613-17-2Relevant academic research and scientific papers
Investigation of the substrate range of CYP199A4: Modification of the partition between hydroxylation and desaturation activities by substrate and protein engineering
Bell, Stephen G.,Zhou, Ruimin,Yang, Wen,Tan, Adrian B. H.,Gentleman, Alexander S.,Wong, Luet-Lok,Zhou, Weihong
, p. 16677 - 16688 (2013/03/28)
The cytochrome P450 enzyme CYP199A4, from Rhodopseudomonas palustris HaA2, can efficiently demethylate 4-methoxybenzoic acid. It is also capable of oxidising a range of other related substrates. By investigating substrates with different substituents and ring systems we have been able to show that the carboxylate group and the nature of the ring system and the substituent are all important for optimal substrate binding and activity. The structures of the veratric acid, 2-naphthoic acid and indole-6-carboxylic acid substrate-bound CYP199A4 complexes reveal the substrate binding modes and the side-chain conformational changes of the active site residues to accommodate these larger substrates. They also provide a rationale for the selectivity of product oxidation. The oxidation of alkyl substituted benzoic acids by CYP199A4 is more complex, with desaturation reactions competing with hydroxylation activity. The structure of 4-ethylbenzoic acid-bound CYP199A4 revealed that the substrate is held in a similar position to 4-methoxybenzoic acid, and that the C β C-H bonds of the ethyl group are closer to the heme iron than those of the Cα (3.5 vs. 4.8 A?). This observation, when coupled to the relative energies of the reaction intermediates, indicates that the positioning of the alkyl group relative to the heme iron may be critical in determining the amount of desaturation that is observed. By mutating a single residue in the active site of CYP199A4 (Phe185) we were able to convert the enzyme into a 4-ethylbenzoic acid desaturase. Engineering a P450 desaturase: The substrate range of CYP199A4 from Rhodopseudomonas palustris was investigated. The partition between the hydroxylation and desaturation activities of 4-ethylbenzoic acid was studied by changing the substrate and by mutation. The activity of CYP199A4 with 4-ethylbenzoic acid was changed to a desaturase by a single mutation at F185. Copyright
Biocatalytic synthesis of dihydroxynaphthoic acids by cytochrome P450 CYP199A2
Furuya, Toshiki,Kino, Kuniki
scheme or table, p. 2797 - 2799 (2010/09/17)
CYP199A2, a bacterial P450 monooxygenase from Rhodopseudomonas palustris, was found to exhibit oxidation activity towards three hydroxynaphthoic acids. Whole cells of the recombinant Escherichia coli strain expressing CYP199A2 efficiently catalyzed the re
Azabicyclic compounds for the treatment of disease
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Page 40, (2010/02/06)
The invention provides compounds of Formula I: wherein Azabicyclo is W is a six-membered heterocyclic ring system having 1-2 nitrogen atoms or a 10-membered bicyclic-six-six-fused-ring system having up to two nitrogen atoms within either or both rings, provided that no nitrogen is at a bridge of the bicyclic-six-six-fused-ring system, and further having 1-2 substitutents independently selected from R3. These compounds may be in the form of pharmaceutical salts or compositions, may be in pure enantiomeric form or racemic mixtures, and are useful in pharmaceuticals to treat diseases or conditions in which α7 is known to be involved.
