Last update 19 Sep 2024

HADH

Last update 19 Sep 2024

Basic Info

Synonyms

HAD, HAD1, HADH

+ [8]

Introduction

Mitochondrial fatty acid beta-oxidation enzyme that catalyzes the third step of the beta-oxidation cycle for medium and short-chain 3-hydroxy fatty acyl-CoAs (C4 to C10) (PubMed:10231530, PubMed:11489939, PubMed:16725361). Plays a role in the control of insulin secretion by inhibiting the activation of glutamate dehydrogenase 1 (GLUD1), an enzyme that has an important role in regulating amino acid-induced insulin secretion (By similarity).

Drugs associated with HADH

HG-1229

Target

HADH x TSPAN16

Mechanism

HADH modulators [+1]

Active Org.-

Originator Org.

Human Genome Sciences, Inc.

Active Indication-

Inactive Indication

Immune System Diseases [+2]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with HADH

100 Translational Medicine associated with HADH

0 Patents (Medical) associated with HADH

903

Literatures (Medical) associated with HADH

01 Jul 2024·Nature Cell Biology

Valine aminoacyl-tRNA synthetase promotes therapy resistance in melanoma

Article

Author: Susaeta Ruiz, Miguel ; Lavergne, Arnaud ; Shostak, Kateryna ; Blomme, Arnaud ; Agami, Reuven ; Pirotte, Bernard ; Chariot, Alain ; Turchetto, Silvia ; Close, Pierre ; Herfs, Michael ; Roncarati, Patrick ; Leclercq, Marine ; Nguyen, Laurent ; Körner, Pierre-René ; Martin-Morales, Lorena ; Rapino, Francesca ; Tarassov, Ivan ; Capron, Coralie ; Marine, Jean-Christophe ; Goffin, Eric ; El-Hachem, Najla ; Thandapani, Palaniraja ; Vanleyssem, Raphael

AbstractTransfer RNA dynamics contribute to cancer development through regulation of codon-specific messenger RNA translation. Specific aminoacyl-tRNA synthetases can either promote or suppress tumourigenesis. Here we show that valine aminoacyl-tRNA synthetase (VARS) is a key player in the codon-biased translation reprogramming induced by resistance to targeted (MAPK) therapy in melanoma. The proteome rewiring in patient-derived MAPK therapy-resistant melanoma is biased towards the usage of valine and coincides with the upregulation of valine cognate tRNAs and of VARS expression and activity. Strikingly, VARS knockdown re-sensitizes MAPK-therapy-resistant patient-derived melanoma in vitro and in vivo. Mechanistically, VARS regulates the messenger RNA translation of valine-enriched transcripts, among which hydroxyacyl-CoA dehydrogenase mRNA encodes for a key enzyme in fatty acid oxidation. Resistant melanoma cultures rely on fatty acid oxidation and hydroxyacyl-CoA dehydrogenase for their survival upon MAPK treatment. Together, our data demonstrate that VARS may represent an attractive therapeutic target for the treatment of therapy-resistant melanoma.

01 Jun 2024·Physiological Reports

Effects of exercise training with intermittent hyperoxic intervention on endurance performance and muscle metabolic properties in male mice

Article

Author: Suzuki, Junichi

AbstractThis study aimed to investigate how intermittent hyperoxic exposure (three cycles of 21% O2 [10 min] and 30% O2 [15 min]) affects exercise performance in mice. Three hours after the acute exposure, there was an observed increase in mRNA levels of phosphofructokinase (Bayes factor [BF] ≥ 10), mitochondrial transcription factor‐A (BF ≥10), PPAR‐α (BF ≥3), and PPAR‐γ (BF ≥3) in the red gastrocnemius muscle (Gr). Four weeks of exercise training under intermittent (INT), but not continuous (HYP), hyperoxia significantly (BF ≥30) increased maximal exercise capacity compared to normoxic exercise‐trained (ET) group. INT group exhibited significantly higher activity levels of 3‐hydroxyacyl‐CoA‐dehydrogenase (HAD) in Gr (BF = 7.9) compared to ET group. Pyruvate dehydrogenase complex activity levels were significantly higher in INT group compared to ET group in white gastrocnemius, diaphragm, and left ventricle (BF ≥3). NT‐PGC1α protein levels in Gr (BF = 7.7) and HAD activity levels in Gr (BF = 6.9) and soleus muscles (BF = 3.3) showed a significant positive correlation with maximal work values. These findings suggest that exercise training under intermittent hyperoxia is a beneficial strategy for enhancing endurance performance by improving fatty acid and pyruvic acid utilization.

22 Apr 2024·JACS Au

Chemo-Enzymatic Strategy for the Efficient Synthesis of Steroidal Drugs with 10α-Methyl Group and a Side Chain at C17-Position from Biorenewable Phytosterols

Article

Author: Wu, Qiaqing ; Ding, Kai ; Li, Xuemei ; Feng, Jinhui ; Zhu, Dunming ; Liu, Yiyin ; Zhang, Rui ; Ma, Yanhe ; Li, Jianjiong ; Zhao, Gang ; Yao, Peiyuan ; Liu, Na ; Chen, Xi

Steroidal pharmaceuticals with a 10α-methyl group or without the methyl group at C10-position are important medicines, but their synthesis is quite challenging, due to that the natural steroidal starting materials usually have a 10β-methyl group which is difficult to be inverted to 10α-methyl group. In this study, 3-((1R,3aS,4S,7aR)-1-((S)-1-hydroxypropan-2-yl)-7a-methyl-5-oxooctahydro-1H-inden-4-yl) propanoic acid (HIP-IPA, 2e) was demonstrated as a valuable intermediate for the synthesis of this kind of active pharmaceutical ingredients (APIs) with a side chain at C17-position. Knockout of a β-hydroxyacyl-CoA dehydrogenase gene and introduction of a sterol aldolase gene into the genetically modified strains of Mycobacterium fortuitum (ATCC 6841) resulted in strains N13Δhsd4AΩthl and N33Δhsd4AΩthl, respectively. Both strains transformed phytosterols into 2e. Compound 2e was produced in 62% isolated yield (25 g) using strain N13Δhsd4AΩthl, and further converted to (3S,3aS,9aS,9bS)-3-acetyl-3a,6-dimethyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-cyclopenta[a]naphthalen-7-one, which is the key intermediate for the synthesis of dydrogesterone. This study not only overcomes a challenging synthetic problem by enabling an efficient synthesis of dydrogesterone-like steroidal APIs from phytosterols, the well-recognized cheap and readily available biobased raw materials, but also provides insights for redesigning the metabolic pathway of phytosterols to produce other new compounds of relevance to the steroidal pharmaceutical industry.

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HADH

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