Mechanistic studies on the drug metabolism and toxicity originating from cytochromes P450

Jaladanki, Chaitanya K.; Gahlawat, Anuj; Rathod, Gajanan K.; Sandhu, Hardeep; Jahan, Kousar; Bharatam, Prasad V.

doi:10.1080/03602532.2020.1765792

Cited by 23 publications

(15 citation statements)

References 137 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cytochromes P450 (P450s) are a superfamily of heme-thiolate enzymes that catalyze a vast array of oxidative transformations related to natural products, biosynthesis, and xenobiotic metabolisms. − In addition to their natural product catalysis, P450s have found wide application in the biotechnology and pharmaceutical industries owing to their substrate promiscuity and the versatile reactions they catalyze. − Figure a shows the typical catalytic cycle of P450s for C–H hydroxylation. The cycle is initiated by the entrance of substrate, leading to the detachment of axially ligated water from heme-Fe(III) .…”

Section: Introductionmentioning

confidence: 99%

Conformational Motion of Ferredoxin Enables Efficient Electron Transfer to Heme in the Full-Length P450_TT

2021

View full text Add to dashboard Cite

Cytochrome P450 monooxygenases (P450s) are versatile biocatalysts used in natural products biosynthesis, xenobiotic metabolisms, and biotechnologies. In P450s, the electrons required for O 2 activation are supplied by NAD(P)H through stepwise electron transfers (ETs) mediated by redox partners. While much is known about the machinery of the catalytic cycle of P450s, the mechanisms of long-range ET are largely unknown. Very recently, the first crystal structure of full-length P450 TT was solved. This enables us to decipher the interdomain ET mechanism between the [2Fe−2S]-containing ferredoxin and the heme, by use of molecular dynamics simulations. In contrast to the "distal" conformation characterized in the crystal structure where the [2Fe−2S] cluster is ∼28 Å away from heme-Fe, our simulations demonstrated a "proximal" conformation of [2Fe−2S] that is ∼17 Å [and 13.7 Å edge-to-edge] away from heme-Fe, which may enable the interdomain ET. Key residues involved in ET pathways and interdomain complexation were identified, some of which have already been verified by recent mutation studies. The conformational transit of ferredoxin between "distal" and "proximal" was found to be controlled mostly by the long-range electrostatic interactions between the ferredoxin domain and the other two domains. Furthermore, our simulations show that the full-length P450 TT utilizes a flexible ET pathway that resembles either P450 Scc or P450 cam . Thus, this study provides a uniform picture of the ET process between reductase domains and heme domain.

show abstract

Section: Introductionmentioning

confidence: 99%

Conformational Motion of Ferredoxin Enables Efficient Electron Transfer to Heme in the Full-Length P450_TT

2021

View full text Add to dashboard Cite

show abstract

“…86 Several experimental and theoretical studies on epoxidation reactions c a t a l y z e d b y C Y P s w e r e r eported. 5,9,[66][67][68][69]84,85,[87][88][89]10,11,26,31,34,47,64,65 Several research groups reported the epoxidation reaction at aliphatic and alicyclic unsaturated centers using quantum chemical methods. 42,66,67,71,90 The mechanism of epoxidation reaction involves two steps, an initial C−O bond formation (via C C bond activation step) followed by ring closure.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…To mimic CYPs, the model species Cpd I was used as the model oxidant, , which is an iron (IV-oxo) radical cation with heme-porphine with SH – at the axial position. This model has been accepted by various scientific groups to provide reasonably accurate energy estimates for CYP-catalyzed metabolic studies. − For this study, the multistate reactivity (both doublet and quartet states) of Cpd I was considered. The geometry optimization of all of the intermediates on the metabolic path of TZ leading to MBI were performed using the hybrid density functional (DFT) method B3LYP, with a basis set 6-31+G(d) − (except Fe) and LanL2DZ basis set on the Fe center.…”

Section: Methodsmentioning

confidence: 99%

“…Epoxidation is one of the important metabolic reactions in drug molecules containing unsaturated functional units such as alkene − and cycloalkene, , thiophene, ,,− furan, ,, thiazole, ,,,,, and phenyl . Several experimental and theoretical studies on epoxidation reactions catalyzed by CYPs were reported. ,,− ,,,− ,,,,,,,, Several research groups reported the epoxidation reaction at aliphatic and alicyclic unsaturated centers using quantum chemical methods. ,,,, The mechanism of epoxidation reaction involves two steps, an initial C–O bond formation (via CC bond activation step) followed by ring closure. In our previous studies, we have elucidated several vital features involved in the epoxidation process of furan and thiophene rings using Cpd I as an oxidant and also investigated the MBI of the epoxide metabolites.…”

Section: Quantum Chemical Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Reactive Metabolites from Thiazole-Containing Drugs: Quantum Chemical Insights into Biotransformation and Toxicity

Jaladanki

Khatun

Gohlke

et al. 2021

Chem. Res. Toxicol.

