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Computational analysis of cytochrome...

Clodfelter, Karl Hoy.

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Computational analysis of cytochrome P450 structure and expression.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Computational analysis of cytochrome P450 structure and expression./
Author:	Clodfelter, Karl Hoy.
Description:	225 p.
Notes:	Adviser: David J. Waxman.
Contained By:	Dissertation Abstracts International68-03B.
Subject:	Biology, Bioinformatics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3254455

Computational analysis of cytochrome P450 structure and expression.
Clodfelter, Karl Hoy.

Computational analysis of cytochrome P450 structure and expression. - 225 p.

Adviser: David J. Waxman.

Thesis (Ph.D.)--Boston University, 2007.

Cytochromes P450, members of a gene superfamily of heme protein monooxygenases, play a significant role in biosynthesis and/or metabolism of cholesterol, steroid hormones and many xenobiotics. The active sites of five P450s with differing substrate specificities were compared using a computational method for the energetically favorable placement of small molecule probes to detect protein surface features. Two bacterial P450 enzymes with narrow substrate specificity, CYP101 and CYP102, computationally bound the probes at important active site residues regardless of protein conformation. By contrast, three mammalian P450s with broad substrate specificity, CYPs 2C5, 2C9, and 2B4, only bound probes when the protein was co-crystallized with a ligand. Furthermore, the presence of a bound ligand in CYP2C9 created a high-affinity site for a second ligand, which may help to explain the prevalence of drug-drug interactions involving this and other mammalian P450s.Subjects--Topical Terms:

1018415
Biology, Bioinformatics.

Computational analysis of cytochrome P450 structure and expression.
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005 20110524
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035 $a (UMI)AAI3254455
035 $a AAI3254455
040 $a UMI $c UMI
100 1 $a Clodfelter, Karl Hoy. $3 1271006
245 1 0 $a Computational analysis of cytochrome P450 structure and expression.
300 $a 225 p.
500 $a Adviser: David J. Waxman.
500 $a Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1386.
502 $a Thesis (Ph.D.)--Boston University, 2007.
520 $a Cytochromes P450, members of a gene superfamily of heme protein monooxygenases, play a significant role in biosynthesis and/or metabolism of cholesterol, steroid hormones and many xenobiotics. The active sites of five P450s with differing substrate specificities were compared using a computational method for the energetically favorable placement of small molecule probes to detect protein surface features. Two bacterial P450 enzymes with narrow substrate specificity, CYP101 and CYP102, computationally bound the probes at important active site residues regardless of protein conformation. By contrast, three mammalian P450s with broad substrate specificity, CYPs 2C5, 2C9, and 2B4, only bound probes when the protein was co-crystallized with a ligand. Furthermore, the presence of a bound ligand in CYP2C9 created a high-affinity site for a second ligand, which may help to explain the prevalence of drug-drug interactions involving this and other mammalian P450s.
520 $a P450s and certain other liver-expressed genes involved in steroid and foreign chemical metabolism are characterized by sex-dependent expression, which is determined by the sex-specific patterning of pituitary growth hormone (GH) secretion. Microarray analysis was used to identify female-specific genes that were activated in male rat liver as a result of feminization of the GH profile, validating the effect of GH patterning on the sexual dimorphism of liver genes. Two subsequent microarray studies examined the impact of targeted disruption of the genes encoding two GH-activated transcription factors, signal transducer and activator of transcription (STAT) 5a and 5b. STAT5b was found to be required for hepatic sexual dimorphism in male mice, whereas STAT5a had a more limited effect on sex-specific genes that was most readily evident in female mouse liver.
520 $a These studies use computational approaches to characterize cytochrome P450 structure and expression. The induced fit mechanism important for the broad substrate specificity necessary for xenobiotic metabolism was investigated by computational mapping of the P450 active site, whereas the sex-dependent expression of cytochromes P450 contributing to sex differences in metabolism of exogenous chemicals was characterized by microarray analysis. This research provides new insight into an enzyme family central to our understanding of diverse biological processes of importance to physiology, pharmacology and environmental toxicology.
590 $a School code: 0017.
650 4 $a Biology, Bioinformatics. $3 1018415
650 4 $a Biology, Biostatistics. $3 1018416
650 4 $a Engineering, Biomedical. $3 1017684
690 $a 0308
690 $a 0541
690 $a 0715
710 2 $a Boston University. $3 1017454
773 0 $t Dissertation Abstracts International $g 68-03B.
790 $a 0017
790 1 0 $a Waxman, David J., $e advisor
791 $a Ph.D.
792 $a 2007
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3254455