode the TFP α and β subunits, respectively, usually result in combined TFP deficiency. A single common mutation, HADHA c.1528G>C (p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase deficiency. TFP also catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid critical to mitochondrial membrane stability and function. We explored the effect of mutations in TFP subunits on CL and other phospholipid content and composition and the consequences of these changes on mitochondrial bioenergetics in patient-derived fibroblasts. Abnormalities in these parameters varied extensively among different fibroblasts, and some cells were able to maintain basal oxygen consumption rates similar to controls. Although CL reduction was universally identified, a simultaneous increase in monolysocardiolipins was discrepant among cells. A similar profile was seen in liver mitochondria isolates from a TFP-deficient mouse model. Response to new potential drugs targeting CL metabolism might be dependent on patient genotype.

2024-07-01·Ecotoxicology and Environmental Safety

DNA demethylase TET2-mediated reduction of HADHB expression contributes to cadmium-induced malignant progression of colorectal cancer

Article

作者: Liu, Zixuan ; Li, Lingling ; Chen, Yansu ; Cao, Xingyue ; Ma, Qun ; Jiang, Min ; Wang, Weimin ; Han, Jingyi ; Huang, Yefei

Environmental exposure to the cadmium (Cd) has been shown to be a risk factor for colorectal cancer (CRC) progression, but the exact mechanism has not been fully elucidated. In this study, we found that chronic Cd (3 μM) exposure promoted the proliferation, adhesion, migration, and invasion of CRC cells in vitro, as well as lung metastasis in vivo. RNA-seq and TCGA-COAD datasets revealed that decreased hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta (HADHB) expression may be a crucial factor in Cd-induced CRC progression. Further analysis using qRT-PCR and tissue microarrays from CRC patients showed that HADHB expression was significantly reduced in CRC tissues compared to adjacent normal tissues, and low HADHB expression was associated with adverse clinical features and poor overall survival, either directly or through TNM stage. Furthermore, HADHB was found to play an important role in the Cd-induced malignant metastatic phenotype of CRC cells and lung metastasis in mice. Mechanistically, we discovered that chronic Cd exposure resulted in hypermethylation of the HADHB promoter region via inhibition of DNA demethylase tet methylcytosine dioxygenase 2 (TET2), which then led to decreased HADHB expression and activation of the FAK signaling pathway, and ultimately contributed to CRC progression. In conclusion, this study provided a new potential insight and evaluable biomarker for Cd exposure-induced CRC progression and treatment.

2024-07-01·Archives of Oral Biology

Identification of ACAA1 and HADHB as potential prognostic biomarkers based on a novel fatty acid oxidation-related gene model in head and neck squamous cell carcinoma: A retrospective study

Article

作者: Wang, Wan-Li ; Shen, Ze-Liang ; Tang, Ya-Ling ; Jiang, Jian ; Liang, Xin-Hua ; Jiang, Hong-Jie

OBJECTIVESTo investigate the importance of fatty acid oxidation (FAO)-related genes in predicting the progression and prognosis of head and neck squamous cell carcinoma (HNSCC).METHODSThe FAO-related gene prognostic model was established employing Cox regression analyses, during which accuracy and sensitivity of the gene model were evaluated in The Cancer Genome Atlas (TCGA) internal testing and Gene Expression Omnibus (GEO) external validation cohorts. Ultimately, hub genes were identified among 13 model genes using STRING and Cytoscape, with preliminary validation carried out through immunohistochemistry.RESULTSThe model, which comprised 13 genes (ABCD2, ACAA1, ACACB, AKT1, CNR1, CPT1C, CROT, ECHDC2, ETFA, HADHB, IRS2, LONP2, and SLC25A17), was established. On the basis of the median risk score, the two cohorts were grouped into low-and high-risk groups in the subsequent test and validation, and the former exhibited significantly higher survival rates than the latter. Nomograms were established based on prognostic factors, including stage and risk score, and individualized for the prediction of HNSCC patients. Ultimately, immunohistochemical staining showed that ACAA1 and HADHB were significantly under-expressed in HNSCC, with a favorable prognosis associated with low HADHB and high ACAA1.CONCLUSIONSThe gene prognostic model has illustrated promising capability in predicting the prognosis, and ACAA1 and HADHB might serve as potential therapeutic biomarkers for HNSCC patients.