Influence of Cytochrome P450, Family 2, Subfamily D, Polypeptide 6 (CYP2D6) Polymorphisms on Pain Sensitivity and Clinical Response to Weak Opioid Analgesics

Degradation of carbohydrates by bacteria represents a key step in energy metabolism that can be inhibited by methylated sugars. Removal of methyl groups, which is critical for further processing, poses a biocatalytic challenge because enzymes need to overcome a high energy barrier. Our structural and computational analysis revealed how a member of the cytochrome P450 family evolved to oxidize a carbohydrate ligand. Using structural biology, we ascertained the molecular determinants of substrate specificity and revealed a highly specialized active site complementary to the substrate chemistry. Invariance of the residues involved in substrate recognition across the subfamily suggests that they are critical for enzyme function and when mutated, the enzyme lost substrate recognition. The structure of a carbohydrate-active P450 adds mechanistic insight into monooxygenase action on a methylated monosaccharide and reveals the broad conservation of the active site machinery across the subfamily.

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Poly(ADP-ribose) polymerase 1 in genome-wide expression control in Drosophila

Scientific Reports ◽

10.1038/s41598-020-78116-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Guillaume Bordet ◽

Niraj Lodhi ◽

Danping Guo ◽

Andrew Kossenkov ◽

Alexei V. Tulin

Keyword(s):

Cytochrome P450 ◽

Transcription Factors ◽

Transcription Regulation ◽

Large Scale ◽

Mobile Elements ◽

Expression Control ◽

Genome Wide ◽

Cytochrome P450 Family ◽

Parp 1

AbstractPoly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme involved in DNA repair and transcription regulation, among other processes. Malignant transformations, tumor progression, the onset of some neuropathies and other disorders have been linked to misregulation of PARP-1 activity. Despite intensive studies during the last few decades, the role of PARP-1 in transcription regulation is still not well understood. In this study, a transcriptomic analysis in Drosophila melanogaster third instar larvae was carried out. A total of 602 genes were identified, showing large-scale changes in their expression levels in the absence of PARP-1 in vivo. Among these genes, several functional gene groups were present, including transcription factors and cytochrome family members. The transcription levels of genes from the same functional group were affected by the absence of PARP-1 in a similar manner. In the absence of PARP-1, all misregulated genes coding for transcription factors were downregulated, whereas all genes coding for members of the cytochrome P450 family were upregulated. The cytochrome P450 proteins contain heme as a cofactor and are involved in oxidoreduction. Significant changes were also observed in the expression of several mobile elements in the absence of PARP-1, suggesting that PARP-1 may be involved in regulating the expression of mobile elements.

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Effects of cytochrome P450 family 3 subfamily A member 5 gene polymorphisms on daunorubicin metabolism and adverse reactions in patients with acute leukemia

Molecular Medicine Reports ◽

10.3892/mmr.2017.6470 ◽

2017 ◽

Vol 15 (6) ◽

pp. 3493-3498 ◽

Cited By ~ 5

Author(s):

Zhen Huang ◽

Juxiang Wang ◽

Jiangchao Qian ◽

Yuan Li ◽

Zhisheng Xu ◽

...

Keyword(s):

Cytochrome P450 ◽

Acute Leukemia ◽

Gene Polymorphisms ◽

Adverse Reactions ◽

Cytochrome P450 Family

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Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

Clinical Chemistry ◽

10.1373/clinchem.2016.264986 ◽

2017 ◽

Vol 63 (7) ◽

pp. 1204-1213 ◽

Cited By ~ 22

Author(s):

Maja Matic ◽

Saskia N de Wildt ◽

Dick Tibboel ◽

Ron H N van Schaik

Keyword(s):

Cytochrome P450 ◽

Treatment Guidelines ◽

Twin Studies ◽

Atp Binding ◽

Clinical Implementation ◽

Large Variability ◽

Gated Channel ◽

Cytochrome P450 Family ◽

Opioid Efficacy ◽

Atp Binding Cassette

Abstract BACKGROUND The use of opioids to alleviate pain is complicated by the risk of severe adverse events and the large variability in dose requirements. Pharmacogenetics (PGx) could possibly be used to tailor pain medication based on an individual's genetic background. Many potential genetic markers have been described, and the importance of genetic predisposition in opioid efficacy and toxicity has been demonstrated in knockout mouse models and human twin studies. Such predictors are especially of value for neonates and young children, in whom the assessment of efficacy or side effects is complicated by the inability of the patient to communicate this properly. The current problem is determining which of the many potential candidates to focus on for clinical implementation. CONTENT We systematically searched publications on PGx for opioids in 5 databases, aiming to identify PGx markers with sufficient robust data and high enough occurrence for potential clinical application. The initial search yielded 4257 unique citations, eventually resulting in 852 relevant articles covering 24 genes. From these genes, we evaluated the evidence and selected the most promising 10 markers: cytochrome P450 family 2 subfamily D member 6 (CYP2D6), cytochrome P450 family 3 subfamily A member 4 (CYP3A4), cytochrome P450 family 3 subfamily A member 5 (CYP3A5), UDP glucuronosyltransferase family 2 member B7 (UGT2B7), ATP binding cassette subfamily B member 1 (ABCB1), ATP binding cassette subfamily C member 3 (ABCC3), solute carrier family 22 member 1 (SLC22A1), opioid receptor kappa 1 (OPRM1), catechol-O-methyltransferase (COMT), and potassium voltage-gated channel subfamily J member 6 (KCNJ6). Treatment guidelines based on genotype are already available only for CYP2D6. SUMMARY The application of PGx in the management of pain with opioids has the potential to improve therapy. We provide a shortlist of 10 genes that are the most promising markers for clinical use in this context.

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