Function of human cytochrome P450s: Characterization of the orphans

Guengerich, F. Peter; Wu, Zhong‐Liu; Bartleson, Cheryl

doi:10.1016/j.bbrc.2005.08.079

Cited by 128 publications

(102 citation statements)

References 39 publications

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“…P450 isoenzymes make up a superfamily of hemoproteins, of which 57 genes and 58 pseudogenes are known in humans. However, only approximately 30 of them code for a protein (Guengerich et al, 2005). CYP1, CYP2, and CYP3 are the main families involved in the majority of phase 1 biotransformation reactions of clinically used drugs, including many antiretroviral agents.…”

Section: B Cytochromes P450mentioning

confidence: 99%

The Dual Role of Pharmacogenetics in HIV Treatment: Mutations and Polymorphisms Regulating Antiretroviral Drug Resistance and Disposition

et al. 2012

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Section: B Cytochromes P450mentioning

confidence: 99%

The Dual Role of Pharmacogenetics in HIV Treatment: Mutations and Polymorphisms Regulating Antiretroviral Drug Resistance and Disposition

et al. 2012

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“…There is still limited information about one-fourth of the human P450s (Table I), and these can be described as "orphans" in this sense [3]. Presently, there is little information about how essential these P450s are.…”

Section: Roles Of P450s In Intermediary Metabolismmentioning

confidence: 99%

“…With the completion of the human genome sequence project, there appear to be 57 distinct P450 genes in humans [2]. Of these, about 13 are "orphan" P450s for which the metabolic function is not yet known [3].There is wide interest in P450s due to applications in a variety of fields including biochemistry, biotechnology, chemistry, environmental sciences, enzymology, microbiology, physiology, pharmacology, plant sciences, and toxicology. Indeed, in the last decade alone, there were more than 1000 publications per year relating to P450s.…”

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Cytochrome P450 enzymes in drug metabolism and chemical toxicology: An introduction

Furge

Guengerich

2006

Biochem Molecular Bio Educ

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144

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Cytochrome P450 (P450) enzymes include a family of related enzymes that are involved in metabolism of vitamins, steroids, fatty acids, and other chemicals. This review presents a brief historical overview of the discovery and characterization of P450 enzymes extending from intermediary metabolism to the fields of drug metabolism and toxicology. Introductions to P450 enzyme structure and function are also presented. The goals of this review are to 1) provide an introduction to a few of the many aspects of P450 research relating to humans, 2) introduce additional ways of thinking about metabolism, 3) provide some basic examples of P450 enzymology, and 4) provide applications to topics widely taught in undergraduate courses in biochemistry.Keywords: Cytochrome P450 enzyme, drug metabolism, chemical toxicity, P450 mechanism.Cytochrome P450 (P450) 1 enzymes are a family of heme-containing proteins found from bacteria to human. In mammals, the enzymes are membrane-bound (usually in the endoplasmic reticulum, although the seven in Families 11, 24, and 27 are found in mitochondria; Table I). P450s serve a variety of functions including steroid, fatty acid, eicosanoid, and vitamin A and D metabolism as well as metabolism of foreign compounds including natural products, pharmaceuticals, and carcinogens. P450s are found in every tissue except skeletal muscle and red blood cells [1]. With the completion of the human genome sequence project, there appear to be 57 distinct P450 genes in humans [2]. Of these, about 13 are "orphan" P450s for which the metabolic function is not yet known [3].There is wide interest in P450s due to applications in a variety of fields including biochemistry, biotechnology, chemistry, environmental sciences, enzymology, microbiology, physiology, pharmacology, plant sciences, and toxicology. Indeed, in the last decade alone, there were more than 1000 publications per year relating to P450s. This review will highlight the roles of human P450s in drug metabolism and chemical toxicity and applications to undergraduate studies. References to more in-depth reviews are also provided. DISCOVERY AND PURIFICATIONThe history of P450 can be traced back to questions related to the metabolism of steroids, drugs, and carcinogens in the 1940s. Early studies of difficult alkyl oxidations of amino acids and fatty acids, such as oxidation at the terminal methyl group of a fatty acid, allowed for the isolation of cell-free extracts capable of performing NAD(P)Hdependent oxidation reactions [4]. The "mixed-function oxidase" stoichiometry.that is now recognized as the basic reaction catalyzed by a P450 was not immediately obvious. In particular, the requirement for a reduced pyridine nucleotide to achieve an overall oxidation was surprising at the time. The concept of mixed-function oxidation was developed by O. Hayaishi et al. in Japan [5] and H. Mason in the U.S [6]. Subsequently, such reactions were shown to occur with steroids and xenobiotics, particularly drugs (J. Axelrod and B. Brodie et al.) [7,8] and carcinogen...

