P4HTM

Last update 08 May 2025

Basic Info

Synonyms

EGLN4, FLJ20262, HIF-PH4

+ [11]

Introduction

Catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates HIF1A at 'Pro-402' and 'Pro-564'. May function as a cellular oxygen sensor and, under normoxic conditions, may target HIF through the hydroxylation for proteasomal degradation via the von Hippel-Lindau ubiquitination complex.

100 Clinical Results associated with P4HTM

100 Translational Medicine associated with P4HTM

0 Patents (Medical) associated with P4HTM

339

Literatures (Medical) associated with P4HTM

09 Apr 2025·Journal of Agricultural and Food Chemistry

Computer-Aided Design and Pharmacophore-Based Screening of a Diverse Combinatorial Library of Phytoselective Aryloxyacetic Acid Derivatives as HPPD Inhibitors

Article

Author: Dali, Brice L. ; Keita, Melalie ; Nanan, Landry F. ; Megnassan, Eugene ; Esmel, Akori E. ; Koblavi-Mansilla, Frederica

We investigated the inhibitory potency of aryloxyacetic acid derivatives (AADs) on 4-hydroxyphenylpyruvate dioxygenase (HPPD), a crucial enzyme target for HPPD herbicide development. Developing a wide-ranging approach combining reported structure-activity relationships (SARs with the observed inhibitory potencies of the enzyme K_i^exp), our simulations for molecular mechanics Poisson-Boltzmann (MM-PB) complexation quantitative SAR (QSAR) (computed relative Gibbs free energies of the HPPD-AADx complex formation ΔΔG_com), and three-dimensional (3D)-QSAR pharmacophore (PH4) models for screening the chemical subspace of aryloxyacetic acid derivatives (a virtual library of AADs, VL), we come out with a handful of novel AADs with promising predictive HPPD inhibitory potency and confirmed molecular dynamics (MD) conformational stability. The 3D-QSAR model revealed a correlation (pK_i^exp = a × ΔΔG_com + b) between computed data and observed inhibition ones: pK_i^exp = -0.0544 × ΔΔG_com + 6.93, R² = 0.87 for a training set (TS) of 30 AAD (AAD1-30). The subsequent 3D-QSAR pharmacophore (PH4) of HPPD inhibition by AADs confirmed the correlation (pK_i^exp = 0.863 × pK_i^pre + 7.92, R² = 0.86) between PH4-predicted pK_i^pre and the observed ones pK_i^exp. The structural information derived from these models suggested suitable substituents for building a virtual library (VL) of AAD analogues representing a chemical subspace of 79,500 compounds to be PH4-screened in search of more potent inhibitors; the best predicted K_i^pre of them reached 40 pM. Finally, the good stability of the AtHPPD-AADx complex and the flexibility of the active conformation of the inhibitor for selected top-ranked AAD analogues were checked with the help of molecular dynamics (MD, 200 ns runs). This computational study proposed a set of new predicted potent inhibitors with herbicidal effects.

01 Jan 2025·Seizure: European Journal of Epilepsy

Novel compound heterozygous P4HTM variants in a girl with developmental and epileptic encephalopathy: First case report of P4HTM variant-associated epileptic encephalopathy

Article

Author: Alomarı, Omar ; Turkyilmaz, Ayberk ; Bebek, Ogun ; Sager, Safiye Gunes

BACKGROUNDHIDEA syndrome (MIM: #618493) is a rare autosomal recessive disorder characterized by hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye anomalies. We present the case of a Turkish female with developmental and epileptic encephalopathy, highlighting a novel compound heterozygous variation in the P4HTM gene.CASE PRESENTATIONA 6-year and 11-month-old girl with early infantile epileptic encephalopathy and abnormal eye movements since the neonatal period has been presented to our clinic. Despite severe developmental delays and a happy demeanor, she showed significant hypotonia and autistic behaviors. Genetic testing revealed a novel heterozygous splice-site variant (c.436+1G>T) in intron 2 and a previously reported missense variant (c.934G>A; p.E312 K) in exon 6 of the P4HTM gene. Imaging showed cortical atrophy and thin corpus callosum, but no dystonia was observed. The patient's phenotype aligns with most reported cases of HIDEA syndrome, yet developmental epileptic encephalopathy had not been documented previously in such patients, emphasizing the uniqueness of this case.CONCLUSIONThis case is the first to associate P4HTM gene variants with epileptic encephalopathy, expanding the phenotypic spectrum of HIDEA syndrome. It underscores the importance of genetic testing and reanalysis in undiagnosed developmental and epileptic encephalopathies. The novel genetic variations identified in this study underscore the necessity for continuous genetic exploration and personalized clinical management to improve outcomes for patients with this rare but impactful syndrome. Finally, the association between developmental epileptic encephalopathy, the patient's clinical presentation, and EEG findings suggests a compelling link to the P4HTM gene.

01 Nov 2024·Biomedicine & Pharmacotherapy

Combined dapagliflozin and roxadustat effectively protected heart and kidney against cardiorenal syndrome-induced damage in rodent through activation of cell stress-Nfr2/ARE signalings and stabilizing HIF-1α

Article

Author: Yip, Hon-Kan ; Chen, Yi-Ling ; Chai, Han-Tan ; Sung, Pei-Hsun ; Chiang, John Y ; Yang, Chih-Chao ; Yue, Ya ; Cheng, Ben-Chung

BACKGROUNDThis study tested whether combined dapagliflozin (DAPA) and roxadustat (ROX) therapy was superior to a singular therapy in protecting heart and kidney functions in rats with cardiorenal syndrome (CRS).METHODS AND RESULTSAn in vitro study demonstrated that the cell survival (PI3K/Akt/mTOR)/cell stress (ERK1/2, JNK/p-38) signaling was significantly activated by combination therapy with ROX-DAPA (all p<0.001). Additionally, these two signaling pathways further significantly upregulated the hypoxia-induced factor (HIF)-1α which, in turn, significantly upregulated Nrf2/ARE (HO-1/NQO-1) and angiogenesis/cell-growth factors (EPO/SDF-1α/VEGF/FGF/IGF-2) and downregulated hypoxia-inducible factor prolyl-4-hydroxylase-1 (all p<0.001). Adult-male SD rats were categorized into Groups 1 (sham-operated control)/2 (CRS)/3 (CRS+ROX)/4 (CRS+DAPA)/5 (CRS+ROX+DAPA). By Day 60 after rodent CRS induction, the levels of BUN/creatinine and the ratio of urine protein to creatinine were lowest in Group 1, highest in Group 2, and significantly lower in Group 5 than in Groups 3 and 4; however, they were similar in the latter two groups, whereas the left-ventricular-ejection-fraction exhibited the opposite trend of creatinine among the groups (all p<0.0001). The protein expression levels of cell-survival (p-PI3K/p-Akt-p-mTOR)/cell-stress (p-JNK/p-p38/p-ERK1/2)/Nrf2-ARE (HO-1/NQO-1/SIRT1/SIRT3) signaling factors and angiogenesis factors (HIF-1α/VEGF/SDF-1α/FGF/IGF-2/EPO) significantly and progressively increased from Groups 1-5 (all p<0.0001).CONCLUSIONCombined DAPA-ROX therapy has a synergistic effect on protecting heart and kidney functions against CRS-induced damage in rodents.

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P4HTM

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