Self Cite

View full text Add to dashboard Cite

Drugs containing thiazole and aminothiazole groups are known to generate reactive metabolites (RMs) catalyzed by cytochrome P450s (CYPs). These RMs can covalently modify essential cellular macromolecules and lead to toxicity and induce idiosyncratic adverse drug reactions. Molecular docking and quantum chemical hybrid DFT study were carried out to explore the molecular mechanisms involved in the biotransformation of thiazole (TZ) and aminothiazole (ATZ) groups leading to RM epoxide, S-oxide, N-oxide, and oxaziridine. The energy barrier required for the epoxidation is 13.63 kcal/mol, that is lower than that of S-oxidation, N-oxidation, and oxaziridine formation (14.56, 17.90, and 20.20, kcal/mol respectively). The presence of the amino group in ATZ further facilitates all the metabolic pathways, for example, the barrier for the epoxidation reaction is reduced by ∼2.5 kcal/mol. Some of the RMs/their isomers are highly electrophilic and tend to form covalent bonds with nucleophilic amino acids, finally leading to the formation of metabolic intermediate complexes (MICs). The energy profiles of these competitive pathways have also been explored.

show abstract

“…Because there is no crystal structure of CyaH available, the computational model system was set up with an oxo-iron(IV)(porphyrin +· ) complex, Fe 4+ O 2– (C 20 N 4 H 12 ) − (SH) − , as the model of compound I (CpdI) of the P450 CyaH. − The nonpolar enzymatic environment was mimicked with the conductor-like polarizable continuum model (CPCM, chlorobenzene (ε = 5.62) was employed as the solvent) in the self-consistent reaction field (SCRF) calculations. The coordinate of the reagent cyanogramide D (Scheme d) was obtained from the Cambridge Crystallographic Data Center with the deposition number CCDC-1956558 .…”

Section: Computation Methodologymentioning

confidence: 99%

Theoretical Investigation on the Elusive Reaction Mechanism of Spirooxindole Formation Mediated by Cytochrome P450s: A Nascent Feasible Charge-Shift C–O Bond Makes a Difference

et al. 2021

View full text Add to dashboard Cite

Spirooxindoles are pivotal biofunctional groups widely distributed in natural products and clinic drugs. However, construction of such subtle chiral skeletons is a long-standing challenge to both organic and bioengineering scientists. The knowledge of enzymatic spirooxindole formation in nature may inspire rational design of new catalysts. To this end, we presented a theoretical investigation on the elusive mechanism of the spiro-ring formation at the 3-position of oxindole mediated by cytochrome P450 enzymes (P450). Our calculated results demonstrated that the electrophilic attack of CpdI, the active species of P450, to the substrate, shows regioselectivity, i.e., the attack at the C9 position forms a tetrahedral intermediate involving an unusual feasible charge-shift C9 δ+ −O δ− bond, while the attack at the C1 position forms an epoxide intermediate. The predominant route is the first route with the charge-shift bonding intermediate due to holding a relatively lower barrier by >5 kcal mol −1 than the epoxide route, which fits the experimental observations. Such a delocalized chargeshift bond facilitates the formation of a spiro-ring mainly through elongation of the C1−C9 bond to eliminate the aromatization of the tricyclic beta-carboline. Our theoretical results shed profound mechanistic insights for the first time into the elusive spirooxindole formation mediated by P450s.

show abstract

Mechanistic studies on the drug metabolism and toxicity originating from cytochromes P450

Cited by 23 publications

References 137 publications

Conformational Motion of Ferredoxin Enables Efficient Electron Transfer to Heme in the Full-Length P450_TT

Conformational Motion of Ferredoxin Enables Efficient Electron Transfer to Heme in the Full-Length P450_TT

Reactive Metabolites from Thiazole-Containing Drugs: Quantum Chemical Insights into Biotransformation and Toxicity

Theoretical Investigation on the Elusive Reaction Mechanism of Spirooxindole Formation Mediated by Cytochrome P450s: A Nascent Feasible Charge-Shift C–O Bond Makes a Difference

Contact Info

Product

Resources

About

Mechanistic studies on the drug metabolism and toxicity originating from cytochromes P450

Cited by 23 publications

References 137 publications

Conformational Motion of Ferredoxin Enables Efficient Electron Transfer to Heme in the Full-Length P450TT

Conformational Motion of Ferredoxin Enables Efficient Electron Transfer to Heme in the Full-Length P450TT

Reactive Metabolites from Thiazole-Containing Drugs: Quantum Chemical Insights into Biotransformation and Toxicity

Theoretical Investigation on the Elusive Reaction Mechanism of Spirooxindole Formation Mediated by Cytochrome P450s: A Nascent Feasible Charge-Shift C–O Bond Makes a Difference

Contact Info

Product

Resources

About

Conformational Motion of Ferredoxin Enables Efficient Electron Transfer to Heme in the Full-Length P450_TT

Conformational Motion of Ferredoxin Enables Efficient Electron Transfer to Heme in the Full-Length P450_TT