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|Title:||Phylogenetic and in silico Functional Analyses of the Cytochrome P450 Families 2 and 4|
|Authors:||Kirischian, Nina L.|
|Advisor:||Wilson, J. Y.|
|Keywords:||English Language and Literature;English Language and Literature|
|Abstract:||<p>The CYP superfamily is present in all domains of life and can metabolize an array of exogenous and endogenous compounds. In vertebrates, the CYP2 family is the largest and most diverse family; in mammals this CYP family is important for drug metabolism. The CYP4 family is the major family involved in the metabolism of fatty acids and eicosanoids. Both families have uncertain phylogenetic relationships amongst the vertebrate subfamilies and functional studies in non-mammalian vertebrates are limited. Vertebrate CYPs usually present a one-to-one subfamily relationship, yet in the CYP2 and in some CYP4 subfamilies this does not hold true, thus extrapolating functional understanding is difficult. Phylogenetic trees were constructed for the CYP2 and CYP4 families using robust phylogenetic methods (maximum likelihood and Bayesian inference) and sequences from all vertebrate classes. An emphasis was placed upon using the full complement of the family from species with completed genomes, particularly from mammalian and actinopterygian species. In the CYP2 phylogeny, subfamilies from distinct vertebrate classes were rarely clustered. CYP substrate recognition sites (SRSs), regions previously proposed as important for determining differences in substrate specificity between CYP genes, did not have elevated rates of evolution in either CYP2 or CYP4 analyses. The CYP4 phylogeny supported the placement of the CYP4V clade with invertebrate sequences and resolved inconsistencies in the placement of mammalian CYP4A/4X/4Z and 4B subfamilies. The evolution of the CYP4T and CYP4B subfamilies will need more consideration. In silico functional analyses raised testable hypotheses regarding the CYP4X and CYP4F22 genes. CYP4X was hypothesized to selectively metabolize long chain fatty acid amides while CYP4F22 was proposed to have overlapping function with other CYP4F genes with metabolic activity towards leukotrienes. Functional testing within the CYP4F clade should begin with long chain fatty acids and eicosanoids, such as leukotriene B<sub>4</sub>.</p>|
|Appears in Collections:||Open Access Dissertations and Theses|
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