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An essential role for bacterial nitric oxide synthase in Staphylococcus aureus electron transfer and colonization.

ABSTRACT: Nitric oxide (NO•) is a ubiquitous molecular mediator in biology. Many signalling actions of NO• generated by mammalian NO• synthase (NOS) result from targeting of the haem moiety of soluble guanylate cyclase. Some pathogenic and environmental bacteria also produce a NOS that is evolutionary related to the mammalian enzymes, but a bacterial haem-containing receptor for endogenous enzymatically generated NO• has not been identified previously. Here, we show that NOS of the human pathogen Staphylococcus aureus, in concert with an NO•-metabolizing flavohaemoprotein, regulates electron transfer by targeting haem-containing cytochrome oxidases under microaerobic conditions to maintain membrane bioenergetics. This process is essential for staphylococcal nasal colonization and resistance to the membrane-targeting antibiotic daptomycin and demonstrates the conservation of NOS-derived NO•-haem receptor signalling between bacteria and mammals.

SUBMITTER: Kinkel TL

PROVIDER: S-EPMC5451252 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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An essential role for bacterial nitric oxide synthase in Staphylococcus aureus electron transfer and colonization.

Kinkel Traci L TL Ramos-Montañez Smirla S Pando Jasmine M JM Tadeo Daniel V DV Strom Erin N EN Libby Stephen J SJ Fang Ferric C FC

Nature microbiology 20161128

Nitric oxide (NO•) is a ubiquitous molecular mediator in biology. Many signalling actions of NO• generated by mammalian NO• synthase (NOS) result from targeting of the haem moiety of soluble guanylate cyclase. Some pathogenic and environmental bacteria also produce a NOS that is evolutionary related to the mammalian enzymes, but a bacterial haem-containing receptor for endogenous enzymatically generated NO• has not been identified previously. Here, we ...[more]

PMID: 27892921

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Project description:Nitric oxide synthase (NOS), a flavo-hemoprotein, tightly regulates nitric oxide (NO) synthesis and thereby its dual biological activities as a key signaling molecule for vasodilatation and neurotransmission at low concentrations, and also as a defensive cytotoxin at higher concentrations. Three NOS isoforms, iNOS, eNOS and nNOS (inducible, endothelial, and neuronal NOS), achieve their key biological functions by tight regulation of interdomain electron transfer (IET) process via interdomain interactions. In particular, the FMN-heme IET is essential in coupling electron transfer in the reductase domain with NO synthesis in the heme domain by delivery of electrons required for O(2) activation at the catalytic heme site. Compelling evidence indicates that calmodulin (CaM) activates NO synthesis in eNOS and nNOS through a conformational change of the FMN domain from its shielded electron-accepting (input) state to a new electron-donating (output) state, and that CaM is also required for proper alignment of the domains. Another exciting recent development in NOS enzymology is the discovery of importance of the the FMN domain motions in modulating reactivity and structure of the catalytic heme active site (in addition to the primary role of controlling the IET processes). In the absence of a structure of full-length NOS, an integrated approach of spectroscopic (e.g. pulsed EPR, MCD, resonance Raman), rapid kinetics (laser flash photolysis and stopped flow) and mutagenesis methods is critical to unravel the molecular details of the interdomain FMN/heme interactions. This is to investigate the roles of dynamic conformational changes of the FMN domain and the docking between the primary functional FMN and heme domains in regulating NOS activity. The recent developments in understanding of mechanisms of the NOS regulation that are driven by the combined approach are the focuses of this review. An improved understanding of the role of interdomain FMN/heme interaction and CaM binding may serve as the basis for the design of new selective inhibitors of NOS isoforms.

Dataset Information

An essential role for bacterial nitric oxide synthase in Staphylococcus aureus electron transfer and colonization.

Publications

An essential role for bacterial nitric oxide synthase in Staphylococcus aureus electron transfer and colonization.

Similar Datasets

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