Cytochrome P450 systems that oxidise carrier protein bound substrates: molecular recognition and specificity in small molecule oxidation

The Cytochromes P450 (P450s) are a superfamily of oxidative haemoproteins that are capable of catalysing a vast range of oxidative transformations, often with high degrees of regio- and stereoselectivity.^{1, 2} The biological roles of P450s are highly variable and system dependent: in eukaryotes they are involved in biosynthetic conversions and cell signalling, along with their crucial role in xenobiotic metabolism. P450s from prokaryotes catalyse an array of biodegradative and biosynthetic oxidation reactions, the latter often affording molecules of medicinal significance.³ Within the P450 superfamily, a small group of P450s have been identified that effect substrate oxidation efficiently when the target molecule is bound to a carrier protein.⁴ Such carrier proteins are found either as isolated proteins, or forming modular domains in complex natural product biosynthetic machineries. The P450 systems that use such carrier protein bound substrates are involved in the biosynthesis of many important natural products, including the vitamin biotin and the clinically important glycopeptide antibiotics, exemplified by vancomycin and teicoplanin. This presentation will report our efforts in the structural and biochemical characterisation of several classes of such P450s systems, including the fatty acyl carrier protein-P450 complex involved in biotin biosynthesis in Bacillus species and the tyrosine ß-hydroxylase involved in vancomycin-type glycopeptide biosynthesis.^{5, 6} The role of the carrier protein in each system will be addressed, together with implications for the future development and exploitation of such systems in oxidation chemistry.

Classes of Carrier Protein-P450 Systems