New cytochrome P450 mechanisms: implications for understanding molecular basis for drug toxicity at the level of the cytochrome.
BACKGROUND
Cytochrome (CYP) P450 is a collective name for a very large group of heme enzymes, which catalyze largely oxidative reactions, including those of pharmacological and toxicological importance. Their efficient operation requires coupling of specific electron donor and O(2) consumption and substrate hydroxylation. Many drug oxidation reactions are partially uncoupled, leading to the formation of highly toxic reactive oxygen species, which can cause unpredictable toxic effects on the cell. Rational approaches to avoid uncoupling require knowledge of the underlying mechanisms.


METHODS
In this communication, attempts have been made to bring together past as well as present information indicating that i) the P450 active site has two differently accessible allosterically interacting subsites geared for entirely different types of functionally relevant interactions; and ii) substrate binding to the specific protein residues (Site I) forming the reducible high-spin complex and product binding at L(6) (Site II) of the heme iron forming inhibited low-spin complex can regulate the functional state of the enzyme during catalysis.


RESULTS
Since P450 enzymes catalyze a wide variety of reactions, understanding the molecular basis for their efficient operation is of interest to many fields, including rational approaches to design safer drugs, tailoring P450 for a given task (e.g., bioremediation).


CONCLUSIONS
It is important to take into account that the two sub-sites function as interacting sites rather than parts of a site functioning as single site for rational approaches to P450 mechanisms. This is important especially in regard to interpretation of the observed effects of drugs, products and inhibitors on these enzymes.
Shakunthala
Narasimhulu
N
University of Pennsylvania, Harrison Department for Surgical Research, PA 19104, USA. Shaknar@comcast.net
D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D064420:Drug-Related Side Effects and Adverse Reactions; D006418:Heme / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D010597:Pharmacogenetics; D011487:Protein Conformation; D013379:Substrate Specificity
D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D007501:Iron