Cytochrome p450 p450 or cyp enzymes are hemoproteins whose fifth axial heme iron ligand is a thiolate group and are found in wide variety of organisms 19, 30. Recent structural insights into cytochrome p450 function. Structure of a cytochrome p450 redox partner electrontransfer complex cytochrome p450 reductase, flavodoxinyproteinprotein interaction irina f. Coverage is interdisciplinary, ranging from bioinorganic chemistry of cytochrome p450 to its relevance in human medicine. Crystal structures of human cytochrome p450 3a4 bound to. Request pdf cytochrome p450 structure, function and clinical significance. Induction or inhibition of cyp enzymes is a major mechanism that underlies drugdrug interactions. Sequence identities between p450 families are generally low 1030%, and consequently, the structure function correlations among p450s are not clear. Cytochrome p450 enzymes p450 or cyp are some of the most versatile biocatalysts, and offer advantages for oxidizing unreactive ch bonds in mild conditions. Characterizing the membranebound state of cytochrome p450 3a4. The first threedimensional structure of cytochrome p450 was reported by poulos in 1985, the soluble bacterial cytochrome p450cam isolated from the bacterium pseudomonas putida. Cytochrome p450 3a4 cyp3a4 metabolizes more drug molecules than all other isoforms combined. The carbon monoxide is an inhibitor that poisons the enzyme. The crystal structure of a cytochrome p450cam sitedirected mutant in which the active site thr252 has been replaced with an ala thr252ala has been refined to an r factor of 0.
Biochemical, biophysical and computational approaches are applied to examine the interactions of p450s with substrates. Guide to cytochrome p450 structure and function, david f. Structure and chemistry of cytochrome p450 acs publications. Cytochrome p450 enzymes, in a strict sense, are not cytochromes in that they do not. Structure, mechanism, and biochemistry is a key resource for scientists, professors, and students interested in fields as diverse as biochemistry, chemistry, biophysics, molecular biology, pharmacology and toxicology.
Cytochromes p450 catalyze the oxidation of a variety of hydrophobic substrates. Department of drug discovery and development, harrison school of pharmacy, auburn university, auburn, alabama 36849, department of biochemistry and biotechnology, faculty of science, annamalai university, annamalainagar 608 002. Cytochrome p450 structure, function and clinical significance ncbi. Cytochrome p450 enzymes are primarily found in liver cells but are also located in cells throughout the body. Structure, mechanism, and biochemistry, 3e, edited by paul r. Cytochrome p450 structure, mechanism, and biochemistry. The microsomal, membraneassociated, p450 isoforms cyp3a4, cyp2d6, cyp2c9, cyp2c19, cyp2e1, and cyp1a2 are responsible for the oxidative metabolism of more than 90% of marketed drugs. The hemes are shown in spheres with the conserved arginine residues arg245 in olet and arg243 in bs.
This reaction utilizes a dioxygen bound as the sixth iron ligand and various redox systems for the cleavage of the oo bond. Cytochrome p450 cyp family 1, 2, and 3 enzymes play an essential role in the metabolic clearance and detoxification of a myriad of structurally and. Cytochrome p450 cyp is a microsomal and mitochondrial enzyme superfamily which catalyzes oxidation of various endogenous and exogenous biological molecules. Kima,2 adepartment of biochemistry, medical college of wisconsin, milwaukee, wi 53226. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown.
The multiple forms of cytochrome p450 metabolize a wide variety of xenobiotic compounds such as drugs and carcinogens, as well as endobiotics such as prostaglandins and steroids. Conformational states of cytochrome p450cam revealed by. Palrasu manikandan and siddavaram nagini affiliation. Crystal structure of a thermophilic cytochrome p450 from. Cytochrome p450 cyp is a hemeprotein that plays a key role in the metabolism of drugs and other xenobiotics estabrook, 2003. In particular, the role of protein structural fluctuations and substrate dynamics in the catalytic function of p450s is critically examined. Cyps have been extensively studied in animals rats,mice dogs and to less extent in zebra fish, in bacteria,in fungi,in insects, in plants and in humans, prokaryotic and eucaryotic. The emphasis is on structure, mechanism, biochemistry, and regulation. Structure and mechanism of function of cytochrome p450.
