TITLE

Oxidative Biotransformation of Fatty Acids by Cytochromes P450: Predicted Key Structural Elements Orchestrating Substrate Specificity, Regioselectivity and Catalytic Efficiency

AUTHOR(S)
Hlavica, Peter; Lehnerer, Michael
PUB. DATE
January 2010
SOURCE
Current Drug Metabolism;Jan2010, Vol. 11 Issue 1, p85
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
In view of the pivotal role played by the diversity of fatty acid-derived oxy-products in a vast array of physiological processes, precise knowledge about the molecular principles dictating substrate specificity and regioselectivity in P450-catalyzed oxidative attack on the distinctly structured carbon chains of the monocarboxylic acids is of paramount importance. Based on a general, CYP102A1-related construct, the majority of prospective key determinants participating in fatty acid recognition/binding were found to cluster near the distal heme face made up by the helical B', F, G and I tetrad as well as the B'-C interhelical loop and certain β-sheet segments. Most of the contact sites examined show a frequency of conservation <10%, hinting at the requirement of some degree of conformational flexibility. Some decisive elements may also have a function in maintaining active-site integrity, governing substrate access to the catalytic centre, and steering the redox machinery to efficiently promote fatty acid oxidations. Physico-chemical factors imposing constraints on orientation of the fatty acid molecules towards the iron-oxene core focus on the variably expressed polarity profile of the diverse docking regions and bulkiness of critical amino acid side chains, acting as selectivity filters for the substrate homologues. Also, dynamic fluctuations of certain contact sites located in the distal backbone of P450s may impact fatty acid positioning. Genetic engineering to introduce versatile properties into fatty acid hydroxylases may give an impetus to biotechnological exploitation of the tailored enzymes in the production of fine chemicals and therapeutic agents.
ACCESSION #
52415875

 

Related Articles

  • Cytochrome P450 4A Fatty Acid Omega Hydroxylases. Okita, R.T.; Okita, J.R. // Current Drug Metabolism;Sep2001, Vol. 2 Issue 3, p265 

    The Cytochrome P450 4A subfamily is one of eighteen subfamilies in the CYP4 family and Presently consists of twenty individual forms in nine different mammalian species. The major substrates for CYP4A forms are fatty acids, but recent studies have shown other non-fatty acid substrates may be...

  • The Cytochrome P450 System: What Is It and Why Should I Care?  // Davis's Drug Guide for Nurses, 12th Edition;2011, p1440 

    Information on the cytochrome P450, the liver's enzyme system, is presented.

  • Cytochrome P450 Enzymes. Guengerich, F. Peter // American Scientist;Sep/Oct93, Vol. 81 Issue 5, p440 

    Provides information on the capability of cytochrome P450 enzymes to defend the human body against environmental pollutants, detoxify drugs and synthesize several important signaling molecules. Chemicals that the enzymes detoxify; Role of cytochrome P450 enzymes in the metabolism of endogenous...

  • Cytochrome P450s. Vohr, Hans-Werner // Encyclopedic Reference of Immunotoxicology;2005, p167 

    The article presents an encyclopedia entry for cytochrome P450s, which are heme-containing proteins that absorb light when carbon monoxide binds to the proteins. Cytochrome P450 proteins ranks first as phase I biotransforming enzymes for its characteristics.

  • Construction of a thermostable cytochrome P450 chimera derived from self-sufficient mesophilic parents.  // Applied Microbiology & Biotechnology;Jul2007, Vol. 75 Issue 5, p1055 

    The P450 monooxygenases CYP102A1 from Bacillus megaterium and CYP102A3 from Bacillus subiilis are fusion flavocytochromes comprising of a P450 heme domain and a FAD/FMN reductase domain. This protein organization is responsible for the extraordinary catalytic activities making both...

  • Cloning, expression and characterisation of CYP102A7, a self-sufficient P450 monooxygenase from Bacillus licheniformis. Dietrich, Matthias; Eiben, Sabine; Asta, Chimene; Do, Tuan; Pleiss, Juergen; Urlacher, Vlada // Applied Microbiology & Biotechnology;Jul2008, Vol. 79 Issue 6, p931 

    Cytochrome P450 monooxygenases of the CYP102A subfamily are single-component natural fusion proteins consisting of a heme domain and a diflavin reductase. The characterised CYP102A enzymes are fatty acid hydroxylases with turnover rates of several thousands per minute. In search of new P450s...

  • Enzyme Kinetics of Cytochrome P450-Mediated Reactions. Magang Shou, A.; Yuh Lin, A.; Ping Lu; Cuyue Tang, A.; Qin Mei, A.; Dan Cui, A.; Wei Tang; Ngui, Jason S.; Lin, C. Charles; Singh, Rominder; Wong, Bradley K.; Yergey, James A.; Lin, Jiunn H.; Pearson, Paul G.; Baillie, Thomas A.; Rodrigues, A. David; Rushmore, Thomas H. // Current Drug Metabolism;Mar2001, Vol. 2 Issue 1, p17 

    The most common drug-drug interactions may be understood in terms of alterations of metabolism, associated primarily with changes in the activity of cytochrome P450 (CYP) enzymes. Kinetic parameters such as K m , V max , K i and K a , which describe metabolism-based drug interactions, are...

  • Polymorphic CYP2A6 and its clinical and toxicological significance. Rautio, A // Pharmacogenomics Journal;2003, Vol. 3 Issue 1, p5 

    Explains the clinical and toxicological significance of the polymorphic cytochrome P450 (CYP) enzymes, specifically CYP2A6. Review of related studies; Mechanism of action of the enzyme; Implications for pharmacology.

  • A New Inhibitor of Mitochondrial Fatty Acid Oxidation1. Hashimoto, Takashi; Shindo, Yasuko; Souri, Masayoshi; Baldwin, Graham S. // Journal of Biochemistry;1996, Vol. 119 Issue 6, p1196 

    The mitochondrial enoyl-CoA hydratase /3-hydroxyacyl-CoA dehydrogenase /3-ketoacyl-CoA thiolase trifunctional protein (trifunctional protein) plays a major role in mitochondrial fatty acid oxidation. The enzyme complex consists of four molecules of α-subunit containing both hydratase and...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics