Cytochrome P450 heme-containing proteins

For most drugs, oxidative biotransformation is performed primarily by the mixed-function oxidase enzyme system, which is present predominantly in the smooth endoplasmic reticulum of the liver. This system comprises (1) the enzyme NADPH cytochrome P450 reductase (2) cytochrome P450, a family of heme-containing proteins that catalyze a variety of oxidative and reductive reactions and (3) a phospholipid bilayer that facilitates interaction between the two proteins. Important exceptions to this rule are ethyl alcohol and caffeine, which are oxidatively metabolized by enzymes primarily present in the soluble, cytosolic fraction of the liver. 

Cytochromes are used in the conversion of cholesterol to the steroid hormones. Iliese hormones include aldosterone, cortisol, and the sex hormones. Synthesis of aldosterone, for example, occurs in the mitochondria of the adrenal cortex. One of the steps in aidostero ne synthesis is a hydroxylation that is cataly .ed by a complex of adrenodoxin reductase (FAD-containing protein), adrenodoxin (nonheme iron protein), and cytochrome P450 (heme protein). 

Kirton SB, Murray CW, Verdonk ML, Taylor RD. Prediction of binding modes for ligands in the cytochromes P450 and other heme-containing proteins. Proteins 2005 58 836-44. 

Fig. 19.13. Cytochrome P450 mono-oxygenases. Electrons are donated by NADPH to O2 and the substrate. The flavin coenzymes FAD and FMN in one subunit transfer single electrons to cytochrome P450, which is an Fe-heme containing protein that absorbs hght at a wavelength of 450 nm. The enzyme is embedded in a membrane, usually the endoplasmic reticulum.

Cytochrome P450 is a heme-containing protein embedded in the endoplasmic reticulum, which exists in multiple forms and has a molecular weight of 45 000-55 000. The heme (Figure 5) is noncovalently bound to the apoprotein and serves as both the oxygen and substrate-binding site. 

Peroxidases are heme iron-containing proteins similar in structure to that of cytochromes P450. The major difference is that peroxidases have histidine as the axial ligand instead of cysteine, and there are also other polar amino acids close to the heme iron that help to catalyze the peroxidase function of the enzyme (41). The result is that the peroxidases very rapidly catalyze the reduction of hydroperoxides to alcohols (or water in the case of... 

NO also has cytotoxic effects when synthesized in large quantities, eg, by activated macrophages. For example, NO inhibits metalloproteins involved in cellular respiration, such as the citric acid cycle enzyme aconitase and the electron transport chain protein cytochrome oxidase. Inhibition of the heme-containing cytochrome P450 enzymes by NO is a major pathogenic mechanism in inflammatory liver disease. 

The protein globule of cytochrome P450 from the adrenal cortex consists of two fragments. The hydrophilic fragment FI has a molecular mass of 27000 and contains a heme and an adrenodoxin-binding site. The hydrophobic fragment of molecular mass 22000 binds the enzyme to the biomemrane. The presence of extensive hydrophobic portions has also been detected in liver cytochrome. 

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