ISSN:0892-6638    

DOI:10.1096/fasebj.6.2.1537452

出版商:Wiley    

年代:1992

数据来源: WILEY

ISSN:0892-6638    

DOI:10.1096/fasebj.6.2.1537453

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

The cytochrome P450 gene superfamily encodes many isoforms that are unusual in the variety of chemical reactions catalyzed and the number of substrates attacked. The latter include physiologically important substances such as steroids, eicosanoids, fatty acids, lipid hydroperoxides, retinoids, and other lipid metabolites, and xenobiotics such as drugs, alcohols, procarcinogens, antioxidants, organic solvents, anesthetics, dyes, pesticides, odorants, and flavorants. Accordingly, it is not surprising that these catalysts have come under intensive study in recent years in fields as diverse as biochemistry and molecular biology, endocrinology, pharmacology, toxicology, anesthesiology, nutrition, pathology, and oncology. In this review, recent advances in our knowledge of the catalytic properties, reaction mechanisms, and regulation of expression and activity of the P450 enzymes are briefly summarized. In addition, the prospects for research in this field are considered, and advances are predicted in four broad areas: improved basic knowledge of enzyme catalysis and regulation; synthesis of fine chemicals, including drug design and screening; removal of undesirable environmental chemicals; and biomedical applications related to steroid, drug, carcinogen, and alcohol metabolism.—Coon, M. J.; Ding, X.; Pernecky, S. J.; Vaz, A. D. N. Cytochrome P450: progress and predictions.FASEB J.6: 669‐673; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.2.1537454

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

Several crystal structures of various substrate and inhibited complexes of the camphor monoxygenase, cytochrome P450camfromPseudomonas putida, are now available. These structures, together with mutagenesis, biochemical, and biophysical studies, have allowed for a detailed penetration into the problem of how P450s activate molecular oxygen, control stereoselectivity, and transfer electrons. This review will provide a summary of the crystallographic work in light of what these structures have taught us about P450 function.—Poulos, T. L.; Raag, R. Cytochrome P450cam: crystallography, oxygen activation, and electron transfer.FASEB J.6: 674‐679; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.2.1537455

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

The membrane topology of the mammalian P450 cytochromes has been studied intensively by computational approaches, proteolysis, chemical modification, genetic engineering, and immunochemistry. Initial results for the cytochromes of the endoplasmic reticulum appeared to indicate a polytopic, four to eight transmembrane anchor model with an active site buried in the membrane. However, recent findings show that the microsomal P450s are bound to the endoplasmic reticulum by only one or two transmembrane peptides located at the NH2‐terminal end, and that the active site is part of a large cytoplasmic domain that may have one or two additional peripheral membrane contacts. The membrane‐bound state is viewed as rather rigid, and the plane of the heme lies between perpendicular and parallel to the plane of the endoplasmic reticulum. The mitochondrial P450 cytochromes lack a hydrophobic NH2terminus in the mature form, and thus differ from the microsomal isozymes in this significant way. However, although the exact topology of cytochrome P450 in the inner mitochondrial membrane remains to be elucidated, certain features are clearly comparable to those of microsomal P450. Therefore, the membrane topology of the P450 gene superfamily may follow a similar pattern.—Black, S. D. Membrane topology of the mammalian P450 cytochromes.FASEB J.6: 680‐685; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.2.1537456

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

The cytochrome P450 enzyme systems catalyze the metabolism of a wide variety of naturally occurring and foreign compounds by reactions requiring NADPH and O2. Cytochrome P450 also catalyzes peroxide‐dependent hydroxylation of substrates in the absence of NADPH and O2. Peroxidases such as chloroperoxidase and horseradish peroxidase catalyze peroxide‐dependent reactions similar to those catalyzed by cytochrome P450. The kinetic and chemical mechanisms of the NADPH and O2‐supported dealkylation reactions catalyzed by P450 have been investigated and compared with those catalyzed by P450 and peroxidases when the reactions are supported by peroxides. Detailed kinetic studies demonstrated that chloroperoxidase‐ and horseradish peroxidase‐catalyzed N‐demethylations proceed by a Ping Pong Bi Bi mechanism whereas P450‐catalyzed O‐dealkylations proceed by sequential mechanisms. Intramolecular isotope effect studies demonstrated that N‐demethylations catalyzed by P450s and peroxidases proceed by different mechanisms. Most hemeproteins investigated catalyzed these reactions via abstraction of anα‐carbon hydrogen whereas reactions catalyzed by P‐450 and chloroperoxidase proceeded via an initial one‐electron oxidation followed byα‐carbon deprotonation.18O‐Labeling studies of the metabolism of NMC also demonstrated differences between the peroxidases and P450s. Because the hemeprotein prosthetic groups of P450, chloroperoxidase, and horseradish peroxidase are identical, the differences in the catalytic mechanisms result from differences in the environments provided by the proteins for the heme active site. It is suggested that the axial heme‐iron thiolate moiety in P450 and chloroperoxidase may play a critical role in determining the mechanism of N‐demethylation reactions catalyzed by these proteins.—Hollenberg, P. F. Mechanisms of cytochrome P450 and peroxidase‐catalyzed xenobiotic mechanism.FASEB J.6: 686‐694; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.2.1537457

