Influence of protein–protein interactions on the cellular localization of cytochrome P450

Szczesna-Skorupa, Elzbieta; Kemper, Byron

doi:10.1517/17425255.4.2.123

Cited by 17 publications

(16 citation statements)

References 87 publications

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“…As soon as the hydrophobic residues have passed through the ER membrane, the translocation halts and the remainder of the protein is translated at the cytoplasmic side of the ER membrane [49, 52–54]. Once translocation is stopped, the signal sequence moves laterally out of the sec61 pore into the lipid bilayer [55]. …”

Section: Bimodal Targeting Of Cyps To the Er And Mitochondriamentioning

confidence: 99%

Bimodal targeting of microsomal cytochrome P450s to mitochondria: implications in drug metabolism and toxicity

Sangar

Bansal

Avadhani

2010

Expert Opinion on Drug Metabolism & Toxicology

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Importance of the field-Microsomal cytochrome P450s are critical for drug metabolism and toxicity. Recent studies show that these CYPs are also present in the mitochondrial compartment of human and rodent tissues. Mitochondrial CYP1A1 and 2E1 show both overlapping and distinct metabolic activities compared to microsomal forms. Mitochondrial CYP2E1 also induces oxidative stress. The mechanisms of mitochondria targeting of CYPs and their role in drug metabolism and toxicity are important factors to consider while determining the drug dose and in drug development.Areas covered in this review-This review highlights the mechanisms of bimodal targeting of CYP1A1, 2B1, 2E1 and 2D6 to mitochondria and microsomes. The review also discusses differences in structure and function of mitochondrial CYPs.What the readers will gain-A comprehensive review of the literature on drug metabolism in the mitochondrial compartment, and their potential for inducing mitochondrial dysfunction.Take home message-Studies on the biochemistry, pharmacology and pharmacogenetic analysis of CYPs are mostly focused on the molecular forms associated with the microsomal membrane. However, the mitochondrial CYPs in some individuals can represent a substantial part of the tissue pool and contribute in a significant way to drug metabolism, clearance and toxicity.

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Section: Bimodal Targeting Of Cyps To the Er And Mitochondriamentioning

confidence: 99%

Bimodal targeting of microsomal cytochrome P450s to mitochondria: implications in drug metabolism and toxicity

Sangar

Bansal

Avadhani

2010

Expert Opinion on Drug Metabolism & Toxicology

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“…These results suggest that HypD affects processes that involve both development and secondary metabolism. Integral membrane proteins can act as permeases or metabolite transporters or function as subunits of proteins such as oxidoreductases or glucan synthases [61,62,63]. At this point we cannot say if HypD plays a role in AF efflux or cytochrome P450 enzyme activity or both.…”

Section: Possible Involvement Of Hypd In Af Accumulation and Fungamentioning

confidence: 99%

Predicted Roles of the Uncharacterized Clustered Genes in Aflatoxin Biosynthesis

Ehrlich

2009

Toxins

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Biosynthesis of the toxic and carcinogenic aflatoxins (AFs) requires the activity of more than 27 enzymes. The roles in biosynthesis of newly described enzymes are discussed in this review. We suggest that HypC catalyzes the oxidation of norsolorinic acid anthrone; AvfA (AflI), the ring-closure step in formation of hydroxyversicolorone; HypB, the second oxidation step in conversion of O-methylsterigmatocystin to AF; and HypE and NorA (AflE), the final two steps in AFB1 formation. HypD, an integral membrane protein, affects fungal development and lowers AF production while AflJ (AflS), has a partial methyltransferase domain that may be important in its function as a transcriptional co-activator.

