Dataset Information

Catalytic promiscuity of a bacterial ?-N-methyltransferase.

ABSTRACT: The posttranslational methylation of N-terminal ?-amino groups (?-N-methylation) is a ubiquitous reaction found in all domains of life. Although this modification usually occurs on protein substrates, recent studies have shown that it also takes place on ribosomally synthesized natural products. Here we report an investigation of the bacterial ?-N-methyltransferase CypM involved in the biosynthesis of the peptide antibiotic cypemycin. We demonstrate that CypM has low substrate selectivity and methylates a variety of oligopeptides, cyclic peptides such as nisin and haloduracin, and the ?-amino group of lysine. Hence it may have potential for enzyme engineering and combinatorial biosynthesis. Bayesian phylogenetic inference of bacterial ?-N-methyltransferases suggests that they have not evolved as a specific group based on the chemical transformations they catalyze, but that they have been acquired from various other methyltransferase classes during evolution.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC3462432 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Catalytic promiscuity of a bacterial α-N-methyltransferase.

Zhang Qi Q van der Donk Wilfred A WA

FEBS letters 20120725 19

The posttranslational methylation of N-terminal α-amino groups (α-N-methylation) is a ubiquitous reaction found in all domains of life. Although this modification usually occurs on protein substrates, recent studies have shown that it also takes place on ribosomally synthesized natural products. Here we report an investigation of the bacterial α-N-methyltransferase CypM involved in the biosynthesis of the peptide antibiotic cypemycin. We demonstrate that CypM has low substrate selectivity and me ...[more]

PMID: 22841713

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Project description:In recent years, it has become increasingly clear that promiscuity plays a key role in the evolution of new enzyme function. This finding has helped to elucidate fundamental aspects of molecular evolution. While there has been extensive experimental work on enzyme promiscuity, computational modeling of the chemical details of such promiscuity has traditionally fallen behind the advances in experimental studies, not least due to the nearly prohibitive computational cost involved in examining multiple substrates with multiple potential mechanisms and binding modes in atomic detail with a reasonable degree of accuracy. However, recent advances in both computational methodologies and power have allowed us to reach a stage in the field where we can start to overcome this problem, and molecular simulations can now provide accurate and efficient descriptions of complex biological systems with substantially less computational cost. This has led to significant advances in our understanding of enzyme function and evolution in a broader sense. Here, we will discuss currently available computational approaches that can allow us to probe the underlying molecular basis for enzyme specificity and selectivity, discussing the inherent strengths and weaknesses of each approach. As a case study, we will discuss recent computational work on different members of the alkaline phosphatase superfamily (AP) using a range of different approaches, showing the complementary insights they have provided. We have selected this particular superfamily, as it poses a number of significant challenges for theory, ranging from the complexity of the actual reaction mechanisms involved to the reliable modeling of the catalytic metal centers, as well as the very large system sizes. We will demonstrate that, through current advances in methodologies, computational tools can provide significant insight into the molecular basis for catalytic promiscuity, and, therefore, in turn, the mechanisms of protein functional evolution.

Dataset Information

Catalytic promiscuity of a bacterial ?-N-methyltransferase.

Publications

Catalytic promiscuity of a bacterial α-N-methyltransferase.

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