F/G Region Rigidity is Inversely Correlated to Substrate Promiscuity of Human CYP Isoforms Involved in Metabolism

2021 ◽  
Author(s):  
Daniel Becker ◽  
Prasad V. Bharatam ◽  
Holger Gohlke
Keyword(s):  
Substrate Promiscuity ◽  
Cyp Isoforms

Probing the Substrate Promiscuity of Isopentenyl Phosphate Kinase as a Platform for Hemiterpene Analogue Production

2019 ◽  
Author(s):  
Sean Lund ◽  
Taylor Courtney ◽  
Gavin Williams
Keyword(s):  
Synthetic Biology ◽  
Building Blocks ◽  
Isoprenoid Biosynthesis ◽  
Thermoplasma Acidophilum ◽  
Substrate Promiscuity ◽  
Enzymatic Pathways ◽  
First Time ◽  
Rate Limiting ◽  
Alcohol Dependent ◽  
Isopentenyl Phosphate

Isoprenoids are a large class of natural products with wide-ranging applications. Synthetic biology approaches to the manufacture of isoprenoids and their new-to-nature derivatives are limited due to the provision in Nature of just two hemiterpene building blocks for isoprenoid biosynthesis. To address this limitation, artificial chemo-enzymatic pathways such as the alcohol-dependent hemiterpene pathway (ADH) serve to leverage consecutive kinases to convert exogenous alcohols to pyrophosphates that could be coupled to downstream isoprenoid biosynthesis. To be successful, each kinase in this pathway should be permissive of a broad range of substrates. For the first time, we have probed the promiscuity of the second enzyme in the ADH pathway, isopentenyl phosphate kinase from Thermoplasma acidophilum, towards a broad range of acceptor monophosphates. Subsequently, we evaluate the suitability of this enzyme to provide non-natural pyrophosphates and provide a critical first step in characterizing the rate limiting steps in the artificial ADH pathway.<br>

Methyl-parathion bioactivation in the male reproductive tract: From mRNA to protein expression of involved CYP isoforms

2009 ◽  
Vol 189 ◽  
pp. S145
Author(s):  
Betzabet Quintanilla-Vega ◽  
Patricia Espíritu-Gordillo ◽  
Yuliana Palacios-Gil ◽  
Margarita Guaderrama-Díaz ◽  
María de Jesús Solís-Heredia ◽  
...  
Keyword(s):  
Protein Expression ◽  
Methyl Parathion ◽  
Reproductive Tract ◽  
Male Reproductive Tract ◽  
Cyp Isoforms

scholarly journals Cytochrome P450-dependent biotransformation capacities in embryonic, juvenile and adult stages of zebrafish (Danio rerio)—a state-of-the-art review

2021 ◽  
Author(s):  
Ann-Kathrin Loerracher ◽  
Thomas Braunbeck
Keyword(s):  
Cytochrome P450 ◽  
Phase I ◽  
Mrna Expression ◽  
Danio Rerio ◽  
Developmental Stages ◽  
State Of The Art ◽  
Adverse Outcome Pathway ◽  
Zebrafish Embryos ◽  
Toxicological Studies ◽  
Cyp Isoforms

AbstractGiven the strong trend to implement zebrafish (Danio rerio) embryos as translational model not only in ecotoxicological, but also toxicological testing strategies, there is an increasing need for a better understanding of their capacity for xenobiotic biotransformation. With respect to the extrapolation of toxicological data from zebrafish embryos to other life stages or even other organisms, qualitative and quantitative differences in biotransformation pathways, above all in cytochrome P450-dependent (CYP) phase I biotransformation, may lead to over- or underestimation of the hazard and risk certain xenobiotic compounds may pose to later developmental stages or other species. This review provides a comprehensive state-of-the-art overview of the scientific knowledge on the development of the CYP1-4 families and corresponding phase I biotransformation and bioactivation capacities in zebrafish. A total of 68 publications dealing with spatiotemporal CYP mRNA expression patterns, activities towards mammalian CYP-probe substrates, bioactivation and detoxification activities, as well as metabolite profiling were analyzed and included in this review. The main results allow for the following conclusions: (1) Extensive work has been done to document mRNA expression of CYP isoforms from earliest embryonic stages of zebrafish, but juvenile and adult zebrafish have been largely neglected so far. (2) There is insufficient understanding of how sex- and developmental stage-related differences in expression levels of certain CYP isoforms may impact biotransformation and bioactivation capacities in the respective sexes and in different developmental stages of zebrafish. (3) Albeit qualitatively often identical, many studies revealed quantitative differences in metabolic activities of zebrafish embryos and later developmental stages. However, the actual relevance of age-related differences on the outcome of toxicological studies still needs to be clarified. (4) With respect to current remaining gaps, there is still an urgent need for further studies systematically assessing metabolic profiles and capacities of CYP isoforms in zebrafish. Given the increasing importance of Adverse Outcome Pathway (AOP) concepts, an improved understanding of CYP capacities appears essential for the interpretation and outcome of (eco)toxicological studies.

scholarly journals Structural Insights into the Substrate Promiscuity of a Laboratory-Evolved Peroxygenase

