Computational identification and binding analysis of orphan human cytochrome P450 4X1 enzyme with substrates

Kumar, Suresh

doi:10.1186/s13104-015-0976-4

Cited by 17 publications

(14 citation statements)

References 40 publications

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“…CYP4X1 is overexpressed in breast cancer and shows correlations with tumor grade (Murray et al, 2010). Computational identification and binding analysis of orphan human cytochrome P450 4X1 enzyme with substrates provide useful information on structure-based drug design (Kumar, 2015). However, the effects of CYP4X1 on glioma angiogenesis and its mechanism of action have not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

CYP4X1 Inhibition by Flavonoid CH625 Normalizes Glioma Vasculature through Reprogramming TAMs via CB2 and EGFR-STAT3 Axis

Wang

Chen

et al. 2018

J Pharmacol Exp Ther

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Tumor-associated macrophages (TAMs) are pivotal effector cells in angiogenesis. Here, we tested whether CYP4X1 inhibition in TAMs by flavonoid CH625 prolongs survival and normalizes glioma vasculature. CH625 was selected against the CYP4X1 3D model by virtual screening and showed inhibitory activity on the CYP4X1 catalytic production of 14,15-EET-EA in the M2-polarized human peripheral blood mononuclear cells (IC = 16.5 M). CH625 improved survival and reduced tumor burden in the C6 and GL261 glioma intracranial and subcutaneous model. In addition, CH625 normalized vasculature (evidenced by a decrease in microvessel density and HIF-1 expression and an increase in tumor perfusion, pericyte coverage, and efficacy of temozolomide therapy) accompanied with the decreased secretion of 14,15-EET-EA, VEGF, and TGF- in the TAMs. Furthermore, CH625 attenuated vascular abnormalization and immunosuppression induced by coimplantation of GL261 cells with CYP4X1 macrophages. In vitro TAM polarization away from the M2 phenotype by CH625 inhibited proliferation and migration of endothelial cells, enhanced pericyte migration and T cell proliferation, and decreased VEGF and TGF- production accompanied with the downregulation of CB2 and EGFR-dependent downstream STAT3 expression. These effects were reversed by overexpression of CYP4X1 and STAT3 or exogenous addition of 14,15-EET-EA, VEGF, TGF-, EGF, and CB2 inhibitor AM630. These results suggest that CYP4X1 inhibition in TAMs by CH625 prolongs survival and normalizes tumor vasculature in glioma via CB2 and EGFR-STAT3 axis and may serve as a novel therapeutic strategy for human glioma.

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Section: Introductionmentioning

confidence: 99%

CYP4X1 Inhibition by Flavonoid CH625 Normalizes Glioma Vasculature through Reprogramming TAMs via CB2 and EGFR-STAT3 Axis

Wang

Chen

et al. 2018

J Pharmacol Exp Ther

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“…Although its function is poorly known,20 there are mounting evidences that arachidonic acid and its derivative anandamide act as possible substrates of CYP4X1 21. The oxidation of the endocannabinoid anandamide, by the action of CYP4X1 enzyme, produces epoxyeicosatrienoic ethanolamide,22 an endogenous brain lipid signalling molecule involved in anti-inflammatory, antiapoptotic and antioxidant activities23 that might theoretically influence onset of prion diseases.…”

Section: Discussionmentioning

confidence: 99%

Age at onset of genetic (E200K) and sporadic Creutzfeldt-Jakob diseases is modulated by the CYP4X1 gene

Poleggi

Lee

Capellari

et al. 2018

J Neurol Neurosurg Psychiatry

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We identified two single nucleotide polymorphisms on the gene locus as candidate disease modifiers in patients with E200K CJD of the cluster area and confirmed this finding in 32 patients with E200K CJD from non-cluster areas and 259 patients with sporadic CJD. Our results indicate that the gene modulates the onset of disease in patients with E200K genetic and sporadic CJD. This finding improves our understanding on the pathogenesis of CJD, suggests new targets for developing novel therapeutic strategies and might be useful for the stratification of patients in future preventive treatment trials.

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“…Modeling of CYP4F22 pathogenic variants was performed using the template created by Kumar [21] based on the comparative modeling method. The CYP4F22 model was used to compare the mutant protein with the wild type.…”

Section: Computational Analysesmentioning

confidence: 99%

Novel CYP4F22 mutations associated with autosomal recessive congenital ichthyosis (ARCI). Study of the CYP4F22 c.1303C>T founder mutation

et al. 2020

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Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis (ARCI). However, less than 10% of all ARCI patients carry a mutation in CYP4F22. In order to identify the molecular basis of ARCI among our patients (a cohort of ninety-two Spanish individuals) we performed a mutational analysis using direct Sanger sequencing in combination with a multigene targeted NGS panel. From these, eight ARCI families (three of them with Moroccan origin) were found to carry five different CYP4F22 mutations, of which two were novel. Computational analysis showed that the mutations found were present in highly conserved residues of the protein and may affect its structure and function. Seven of the eight families were carriers of a highly recurrent CYP4F22 variant, c.1303C>T; p.(His435Tyr). A 12Mb haplotype was reconstructed in all c.1303C>T carriers by genotyping ten microsatellite markers flanking the CYP4F22 gene. A prevalent 2.52Mb haplotype was observed among Spanish carrier patients suggesting a recent common ancestor. A smaller core haplotype of 1.2Mb was shared by Spanish and Moroccan families. Different approaches were applied to estimate the time to the most recent common ancestor (TMRCA) of carrier patients with Spanish origin. The age of the mutation was calculated by using DMLE and BDMC2. The algorithms estimated that the c.1303C>T variant arose approximately 2925 to 4925 years ago, while Spanish carrier families derived from a common ancestor who lived in the XIII century. The present study reports five CYP4F22 mutations, two of them novel, increasing the number of CYP4F22 mutations currently listed. Additionally, our results suggest that the recurrent c.1303C>T change has a founder effect in Spanish population and c.1303C>T carrier families originated from a single ancestor with probable African ancestry.

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Computational identification and binding analysis of orphan human cytochrome P450 4X1 enzyme with substrates

Cited by 17 publications

References 40 publications

CYP4X1 Inhibition by Flavonoid CH625 Normalizes Glioma Vasculature through Reprogramming TAMs via CB2 and EGFR-STAT3 Axis

CYP4X1 Inhibition by Flavonoid CH625 Normalizes Glioma Vasculature through Reprogramming TAMs via CB2 and EGFR-STAT3 Axis

Age at onset of genetic (E200K) and sporadic Creutzfeldt-Jakob diseases is modulated by the CYP4X1 gene

Novel CYP4F22 mutations associated with autosomal recessive congenital ichthyosis (ARCI). Study of the CYP4F22 c.1303C>T founder mutation

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