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“…It has been speculated that heteromerization of P450s may exist to ensure proper cellular targeting into the membrane, cytosol, and Golgi complexes (Szczesna-Skorupa and Kemper, 2008). Another study showed that CYP3A4 catalyzed the oxidation and peroxidation of microsomal Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.…”

Section: Introductionmentioning

confidence: 99%

“…Inefficiencies in the catalytic pathway, in part, govern the rate of transformation. P450s and CPR are bound to the cell membrane via a hydrophobic N terminus, whereas b5 is bound via its C terminus, each terminal being composed of 30 to 60 amino acids (Szczesna-Skorupa and Kemper, 2008). This hydrophobic region also contributes to protein aggregation, resulting in the formation of high molecular weight polymers in membranes and reconstituted systems (SzczesnaSkorupa and Kemper, 2008).…”

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confidence: 99%

CYP2C9-CYP3A4 Protein-Protein Interactions: Role of the Hydrophobic N Terminus

Subramanian

Tam²,

Zheng³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Cytochromes P450 (P450s) interact with redox transfer proteins, including P450 reductase (CPR) and cytochrome b 5 (b5), all being membrane-bound. In multiple in vitro systems, P450-P450 interactions also have been observed, resulting in alterations in enzymatic activity. The current work investigated the effects and mechanisms of interaction between CYP2C9 and CYP3A4 in a reconstituted system. CYP2C9-mediated metabolism of S-naproxen and S-flurbiprofen was inhibited up to 80% by coincubation with CYP3A4, although K m values were unchanged. Increasing CYP3A4 concentrations increased the degree of inhibition, whereas increasing CPR concentrations resulted in less inhibition. Addition of b5 only marginally affected the magnitude of inhibition. In contrast, CYP2C9 did not alter the CYP3A4-mediated metabolism of testosterone. The potential role of the hydrophobic N terminus on these interactions was assessed by incubating truncated CYP2C9 with full-length CYP3A4, and vice versa. In both cases, the inhibition was fully abolished, indicating an important role for hydrophobic forces in CYP2C9-CYP3A4 interactions. Finally, a CYP2C9/CYP3A4 heteromer complex was isolated by coimmunoprecipitation techniques, confirming the physical interaction of the proteins. These results show that the N-terminal membrane binding domains of CYP2C9 and CYP3A4 are involved in heteromer complex formation and that at least one consequence is a reduction in CYP2C9 activity.Cytochromes P450 (P450s) are the primary oxidative enzymes responsible for the metabolism of xenobiotics by humans and animals (Guengerich, 2006). P450s can oxidize structurally diverse substrates ranging from small hydrocarbons to large molecules such as cyclosporine. P450s function by transferring electrons via a P450 catalytic pathway, wherein the first electron is transferred to the P450 via cytochrome NADPH P450 reductase (CPR) and the second electron is transferred via either CPR or cytochrome b 5 (b5) (Guengerich, 2002). Inefficiencies in the catalytic pathway, in part, govern the rate of transformation. P450s and CPR are bound to the cell membrane via a hydrophobic N terminus, whereas b5 is bound via its C terminus, each terminal being composed of 30 to 60 amino acids (Szczesna-Skorupa and Kemper, 2008). This hydrophobic region also contributes to protein aggregation, resulting in the formation of high molecular weight polymers in membranes and reconstituted systems (SzczesnaSkorupa and Kemper, 2008). Considering that P450s and CPR, and P450s and b5 interact within the cell membrane, P450-P450 interactions also appear conceivable. Indeed, in vitro evidence of P450-P450 interactions have been observed in several studies, including interactions of human CYP2C9-CYP2C19, rabbit CYP1A2-CYP2B4, rabbit CYP1A2-CYP2E1, human CYP3A4-CYP1A1, human CYP3A4-CYP1A2, and human CYP2C9-CYP2D6 (Cawley et al., 1995;Yamazaki et al., 1997;Backes et al., 1998;Backes and Cawley, 1999;Kelley et al., 2005Kelley et al., , 2006Subramanian et al., 2009). Substrate-dependent activation o...

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Influence of protein–protein interactions on the cellular localization of cytochrome P450

Cited by 17 publications

References 87 publications

Bimodal targeting of microsomal cytochrome P450s to mitochondria: implications in drug metabolism and toxicity

Bimodal targeting of microsomal cytochrome P450s to mitochondria: implications in drug metabolism and toxicity

Predicted Roles of the Uncharacterized Clustered Genes in Aflatoxin Biosynthesis

CYP2C9-CYP3A4 Protein-Protein Interactions: Role of the Hydrophobic N Terminus

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