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“…Conversely, the Symbiodinium CYP-3 gene product showed a high level of sequence similarity with the known cytochrome P450 CYP20A1. Because its biological function is not known, this CYP20A1 protein is the so-called "orphan" P450 (28,60,61), and its possible role during heat stress in the coral-alga symbiosis has not been elucidated yet. The high level of similarity of the CYP-1 and CYP-3 sequences to the sequences of metazoan P450 genes suggests that there might have been host contamination, while our results for aposymbiotic A. millepora coral egg-sperm specimens indicated that CYP genes discovered did not originate from coral.…”

mentioning

confidence: 99%

Differential Regulation by Heat Stress of Novel Cytochrome P450 Genes from the Dinoflagellate Symbionts of Reef-Building Corals

Rosic

Pernice

Dunn

et al. 2010

Appl Environ Microbiol

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Exposure to heat stress has been recognized as one of the major factors leading to the breakdown of the coral-alga symbiosis and coral bleaching. Here, we describe the presence of three new cytochrome P450 (CYP) genes from the reef-building coral endosymbiont Symbiodinium (type C3) and changes in their expression during exposure to severe and moderate heat stress conditions. Sequence analysis of the CYP C-terminal region and two conserved domains, the "PERF" and "heme-binding" domains, confirmed the separate identities of the CYP genes analyzed. In order to explore the effects of different heat stress scenarios, samples of the scleractinian coral Acropora millepora were exposed to elevated temperatures incrementally over an 18-h period (rapid thermal stress) and over a 120-h period (gradual thermal stress). After 18 h of gradual heating and incubation at 26°C, the Symbiodinium CYP mRNA pool was approximately 30% larger, while a further 6°C increase to a temperature above the average sea temperature (29°C after 72 h) resulted in a 2-to 4-fold increase in CYP expression. Both rapid heat stress and gradual heat stress at 32°C resulted in 50% to 90% decreases in CYP gene transcript abundance. Consequently, the initial upregulation of expression of CYP genes at moderately elevated temperatures (26°C and 29°C) was followed by a decrease in expression under the greater thermal stress conditions at 32°C. These findings indicate that in the coral-alga symbiosis under heat stress conditions there is production of chemical stressors and/or transcriptional factors that regulate the expression of genes, such as the genes encoding cytochrome P450 monooxygenases, that are involved in the first line of an organism's chemical defense.

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Function of human cytochrome P450s: Characterization of the orphans

Cited by 128 publications

References 39 publications

The Dual Role of Pharmacogenetics in HIV Treatment: Mutations and Polymorphisms Regulating Antiretroviral Drug Resistance and Disposition

The Dual Role of Pharmacogenetics in HIV Treatment: Mutations and Polymorphisms Regulating Antiretroviral Drug Resistance and Disposition

Cytochrome P450 enzymes in drug metabolism and chemical toxicology: An introduction

Differential Regulation by Heat Stress of Novel Cytochrome P450 Genes from the Dinoflagellate Symbionts of Reef-Building Corals

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