Structure, mechanism, and biochemistry, 3rd ed edited by paul r. The cytochrome p450 cyp enzymes are a protein superfamily involved in the synthesis and metabolism of drugs, toxins and normal cellular components. Cytochrome p450 family 1 inhibitors and structureactivity. Journal of the american chemical society 20, 5 23, 85428551.
Binju wang, chunsen li, kyungbin cho, wonwoo nam, and sason shaik. On the left pdb entry 3cpp is a structure with camphor and carbon monoxide bound in the active site. Structure and function of the cytochrome p450 peroxygenase. Cytochrome p450 structure, function and clinical significance. Electron transfer to cytochrome p450 is by nadph cytochrome p450 reductase relays the electron from nadph to cytochrome p450. Kinetics introduction cytochrome p450 p450 enzymes are involved in the oxidation of a wide variety of drugs, carcinogens, steroids, pesticides, and other chemicals 14. The cytochrome p450 cyp enzymes are membranebound hemoproteins that play a pivotal role in the detoxification of xenobiotics, cellular metabolism and homeostasis. Enzymes produced from cytochrome p450 genes are involved in the formation and breakdown metabolism of various molecules and chemicals within cells. The cyp2c19 gene is a member of the cytochrome p450 gene family.
Cytochromes p450 p450s metabolize a wide range of endogenous compounds and xenobiotics, such as pollutants, environmental compounds, and drug molecules. Crystal structure of a thermophilic cytochrome p450 from the archaeon sulfolobus solfataricus jason k. Cytochrome p450 cyp is a collective term that is used to describe a superfamily of haem proteins 1. Structure of a cytochrome p450redox partner electron. Structure, function and mechanism of cytochrome p450. Xray crystal structures are available for 29 eukaryotic microsomal, chloroplast or. The beststudied cytochrome p450 enzyme is a bacterial enzyme that adds oxygen to camphor. Cytochrome p450 enzymes in the generation of commercial. Cytochrome p450 drug interaction table drug interactions. Two early examples of these enzymes, called cytochrome p450cams, are shown here.
Structure and chemistry of cytochrome p450 request pdf. Furthermore, the sequence identity with human cyp2c9, for which the crystal structure was recently determined 18, is only 24%. Similar intermediates have been observed and characterized in novel hemethiolate proteins. The majority of p450s catalyze the monooxygenation hydroxylation of hydrophobic substrates. Electron transfer to cytochrome p450 is by nadph cytochrome p450 reductase relays the electron from nadph to cytochrome p450 one at a time. Crystal structure of human cytochrome p450 2c9 with bound. P450 1a2 is one of the major cytochrome p450 enzymes in human liver about % responsible for the metabolism of a variety of arylamines and heterocyclic arylamines which include numerous therapeutic drugs such as phenacetin, lidocaine, tacrine, and theophylline 2,7. Understanding the cyp system is essential for advanced practitioners aps, as the consequences of drugdrug interactions can be profound. Structural basis for human nadph cytochrome p450 oxidoreductase deficiency chuanwu xiaa, satya p. A crystal structure of the olet p450 blue with arachidic acid bound pdb 4l40 and of the bs. Pdf cytochrome p450 cyp family 1, 2, and 3 enzymes play an essential role in the metabolic clearance and detoxification of a myriad of. Our group has more than three decades of experience studying these enzymes. Structures for three human cytochrome p450 enzymes cyp2a6, cyp2a, and cyp2a binding the common inhibitor pilocarpine, a muscarinic receptor agonist, reveal how individual amino acids result in different binding orientations.
Cytochrome p450 cyp enzymes are the primary proteins of drug metabolism and steroid biosynthesis. These crucial proteins have long been known to harbor a cysteine thiolate bound to the heme iron. Cytochromes p450 cyps are a family of enzymes containing heme as a cofactor that function as monooxygenases. We report crystal structures of cyp3a4, both unliganded and. Pdf crystal structure of human cytochrome p450 2d6.