Example of cytochrome

Cytochrome P450 enzymes have been the subject of a number of recent reviews in which their mechanism and scope of action are covered in much detail [1, 6, 10, 11]. The reader is referred to these articles for a more thorough account of the mechanism and reactivity of cytochrome P450 enzymes, while we present a few representative examples of cytochrome P450-catalyzed epoxidation below. The enzymes we chose are all involved in the biosynthesis of polyketide natural products. Polyketides are a large, structurally diverse family of compounds and have provided a wealth of therapeutically useful drugs and drug leads. 

Whilst reductions at external surface (for example of cytochrome c) Take electrons alone to pass inwards leaving protonic charges free. 

The question has been asked as regards the great diflFerence in reactivity between the various heme proteins what structural diflPerences are responsible for this Here are three examples of cytochromes (a, b, c) which have exactly the same inner sphere coordination as do certain compounds of hemoglobin. Thus the great diflFerences in reactions of the cytochromes are brought about by diflFerences in structure further out than that. Clearly, the cytochromes and hemoglobin diflFer greatly as one proceeds further out from the iron atom. 

Once absorbed from the intestine, flavonoids will be subjected to metabolism involving phase I or phase II enzymes. Hydroxylation and demethylation are examples of cytochrome P450 mono-oxygenase-dependent (phase I) activities that may be involved in the metabolism of flavonoids. Nielsen et al. [24] showed that microsomes prepared from normal and Aroclor-treated rats were capable of hydroxylating certain flavonols and... 

Examples of cytochrome P450-based drug interactions... 

SCHEME 36.16. Examples of cytochrome P450 monooxygenase-catalyzed oxidations. 

The electron transport protein, cytochrome c, found in the mitochondria of all eukaryotic organisms, provides the best-studied example of homology. The polypeptide chain of cytochrome c from most species contains slightly more than 100 amino acids and has a molecular weight of about 12.5 kD. Amino acid sequencing of cytochrome c from more than 40 different species has revealed that there are 28 positions in the polypeptide chain where the same amino acid residues are always found (Figure 5.27). These invariant residues apparently serve roles crucial to the biological function of this protein, and thus substitutions of other amino acids at these positions cannot be tolerated. 

FIGURE 6.28 Examples of protein domains with different numbers of layers of backbone strnctnre. (a) Cytochrome c with two layers of a-helix. (b) Domain 2 of phosphoglycerate kinase, composed of a /3-sheet layer between two layers of helix, three layers overall, (c) An nnnsnal five-layer strnctnre, domain 2 of glycogen phosphorylase, a /S-sheet layer sandwiched between four layers of a-helix. (d) The concentric layers of /S-sheet (inside) and a-helix (outside) in triose phosphate isomerase. Hydrophobic residnes are bnried between these concentric layers in the same manner as in the planar layers of the other proteins. The hydrophobic layers are shaded yellow. (Jane Richarelson)... 

Like the examples above, dihydroxyacetanilide epoxidase (DHAE) uses an olefin as the substrate for epoxidation. Its mechanism, however, is fundamentally different from those of cytochrome P450 or flavin-dependent enzymes. Dihydroxyacetanilide is an intermediate in the biosynthesis of the epoxyquinones LL-C10037a, an antitumor agent produced by the actinomycete Streptomyces LL-C10037 [75, 76], and MM14201, an antibiotic produced by Streptomyces MPP 3051 (Scheme 10.20) [77]. The main structural difference between the two antibiotics lies in the opposite stereochemistry of the oxirane ring. 

Many examples of microbial hydroxylation of sterols/steroids have been reported. These hydroxylations usually involve mixed function oxidases which utilise molecular oxygen and cytochrome P-450. The reaction can be represented by ... 

Two important examples of reductive metabolism of xenobiotics are the reductive dehalogenation of organohalogen compounds, and the reduction of nitroaromatic compounds. Examples of each are shown in Figure 2.13. Both types of reaction can take place in hepatic microsomal preparations at low oxygen tensions. Cytochrome P450 can catalyze both types of reduction. If a substrate is bound to P450 in the... 

The toxicology of PCBs is complex and not fully understood. Coplanar PCBs interact with the Ah-receptor, with consequent induction of cytochrome P4501A1/2 and Ah-receptor-mediated toxicity. Induction of P4501A1 provides the basis of valuable biomarker assays, including bioassays such as CALUX. Certain PCBs, for example, 3,3, 4,4 -TCB, are converted to monohydroxymetabolites, which act as thyroxine antagonists. PCBs can also cause immunotoxicity (e.g., in seals). 

The other major mechanism of pyrethroid resistance found in some field strains of Heliothis virescens was enhanced detoxication due to a high rate of oxidative detoxication, mediated by a form of cytochrome P450 (McCaffery 1998). Some strains, such as PEG 87, which was subjected to a high level of field and laboratory selection, possessed both mechanisms. Other example of pyrethroid resistance due to enhanced detoxication may be found in the literature on pesticides. 

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