Posttranslational modification by an isolevuglandin diminishes activity of the mitochondrial cytochrome P450 27A1

Charvet, Casey D.; Laird, James; Xu, Yunfeng; Salomon, Robert G.; Pikuleva, Irina A.

doi:10.1194/jlr.m035790

Cited by 18 publications

(25 citation statements)

References 57 publications

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“…Drug selection was based on approaches developed in our prior studies of CYP46A1 and CYP11A1 (Mast et al, 2012(Mast et al, , 2013a, which like CYP27A1 act on cholesterol as a substrate, but generate different products, 24-hydroxycholesterol and pregnenolone, respectively. We used intuitive predictions and were guided by the knowledge of the CYP27A1 substrate specificities, shape of the active sites of CYP46A1 and CYP11A1, and the previously generated CYP27A1 model based on crystal structure of CYP11A1 (Mast et al, 2006(Mast et al, , 2008(Mast et al, , 2011Charvet et al, 2013). Cumulatively, these data suggested that the CYP27A1 active site should represent a banana-shaped tunnel connecting the protein surface and buried heme group, the site of catalysis in P450 enzymes.…”

Section: Resultsmentioning

confidence: 99%

Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

2015

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Cytochrome P450 CYP27A1 is the only enzyme in humans converting cholesterol to 27-hydroxycholesterol, an oxysterol of multiple functions, including tissue-specific modulation of estrogen and liver X receptors. Both receptors seem to mediate adverse effects of 27-hydroxycholesterol in breast cancer when the levels of this oxysterol are elevated. The present work assessed druggability of CYP27A1 as a potential antibreast cancer target. We selected 26 anticancer and noncancer medications, most approved by the Food and Drug Administration, and evaluated them first in vitro for inhibition of purified recombinant CYP27A1 and binding to the enzyme active site. Six strong CYP27A1 inhibitors/binders were identified. These were the two antibreast cancer pharmaceuticals anastrozole and fadrozole, antiprostate cancer drug bicalutamide, sedative dexmedetomidine, and two antifungals ravuconazole and posaconazole. Anastrozole was then tested in vivo on mice, which received subcutaneous drug injections for 1 week. Mouse plasma and hepatic 27-hydroxycholesterol levels were decreased 2.6-and 1.6-fold, respectively, whereas plasma and hepatic cholesterol content remained unchanged. Thus, pharmacologic CYP27A1 inhibition is possible in the whole body and individual organs, but does not negatively affect cholesterol elimination. Our results enhance the potential of CYP27A1 as an antibreast cancer target, could be of importance for the interpretation of Femara versus Anastrozole Clinical Evaluation Trial, and bring attention to posaconazole as a potential complementary anti-breast cancer medication. More medications on the US market may have unanticipated off-target inhibition of CYP27A1, and we propose strategies for their identification.

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Section: Resultsmentioning

confidence: 99%

Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

2015

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“…Quantification of Total Lys-iso [4]LGE 2 Lactam Adducts in Mouse Retina-This was as described (58). Briefly, four retinas from three mice (1 mg of total protein) from each group were pooled, homogenized by sonication in 100 l of 25 mM Tris-Cl, pH 7.5, containing 10 mM CaCl 2 , 100 mM KCl, 100 g/ml butylated hydroxytoluene, and 0.02% Triton X-100 (PLA 2 digest buffer).…”

Section: Methodsmentioning

confidence: 99%

Pretreatment with Pyridoxamine Mitigates Isolevuglandin-associated Retinal Effects in Mice Exposed to Bright Light

Charvet

Saadane

Wang

et al. 2013

Journal of Biological Chemistry

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Background: Current antioxidant therapies do not directly target lipid peroxidation products. Results: Pyridoxamine treatment scavenges lipid peroxides in mouse retina, as exemplified by isolevuglandins, and improves retinal mitochondrial morphology after animal exposure to bright light. Conclusion: Pyridoxamine reduces deleterious effects of lipid peroxidation in the retina. Significance: Pyridoxamine supplementation should be considered for inclusion in antioxidant vitamin formulations.

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“…Subsequently, the specificity of isoLG modification was confirmed, providing direct evidence that isoLG adduction impairs enzyme activity and supporting the hypothesis that isoLG modification in the retina is detrimental to CYP27A1 enzyme activity, potentially disrupting cholesterol homeostasis. Thus, the effect of Lys 358 modification on enzyme activity was investigated by characterizing catalytic properties of Lys 358 as well as Lys 476 CYP27A1 mutants both before and after isoLG treatment (17). The K 358 R mutant was less susceptible to isoLG-induced loss of catalytic activity than the wild type (WT), whereas the K 476 R mutant was nearly as vulnerable as the WT.24 Thus, modification of Lys 358 , a residue involved in redox partner interactions, is the major contributor to isoLG-associated loss of CYP27A1 activity.…”

Section: Inhibition Of Proteolysis: Neurodegeneration and Glaucomamentioning

confidence: 99%

Isolevuglandin Adducts in Disease

Salomon

2015

Antioxidants & Redox Signaling

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Significance: A diverse family of lipid-derived levulinaldehydes, isolevuglandins (isoLGs), is produced by rearrangement of endoperoxide intermediates generated through both cyclooxygenase (COX) and free radicalinduced cyclooxygenation of polyunsaturated fatty acids and their phospholipid esters. The formation and reactions of isoLGs with other biomolecules has been linked to alcoholic liver disease, Alzheimer's disease, age-related macular degeneration, atherosclerosis, cardiac arythmias, cancer, end-stage renal disease, glaucoma, inflammation of allergies and infection, mitochondrial dysfunction, multiple sclerosis, and thrombosis. This review chronicles progress in understanding the chemistry of isoLGs, detecting their production in vivo and understanding their biological consequences. Critical Issues: IsoLGs have never been isolated from biological sources, because they form adducts with primary amino groups of other biomolecules within seconds. Chemical synthesis enabled investigation of isoLG chemistry and detection of isoLG adducts present in vivo. Recent Advances: The first peptide mapping and sequencing of an isoLG-modified protein present in human retina identified the modification of a specific lysyl residue of the sterol C27-hydroxylase Cyp27A1. This residue is preferentially modified by iso [4]LGE 2 in vitro, causing loss of function. Adduction of less than one equivalent of isoLG can induce COX-associated oligomerization of the amyloid peptide Ab 1-42 . Adduction of isoLGE 2 to phosphatidylethanolamines causes gain of function, converting them into proinflammatory isoLGE 2 -PE agonists that foster monocyte adhesion to endothelial cells. Future Directions: Among the remaining questions on the biochemistry of isoLGs are the dependence of biological activity on isoLG isomer structure, the structures and mechanism of isoLG-derived protein-protein and DNA-protein cross-link formation, and its biological consequences.

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Posttranslational modification by an isolevuglandin diminishes activity of the mitochondrial cytochrome P450 27A1

Cited by 18 publications

References 57 publications

Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

Pretreatment with Pyridoxamine Mitigates Isolevuglandin-associated Retinal Effects in Mice Exposed to Bright Light

Isolevuglandin Adducts in Disease

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