Redox Partners: Function Modulators of Bacterial P450 Enzymes

Ubiquitous P450s catalyze various oxidative reactions towards an enormous number of substrates. Bacterial P450s in soluble forms represent the most diverse subset with great application value and potential. In the conventional notion, redox partners are auxiliary proteins influencing electron transfer efficiency and product distribution. Lately, growing evidence has demonstrated that redox partners can endow their paired P450s with novel functionalities and may have more unexplored physiological roles. Bacterial redox partners can form various combinations to serve different P450s in vivo. This flexibility may be important for the host microorganisms to deal with ever-changing environments. Selection and engineering of redox partners for an optimized P450–redox partner interaction interface will become an important strategy for the improvement of industrially relevant P450 catalysts. The superfamily of cytochrome P450 monooxygenases (P450s) is widespread in all kingdoms of life. Functionally versatile P450s are extensively involved in diverse anabolic and catabolic processes. P450s require electrons to be transferred by redox partners (RPs) for O2 activation and substrate monooxygenation. Unlike monotonic eukaryotic cytochrome P450 reductases, bacterial RP systems are more diverse and complicated. Recent studies have demonstrated that the type, the amount, the combination, and the mode of action of bacterial RPs can affect not only the catalytic rate and product distribution but also the type and selectivity of P450 reactions. These results are leading to a novel opinion that RPs not only function as auxiliary electron transfer proteins but are also important P450 function modulators. The superfamily of cytochrome P450 monooxygenases (P450s) is widespread in all kingdoms of life. Functionally versatile P450s are extensively involved in diverse anabolic and catabolic processes. P450s require electrons to be transferred by redox partners (RPs) for O2 activation and substrate monooxygenation. Unlike monotonic eukaryotic cytochrome P450 reductases, bacterial RP systems are more diverse and complicated. Recent studies have demonstrated that the type, the amount, the combination, and the mode of action of bacterial RPs can affect not only the catalytic rate and product distribution but also the type and selectivity of P450 reactions. These results are leading to a novel opinion that RPs not only function as auxiliary electron transfer proteins but are also important P450 function modulators. mammalian [2Fe–2S]-containing ferredoxin, which was first found in adrenal mitochondria. It is soluble and is localized in the mitochondrial matrix. mitochondrial FAD-containing reductase that transfers electrons from NADPH to adrenodoxin. It is associated with the inner mitochondrial membrane. the membrane-bound FAD- and FMN-containing reductase that transfers electrons from NADPH to the eukaryotic endoplasmic reticulum-associated cytochrome P450s. an iron–sulfur protein that mediates electron transfer in a range of metabolic reactions. FAD-containing oxidoreductase catalyzing the following reversible reaction: two reduced ferredoxins + NAD(P)+ + H+ ⇌ two oxidized ferredoxins + NAD(P)H. proteins which have a cysteine residue as the fifth ligand of the heme iron. Cytochrome P450 enzymes are prominent examples. the most recent ancestor of all existing organisms on earth. oxygenases that catalyze the insertion of one oxygen atom into a substrate. nicotinamide adenine dinucleotide (phosphate), a hydride donor. the P450 protein surface nearest to the heme plane. The positively charged surface on the proximal side provides the docking sites for the negatively charged side of a ferredoxin or a reductase. the protein(s) that transfer electrons from NAD(P)H to P450s (or other oxidoreductases). An RP partner protein possesses a cofactor, such as FAD, FMN, or iron–sulfur cluster, to take up and release electrons. chemical species that transfer the equivalent of one electron in redox reactions. As an electron donor, a reducing equivalent can be a lone electron, a hydrogen atom, or a hydride.