Measuring the structural impact of mutations on cytochrome P450 21A2, the major steroid 21-hydroxylase related to congenital adrenal hyperplasia

Cruz, Jorddy Neves; Costa, Kauê Santana da; Carvalho, Tarcísio André Amorim de; Alencar, Nelson

doi:10.1080/07391102.2019.1607560

Cited by 36 publications

(22 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies have suggested that the amino acid tryptophan played a key role in the agonistic binding of an inducer of CYP450 by activation of the constitutive androstane receptor and confirmed the structural impact of mutations of tryptophan on CYP450 [19,20]. Therefore, we hypothesized that diarrhea caused by Folium sennae could affect tryptophan metabolism by diversity disorder of intestinal microbiota.…”

Section: Kyoto Encyclopedia Of Genes and Genomes (Kegg) Metabolic Sigsupporting

confidence: 62%

Role of Tryptophan-Metabolizing Microbiota On Diarrhea Mice Caused by Folium sennae Extracts

Zhang

Shao

et al. 2020

Preprint

View full text Add to dashboard Cite

Abstract Background: Although reports have provided evidence that diarrhea caused by Folium sennae can result in intestinal microbiota diversity disorder, the intestinal bacterial characteristic and specific mechanism are still unknown. The objective of our study was to investigate the mechanism of diarrhea caused by Folium sennae, which was associated with intestinal bacterial characteristic reshaping and metabolic abnormality. Results: For the intervention of Folium sennae extracts, Chao1 index and Shannon index were statistical decreased. The Beta diversity clusters of mice interfered by Folium sennae extracts were distinctly separated from control group. Combining PPI network analysis, cytochrome P450 enzymes metabolism was the main signaling pathway of diarrhea caused by Folium sennae. Moreover, 10 bacterial flora communities had statistical significant difference with Folium sennae intervention: the abundance of Paraprevotella, Streptococcus, Epulopiscium, Sutterella and Mycoplasma increased significantly; and the abundance of Adlercreutzia, Lactobacillus, Dehalobacterium, Dorea and Oscillospira reduced significantly. 7 of the 10 intestinal microbiota communities were related to the synthesis of tryptophan derivatives, which affected the transformation of aminotryptophan into L-tryptophan, leading to abnormal tryptophan metabolism in the host. Conclusions: Folium sennae targeted cytochrome P450 3A4 to alter intestinal bacterial characteristic and intervene the tryptophan metabolism of intestinal microbiota, such as Streptococcus, Sutterella and Dorea, which could be the intestinal microecological mechanism of diarrhea caused by Folium sennae extracts.

show abstract

Section: Kyoto Encyclopedia Of Genes and Genomes (Kegg) Metabolic Sigsupporting

confidence: 62%

Role of Tryptophan-Metabolizing Microbiota On Diarrhea Mice Caused by Folium sennae Extracts

Zhang

Shao

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Molecular characterization of the CYP21A2 mutations and their impact upon the structure of the 21-hydroxylase enzyme influence the phenotype and the severity of the disease [7,31,39,[42][43][44][45]. The human crystal structure model of the 21-hydroxylase enzyme has been unraveled recently and the impact of numerous different mutations has been explored, explaining the SW, SV, and NC phenotypes [31,46,47]. The CYP21A2 molecule resides in the membranes of endoplasmatic reticulum.…”

Section: Molecular Structure Of P30l Mutation and Functional Analysismentioning

confidence: 99%

“…There are two binding sites for 17hydroxyprogesterone (17OHP), proximal and distal, both in the proximity of the heme moiety. Hydrogen bonds of residues connected to the heme, as well as the electron transfer are crucial for the proper function of the enzyme [31,33,47]. Mutations which cause irregular clashes with heme of the enzyme, disruption of hydrogen bonds, substrate binding, mutations causing impaired secondary structure or structural stability, all abrogate the enzyme function and cause the severe SW form of the disease [31,46,[48][49][50].…”

Section: Molecular Structure Of P30l Mutation and Functional Analysismentioning

confidence: 99%

Clinical outcomes and characteristics of P30L mutations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