2018 ◽  
Vol 13 (12) ◽  
pp. 3259-3268 ◽  
Author(s):  
Mercedes Ramirez-Escudero ◽  
Patricia Molina-Espeja ◽  
Patricia Gomez de Santos ◽  
Martin Hofrichter ◽  
Julia Sanz-Aparicio ◽  
...  
Keyword(s):  
Substrate Promiscuity ◽  
Structural Insights

scholarly journals The metabolism of amiodarone by various CYP isoenzymes of human and rat, and the inhibitory influence of ketoconazole

2008 ◽  
Vol 11 (1) ◽  
pp. 147 ◽  
Author(s):  
Marwa E. Elsherbiny ◽  
Ayman O.S. El-Kadi ◽  
Dion R. Brocks
Keyword(s):  
Cytochrome P450 ◽  
Inhibitory Effect ◽  
Intrinsic Clearance ◽  
Significant Inhibition ◽  
Inhibitory Influence ◽  
Relative Kinetic ◽  
Cyp Isoforms ◽  
High Concentrations ◽  
In Vivo Administration

PURPOSE. To evaluate the metabolism of amiodarone (AM) to desethylamiodarone (DEA) by selected human and rat cytochrome P450, and the inhibitory effect of ketoconazole (KTZ). METHODS. Some important CYP isoenzymes (rat CYP1A1, 1A2, 2C6, 2C11, 2D1, 2D2, and 3A1 and human CYP1A1, 1A2, 2D6 and 3A4) were spiked with various concentrations of AM to determine the relative kinetic parameters for formation of DEA in the presence and absence of various concentrations of KTZ. RESULTS. The formation of DEA was observed when AM was exposed to each of the CYP tested, although the rates were varied. Human CYP1A1 followed by 3A4 had the highest intrinsic clearance (CLint) for DEA formation whereas in rat, CYP2D1 followed by CYP2C11 had the highest CLint. Human and rat CYP1A2 seemed to have the lowest CLint. At high concentrations of AM and KTZ, near those expected in vivo, significant inhibition of all isoforms except for rat CYP1A2 was observed. At lower concentration ranges of both drugs, the inhibitory constant was determined. At these levels, KTZ was found to potently inhibit human CYP1A1 and 3A4 and rat 2D2 and 1A1. CONCLUSION. Human CYP1A1 and 3A4 and rat CYP2D1 and 2C11 were most efficient in converting AM to DEA. For DEA formation, the in vivo administration of KTZ could inhibit other CYP isoforms besides CYP3A in human and rat.

scholarly journals Selective Inhibition of Bakuchicin Isolated fromPsoralea corylifoliaon CYP1A in Human Liver Microsomes

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Sun Joo Kim ◽  
Heung Chan Oh ◽  
Youn-Chul Kim ◽  
Gil-Saeng Jeong ◽  
Sangkyu Lee
Keyword(s):  
Human Liver ◽  
Competitive Inhibition ◽  
Biological Activities ◽  
Biological Effects ◽  
Liver Microsomes ◽  
Selective Inhibition ◽  
Human Liver Microsomes ◽  
Inhibition Mechanism ◽  
Inhibitory Effects ◽  
Cyp Isoforms

Bakuchicin is a furanocoumarin isolated fromPsoralea corylifoliaand shows several biological activities. Although there have been studies on the biological effects of bakuchicin, its modulation potency of CYP activities has not been previously investigated. Here, we investigated the inhibitory effects of bakuchicin on the activities of CYP isoforms by using a cocktail of probe substrates in pooled human liver microsomes (HLMs) and human recombinantcDNA-expressedCYP. Bakuchicin strongly inhibited CYP1A-mediated phenacetinO-deethylation with an IC50value of 0.43 μM in HLMs. It was confirmed by human recombinantcDNA-expressedCYP1A1 and CYP1A2 with aKivalue of 0.11 μM and 0.32 μM, respectively. A Lineweaver-Burk plot indicated that the inhibition mechanism of bakuchicin was competitive inhibition. Overall, this is the first study to investigate the potential CYP1A1 and CYP1A2 inhibition associated with bakuchicin and to report its competitive inhibitory effects on HLMs.

scholarly journals Extreme Substrate Promiscuity of theNeisseriaOligosaccharyl Transferase Involved in ProteinO-Glycosylation

2008 ◽  
Vol 283 (50) ◽  
pp. 34596-34604 ◽  
Author(s):  
Amirreza Faridmoayer ◽  
Messele A. Fentabil ◽  
M. Florencia Haurat ◽  
Wen Yi ◽  
Robert Woodward ◽  
...  
Keyword(s):  
Substrate Promiscuity

scholarly journals Functional Characterization and Substrate Promiscuity of UGT71 Glycosyltransferases from Strawberry (Fragaria × ananassa)

2015 ◽  
Vol 56 (12) ◽  
pp. 2478-2493 ◽  
Author(s):  
Chuankui Song ◽  
Le Gu ◽  
Jingyi Liu ◽  
Shuai Zhao ◽  
Xiaotong Hong ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Fragaria Ananassa ◽  
Substrate Promiscuity
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