Catalytic modulation of human cytochromes P450 17A1 and P450 11B2 by phospholipid

Peng, Hwei Ming; Barlow, Chase; Auchus, Richard J.

doi:10.1016/j.jsbmb.2018.03.003

Cited by 11 publications

(16 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…When started from 18-OH corticosterone added in solution, this reaction was very slow. Our result contrasts with reports from other laboratories that this reaction does not occur at all (11,12,21). The enzyme concentration, substrate concentration, and reaction time all had to be increased significantly for this reaction to be observed (Fig.…”

Section: P450 11b2 Kinetics Of Aldosterone Synthesiscontrasting

confidence: 99%

“…Studies with human P450 11B2 from other laboratories have indicated that the enzyme catalyzes its reactions with varied reaction rates and specificities (11,12,21). These studies each focused on different aspects of human P450 11B2 reactivity.…”

mentioning

confidence: 99%

“…testosterone and progesterone) but did not test substrate specificity or binding. Peng et al (21) investigated the influence of the stabilizing phospholipid utilized in assays on catalysis. Strushkevich et al and Martin et al (11,22) have both reported crystal structures of human P450 11B2 (Protein Data Bank codes 4DVQ, 4FDH, and 4ZGX).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Human cytochrome P450 11B2 produces aldosterone by a processive mechanism due to the lactol form of the intermediate 18-hydroxycorticosterone

Reddish

Guengerich

2019

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Ruma Banerjee Human cytochrome P450 (P450) 11B2 catalyzes the formation of aldosterone, the major endogenous human mineralocorticoid. Aldosterone is important for the regulation of electrolyte homeostasis. Mutations and overexpression of P450 11B2 (also known as aldosterone synthase) can lead to hypertension, congestive heart failure, and diabetic nephropathy. The enzyme is therefore a target for drug development to manage these various disorders. P450 11B2 catalyzes aldosterone formation from 11-deoxycorticosterone through three distinct oxidation steps. It is currently unknown to which degree these reactions happen in sequence without the intermediate products dissociating from the enzyme (i.e. processively) or whether these reactions happen solely distributively, in which the intermediate products must first dissociate and then rebind to the enzyme before subsequent oxidation. We present here a comprehensive investigation of processivity in P450 11B2-catalyzed reactions using steadystate, pre-steady-state, pulse-chase, equilibrium-binding titrations, and stopped-flow binding studies. We utilized the data obtained to develop a kinetic model for P450 11B2 and tested this model by enzyme kinetics simulations. We found that although aldosterone is produced processively, the enzyme preferentially utilizes a distributive mechanism that ends with the production of 18-OH corticosterone. This seemingly contradictory observation could be resolved by considering the ability of the intermediate product 18-OH corticosterone to exist as a lactol form, with the equilibrium favoring the ring-closed lactol configuration. In summary, our refined model for P450 11B2 catalysis indicates isomerization of the intermediate to a lactol can explain why P450 11B2 must produce aldosterone through a processive mechanism despite favoring a distributive mechanism. This work was supported by National Institutes of Health Grants R01 GM118122 (to F. P. G.) and T32 ES007028 (to F. P. G. for support of M. J. R.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This article contains Figs. S1-S6 and Tables S1 and S2.

show abstract

Section: P450 11b2 Kinetics Of Aldosterone Synthesiscontrasting

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Human cytochrome P450 11B2 produces aldosterone by a processive mechanism due to the lactol form of the intermediate 18-hydroxycorticosterone

Reddish

Guengerich

2019

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The oxygenations of inert organic substrates by CYP450 would destroy nearby amino acids, as these reactions involve multiply bonded iron-oxos [29]. Peng et al [30] found that tryptophan was soluble to CYP450 and Phosphatidylethanolamine (PE) decreased solvent accessibility for tryptophan in CYP450. Besides, previous studies have reported interactions of natural medicinal ingredients interactions can regulate tryptophan metabolism [31].…”

Section: Discussionmentioning

confidence: 99%

Role of tryptophan-metabolizing microbiota in mice diarrhea caused by Folium sennae extracts

Zhang

Shao

et al. 2020

BMC Microbiol

View full text Add to dashboard Cite

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. Seven 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

“…Peng et al [35] found that tryptophan was soluble to CYP450 and Phosphatidylethanolamine (PE) decreased solvent accessibility for tryptophan in CYP450. Besides, previous studies have reported interactions of natural medicinal ingredients interactions can regulate tryptophan metabolism [36].…”

Section: Discussionmentioning

confidence: 99%

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 (1) Background: Although reports have provided evidence that diarrhea caused by Folium sennae can result in intestinal flora 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. (2) Methods: The intestinal contents of 2 groups of mice, intervened with Folium sennae extracts and distilled water respectively, were collected and its DNA was extracted for high-throughput sequencing analysis. The active compounds of Folium sennae were filtrated, and their diarrhea-related targets and metabolic pathways were predicted. Virtual Metabolic Human (VMH) was utilized to simulated metabolic function of bacteria associated with Folium sennae -induced diarrhea to verified the metabolic pathways of the drug. (3) 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 separate from control group. Combining PPI network analysis, cytochrome P450 (CYP) enzymes metabolism was the main signaling pathway of diarrhea caused by Folium sennae. Moreover, the abundance of 10 bacterial flora communities had statistical significance with Folium sennae intervention: the abundance of Paraprevotella, streptococcus, Epulopiscium, Sutterella and Mycoplasma were increased significantly; and the abundance of Adlercreutzia, Lactobacillus, Dehalobacterium, Dorea and Oscillospira were reduced significantly. 7 of the 10 intestinal flora 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. (4) Conclusions: Folium sennae targeted cytochrome P450 (CYP) 3A4 to alterd intestinal bacterial characteristic and interven the tryptophan metabolism of intestinal microflora, such as Streptococcus, Sutterella and Dorea, which could be the intestinal microecological mechanism of diarrhea caused by Folium sennae extracts.

show abstract

Catalytic modulation of human cytochromes P450 17A1 and P450 11B2 by phospholipid

Cited by 11 publications

References 60 publications

Human cytochrome P450 11B2 produces aldosterone by a processive mechanism due to the lactol form of the intermediate 18-hydroxycorticosterone

Human cytochrome P450 11B2 produces aldosterone by a processive mechanism due to the lactol form of the intermediate 18-hydroxycorticosterone

Role of tryptophan-metabolizing microbiota in mice diarrhea caused by Folium sennae extracts

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

Contact Info

Product

Resources

About