2020

View full text Add to dashboard Cite

Despite numerous studies in the field of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, some clinical variability of the presentation and discrepancies in the genotype/phenotype correlation are still unexplained. Some, but not all, discordant phenotypes caused by mutations with known enzyme activity have been explained by in silico structural changes in the 21-hydroxylase protein. The incidence of P30L mutation varies in different populations and is most frequently found in several Central and Southeast European countries as well as Mexico. Patients carrying P30L mutation present predominantly as non-classical CAH; however, simple virilizing forms are found in up to 50% of patients. Taking into consideration the residual 21-hydroxulase activity present with P30L mutation this is unexpected. Different mechanisms for increased androgenization in patients carrying P30L mutation have been proposed including influence of different residues, accompanying promotor allele variability or mutations, and individual androgene sensitivity. Early diagnosis of patients who would present with SV is important in order to improve outcome. Outcome studies of CAH have confirmed the uniqueness of this mutation such as difficulties in phenotype classification, different fertility, growth, and psychologic issues in comparison with other genotypes. Additional studies of P30L mutation are warranted.

show abstract

“…The MM/GBSA method was used to determine the energy contribution of each protein residue, thus, rendering it possible to determine which residues are most important for the ligand interaction with the active site. The interaction energy of residues with the inhibitor can be described from four terms: van der Waals contribution (ΔE vdW ), electrostatic contribution (ΔE ele ), polar solvation contribution (ΔG pol ), and nonpolar solvation contribution (ΔG nonpol ), according to the equation [ 25 , 122 , 123 ]: ΔG ligand-residue = ΔE vdW + ΔE ele + ΔG pol + ΔG nonpol …”

Section: Methodsmentioning

confidence: 99%

Identification of New Rofecoxib-Based Cyclooxygenase-2 Inhibitors: A Bioinformatics Approach

et al. 2020

Self Cite

View full text Add to dashboard Cite

The cyclooxygenase-2 receptor is a therapeutic target for planning potential drugs with anti-inflammatory activity. The selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib was selected as a pivot molecule to perform virtual ligand-based screening from six commercial databases. We performed the search for similarly shaped Rapid Overlay of Chemical Structures (ROCS) and electrostatic (EON) compounds. After, we used pharmacokinetic and toxicological parameters to determine the best potential compounds, obtained through the softwares QikProp and Derek, respectively. Then, the compounds proceeded to the molecular anchorage study, which showed promising results of binding affinity with the hCOX-2 receptor: LMQC72 (∆G = −11.0 kcal/mol), LMQC36 (∆G = −10.6 kcal/mol), and LMQC50 (∆G = −10.2 kcal/mol). LMQC72 and LMQC36 showed higher binding affinity compared to rofecoxib (∆G = −10.4 kcal/mol). Finally, molecular dynamics (MD) simulations were used to evaluate the interaction of the compounds with the target hCOX-2 during 150 ns. In all MD simulation trajectories, the ligands remained interacting with the protein until the end of the simulation. The compounds were also complexing with hCOX-2 favorably. The compounds obtained the following affinity energy values: rofecoxib: ΔGbind = −45.31 kcal/mol; LMQC72: ΔGbind = −38.58 kcal/mol; LMQC36: ΔGbind = −36.10 kcal/mol; and LMQC50: ΔGbind = −39.40 kcal/mol. The selected LMQC72, LMQC50, and LMQC36 structures showed satisfactory pharmacokinetic results related to absorption and distribution. The toxicological predictions of these compounds did not display alerts for possible toxic groups and lower risk of cardiotoxicity compared to rofecoxib. Therefore, future in vitro and in vivo studies are needed to confirm the anti-inflammatory potential of the compounds selected here with bioinformatics approaches based on rofecoxib ligand.

show abstract

Measuring the structural impact of mutations on cytochrome P450 21A2, the major steroid 21-hydroxylase related to congenital adrenal hyperplasia

Cited by 36 publications

References 45 publications

Role of Tryptophan-Metabolizing Microbiota On Diarrhea Mice Caused by Folium sennae Extracts

Role of Tryptophan-Metabolizing Microbiota On Diarrhea Mice Caused by Folium sennae Extracts

Clinical outcomes and characteristics of P30L mutations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Identification of New Rofecoxib-Based Cyclooxygenase-2 Inhibitors: A Bioinformatics Approach

Contact Info

Product

Resources

About