1) are collectively involved in the preservation, replication, and expression of hereditary information in every living cell. The primary biological role of RNA is to direct the process of protein synthesis.Īn acidic, chainlike biological macromolecule consisting of multiple repeated units of phosphoric acid, sugar, and purine and pyrimidine bases. Information is contained in the DNA in the form of the sequence of nucleotide building blocks in the nucleic acid chain. There are two types of nucleic acids-deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).ĭNA is the chemical constituent of the genes of an organism. Nucleic acids are involved in the preservation, replication, and expression of hereditary information in every living cell. This demonstration that a correctly positioned α-hydroxy ketone substrate can realize lyase activity with an unusual inverse solvent isotope effect in an engineered microbial system opens the door for further detailed biophysical and structural characterization of CYP catalytic intermediates.ĭepartment of Chemistry, University of Adelaide, Adelaide, South Australia 5005, Australia.A nucleic acid is an acidic, chainlike biological macromolecule consisting of multiple repeated units of phosphoric acid, sugar, and purine and pyrimidine bases. Molecular dynamics simulations with an oxy-ferrous model of CYP199A4 revealed a displacement of the substrate to allow for oxygen binding and the formation of the lyase transition state proposed for CYP17A1. Co-crystallization of F182L-CYP199A4 with this α-hydroxy ketone showed that the substrate bound in the active site with a preference for the (S)-enantiomer in a position which could mimic the topology of the lyase reaction in CYP17A1. This C-C cleavage reaction was subject to an inverse kinetic solvent isotope effect analogous to that observed in the lyase activity of the human P450 CYP17A1, suggesting the involvement of a species earlier than Compound I in the catalytic cycle. After observing low activity with wild-type CYP199A4, subsequent assays with an F182L mutant demonstrated enzyme-dependent C-C bond cleavage toward one of the α-hydroxy ketones. Seeking to study the carbon-carbon cleavage reaction of α-hydroxy ketones in mechanistic detail using a microbial P450, we synthesized α-hydroxy ketone probes based on the physiological substrate for a well-characterized benzoic acid metabolizing P450, CYP199A4. The cytochrome P450 (CYP) superfamily of heme monooxygenases has demonstrated ability to facilitate hydroxylation, desaturation, sulfoxidation, epoxidation, heteroatom dealkylation, and carbon-carbon bond formation and cleavage (lyase) reactions.
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