Tuning a P450 Enzyme for Methane Oxidation

Zilly, Felipe E.; Acevedo, Juan Pablo; Augustyniak, W; Deege, Alfred; Häusig, Ulrich W.; Reetz, Manfred T.

doi:10.1002/anie.201006587

Cited by 143 publications

(107 citation statements)

References 82 publications

Supporting

Mentioning

101

Contrasting

Unclassified

Order By: Relevance

“…In CYP102, the presence of perfluorinated fatty acids greatly improved the ability of the enzyme to hydroxylate the gaseous hydrocarbons, such as butane, propane, ethane, and even methane [50, 106]. Similar approach termed ‘decoy substrate’ was successfully used in peroxygenase CYP152A1 to significantly improve the efficiency of catalytic oxidation of styrene and ethylbenzene by addition of the short-chain fatty acids [107-108].…”

Section: Heterotropic Cooperativitymentioning

confidence: 99%

A novel type of allosteric regulation: Functional cooperativity in monomeric proteins

Denisov¹,

Sligar²

2012

Archives of Biochemistry and Biophysics

View full text Add to dashboard Cite

Cooperative functional properties and allosteric regulation in cytochromes P450 play an important role in xenobiotic metabolism and define one of the main mechanisms of drugdrug interactions. Recent experimental results suggest that ability to bind simultaneously two or more small organic molecules can be the essential feature of cytochrome P450 fold, and often results in rich and complex pattern of allosteric behavior. Manifestations of non-Michaelis kinetics include homotropic and heterotropic activation and inhibition effects depending on the stoichiometric ratios of substrate and effector, changes in the regio- and stereospecificity of catalytic transformations, and often give rise to the clinically important drug – drug interactions. In addition, functional response of P450 systems is modulated by the presence of specific and non-specific effector molecules, metal ions, membrane incorporation, formation of homo- and hetero oligomers and interactions with the protein redox partners. In this article we briefly overview the main factors contributing to the allosteric effects in cytochromes P450 with the main focus on the sources of cooperative behavior in xenobiotic metabolizing monomeric heme enzymes with their conformational flexibility and extremely broad substrate specificity. The novel mechanism of functional cooperativity in P450 enzymes does not require substantial binding cooperativity, rather it implies the presence of one or more binding sites with higher affinity than the single catalytically active site in the vicinity of the heme iron.

show abstract

Section: Heterotropic Cooperativitymentioning

confidence: 99%

A novel type of allosteric regulation: Functional cooperativity in monomeric proteins

Denisov¹,

Sligar²

2012

Archives of Biochemistry and Biophysics

View full text Add to dashboard Cite

show abstract

“…1b, left), our research group and Zilly et al recently reported that even wildtype P450BM3 can catalyze the hydroxylation of small alkanes in the presence of a series of perfluorocarboxylic acids (PFs) with alkyl chain lengths from 5 to ; the latter perfluorinated compounds were named "decoy molecules" (Fig. 1b, right) [12,13]. According to the reaction mechanism of fatty acid hydroxylation by P450BM3 (Fig.…”

Section: Introductionmentioning

confidence: 89%

Highly efficient hydroxylation of gaseous alkanes at reduced temperature catalyzed by cytochrome P450BM3 assisted by decoy molecules

Kawakami

Cong

Okada

et al. 2015

J. Porphyrins Phthalocyanines

View full text Add to dashboard Cite

show abstract

“…30,31 While the conversion of propane to propanol in the presence of PFC10 proceeded successfully, 30 the original conclusion that methane was oxidized to methanol was later refuted. 35 In the presence of decanoic acid P450 BM3 did not convert propane to propanol, suggesting that the fluorine atoms in the decoy molecule are crucial for coercing the enzyme to accept small alkane substrates. 31 More recently, Watanabe, Shoji and colleagues reported successful hydroxylation of aromatic rings such as those of benzene, toluene, anisole, chlorobenzene, nitrobenzene and acetophenone using P450 BM3 and various PFCs (Table 3).…”

Section: Effect Of Perfluorinated Fatty Acid Decoy Molecules On P450 mentioning

confidence: 99%

Controlling substrate specificity and product regio- and stereo-selectivities of P450 enzymes without mutagenesis

Polic

Auclair

2014

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

P450 enzymes (P450s) are well known for their ability to oxidize unactivated C-H bonds with high regio-and stereoselectivity. Hence, there is emerging interest in exploiting P450s as potential biocatalysts. Although bacterial P450s typically show higher activity than their mammalian counterparts, they tend to be more substrate selective. Most drug-metabolizing P450s on the other hand, display remarkable substrate promiscuity, yet product prediction remains challenging. Protein engineering is one established strategy to overcome these issues. A less explored, yet promising alternative involves substrate engineering. This review discusses the use of small molecules for controlling the substrate specificity and product selectivity of P450s. The focus is on two approaches, one taking advantage of non-covalent decoy molecules, and the other involving covalent substrate modifications

show abstract

Tuning a P450 Enzyme for Methane Oxidation

Cited by 143 publications

References 82 publications

A novel type of allosteric regulation: Functional cooperativity in monomeric proteins

A novel type of allosteric regulation: Functional cooperativity in monomeric proteins

Highly efficient hydroxylation of gaseous alkanes at reduced temperature catalyzed by cytochrome P450BM3 assisted by decoy molecules

Controlling substrate specificity and product regio- and stereo-selectivities of P450 enzymes without mutagenesis

Contact Info

Product

Resources

About