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

The use of three mechanism‐based probes to investigate the topology and function of fatty acid hydroxylases is discussed.1) The observation of protein rather than heme alkylation in the reaction of cytochrome P4504A1 with 10‐undecynoic acid supports the argument that the enzyme circumvents the inherent preference forω‐1 hydroxylation by restricting access to the ferryl oxygen.2) The regiochemistry of the ferricyanide‐mediated iron‐to‐nitrogen shift of the cytochrome P450102 (P450BM‐3) phenyl‐iron complex indicates that the active site of this bacterial fatty acid hydroxylase is open primarily above pyrrole ring A of the prosthetic heme group,3) Inhibition of clofibrate‐mediated peroxisome proliferation in cultured rat hepatocytes by inactivation of cytochrome P4504A1 indicates thatω‐hydroxylation of fatty acids provides a signal for peroxisome proliferation.—Ortiz de Montellano, P. R.; Chan, W. K.; Tuck, S. F.; Kaikaus, R. M.; Bass, N. M.; Peterson, J. A. Mechanism‐based probes of the topology and function of fatty acid hydroxylases.FASEB J.6: 695‐699; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.2.1537458

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

The way in which structural diversity encodes the capacity of individual P450 enzymes to metabolize multiple, structurally distinct substrates remains largely unknown. The tools of molecular biology provide a means of identifying amino acid residues among closely related P450s that are determinants of their distinct catalytic properties. Work in our laboratory has identified two substrate specificity‐determining segments of the amino acid sequences of subfamily 2C P450s. A pattern has emerged from this work, and that of others, which suggests a model for the structural basis of P450 catalytic diversity.—Johnson, E. F.; Kronbach, T.; Hsu, M.‐H. Analysis of the catalytic specificity of cytochrome P450 enzymes through site‐directed mutagenesis.FASEB J.6: 700‐705; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.2.1537459

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

CYP1A1is considered to be involved mainly in oxidative metabolism of exogenous chemicals and drugs. Synthesis of this hemoprotein is induced in livers, lungs, and other tissues of experimental animals by the administration of these chemicals. Regulatory mechanisms of the induction process of the protein have been investigated by the DNA transfer method using the isolated genomic DNA. At least two kinds of cis‐acting regulatory DNA sequences are localized 5′ upstream of the gene. One is distributed five times in a relatively wide range from –0.5 to –3.5 kb and functions as an inducible enhancer‐designated xenobiotic responsive element or XRE. The other is localized just upstream of the TATA sequence and acts as a regulatory element for the constitutive expression. The two DNA elements are required for a high level of the inducible expression. Their cognate DNA binding factors are recognized in the nuclear extracts of Hepa‐1 cells and rat liver cells which show the inducible expression ofCYP1A1in response to the inducer. This paper discusses the regulatory mechanisms ofCYP1A1gene expression by summarizing the present state of knowledge about properties of the DNA regulatory elements and their cognate DNA‐binding factors.—Fujii‐Kuriyama, Y.; Imataka, H.; Sogawa, K.; Yasumoto, K.‐i.; Kikuchi, Y. Regulation ofCYP1A1expression.FASEB J.6: 706‐710; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.2.1537460

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

In rats, the onset of the sexually dimorphic pattern of growth hormone (GH) secretion and increased hepatic GH‐binding capacity at puberty are temporally correlated with the sex‐dependent expression of some hepatic cytochrome P450 enzymes involved in steroid metabolism. There are indications that the expression of the GH receptor gene itself is dependent on the sexually differentiated pattern of GH secretion. However, the molecular mechanisms by which a given pattern of GH secretion turns on a specific set of genes in the hepatocyte are not yet understood. Studies of the cytochrome P450 2C gene subfamily in hypophysectomized rats and isolated hepatocytes suggest that one major mechanism of GH action in the liver occurs through modulation of gene transcriptional initiation. The occurrence, in dwarf rats and in rats treated neonatally with monosodium glutamate, of sex differences in GH secretion and liver steroid metabolism typical of normal rats, in spite of a 95% reduction in pituitary GH levels, is compatible with the notion that extremely low levels of circulating GH are sufficient to regulate the expression of liver steroid‐metabolizing enzymes. This, together with the fact that single daily subcutaneous injections of GH are sufficient to masculinize the liver of a hypophysectomized rat, indicates that neither the amplitude nor the frequency of the GH pulse is recognized as male or female by the hepatocyte, but rather the complete and prolonged suppression (in males) or the persistence (in females) of circulating GH during the trough period after a GH surge.—Legraverend, C.; Mode, A.; Wells, T.; Robinson, I.; Gustafsson, J.‐A. Hepatic steroid hydroxylating enzymes are controlled by the sexually dimorphic pattern of growth hormone secretion in normal and dwarf rats.FASEB J.6: 711‐718; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.2.1537461

出版商:Wiley    

年代:1992

数据来源: WILEY