Protection from nitrosative stress: A central role for microbial flavohemoglobin

• Published in: Free radical biology & medicine 2012-05, Vol.52 (9), p.1620-1633
• Main Authors: Forrester, Michael T., Foster, Matthew W.
• Format: Article
• Language: English
• Subjects: Aerobiosis; Amino Acid Sequence; Anaerobiosis; Bacteria; cytotoxicity; Dihydropteridine Reductase - chemistry; Dihydropteridine Reductase - genetics; Dihydropteridine Reductase - physiology; Dioxygenase; electron transport chain; Escherichia coli; Escherichia coli Proteins - chemistry; Escherichia coli Proteins - genetics; Escherichia coli Proteins - physiology; Flavohemoglobin; Free radicals; Fungi; Gene Expression Regulation, Bacterial; genomics; Hemeproteins - chemistry; Hemeproteins - genetics; Hemeproteins - physiology; Humans; Molecular Sequence Data; NADH, NADPH Oxidoreductases - chemistry; NADH, NADPH Oxidoreductases - genetics; NADH, NADPH Oxidoreductases - physiology; neoplasms; nitrates; Nitric oxide; Nitric Oxide - physiology; Nitrosation; Nitrosative stress; Oxidative Stress; Oxidoreductase; oxygen; Protein Conformation; proteins; Protozoa; Redox; S-nitrosylation; Sequence Homology, Amino Acid; transcription (genetics); Transcription, Genetic
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2012.01.028

Nitric oxide (NO) is an inevitable product of life in an oxygen- and nitrogen-rich environment. This reactive diatomic molecule exhibits microbial cytotoxicity, in large part by facilitating nitrosative stress and inhibiting heme-containing proteins within the aerobic respiratory chain. Metabolism of NO is therefore essential for microbial life. In many bacteria, fungi, and protozoa, the evolutionarily ancient flavohemoglobin (flavoHb) converts NO and O2 to inert nitrate (NO3−) and undergoes catalytic regeneration via flavin-dependent reduction. Since its identification, widespread efforts have characterized roles for flavoHb in microbial nitrosative stress protection. Subsequent genomic studies focused on flavoHb have elucidated the transcriptional machinery necessary for inducible NO protection, such as NsrR in Escherichia coli, as well as additional proteins that constitute a nitrosative stress protection program. As an alternative strategy, flavoHb has been heterologously employed in higher eukaryotic organisms such as plants and human tumors to probe the function(s) of endogenous NO signaling. Such an approach may also provide a therapeutic route to in vivo NO depletion. Here we focus on the molecular features of flavoHb, the hitherto characterized NO-sensitive transcriptional machinery responsible for its induction, the roles of flavoHb in resisting mammalian host defense systems, and heterologous applications of flavoHb in plant/mammalian systems (including human tumors), as well as unresolved questions surrounding this paradigmatic NO-consuming enzyme. [Display omitted] ► Nitric oxide (NO) is a ubiquitous biological gas and central mediator of cytotoxic nitrosative stress. ► Bacteria and fungi counteract nitrosative stress by expressing flavohemoglobin (flavoHb), an efficient NO dioxygenase. ► FlavoHb deletion or inhibition confers hypersensitivity to nitrosative stress and impaired colonization in mammalian models of infection. ► Antifungal azoles may inhibit flavoHb, encouraging the development of more potent flavoHb inhibitors and antimicrobial drugs. ► In higher eukaryotes, heterologous expression of bacterial flavoHb may be used to study endogenous NO signaling pathways and therapeutically deplete NO.