Deciphering microbial metalloenzyme functions in microaerobic host environments

项目总结

Project Summary Commensal and pathogenic bacteria inhabit various oxygen-depleted niches in the human body, such as the gastrointestinal tract, wound tissue, and the lung mucosa. Adaptation to these environments requires distinct anaerobic biochemistry to support colonization and survival. An understanding of these biochemical strategies could present unique opportunities to develop novel therapeutics that overcome challenges of antibiotic resistance and bacterial persistence. However, we lack fundamental knowledge of the diverse chemistry that microbes use in anaerobic and microaerobic environments. The proposed studies outline our approach to elucidate the molecular mechanisms, biochemical reactions, and biological roles of metalloenzymes in host- microbe interactions. Metalloenzymes play central roles in cellular redox chemistry. Whereas classes of metalloenzymes that active oxygen for redox reactions have been studied for decades, metalloenzyme families that function in the absence of oxygen remain poorly characterized. In this project, we interrogate the chemical and biological functions of a newly discovered family of metalloenzyme oxidases that are prevalent in bacterial pathogens and human gut microbes. The few known representatives of this family catalyze oxygen-independent hydroxylation reactions in key cellular processes, including cofactor biosynthesis and RNA modification. We will use these known enzymes to establish the requirements for catalysis and to discern their postulated roles in microoxic conditions. Beyond the members with established functions, emerging metalloenzyme families also represent an untapped source of biochemical diversity. We will leverage genomics and protein bioinformatics to discover new enzymatic chemistry within this poorly characterized superfamily. The proposed work will reveal previously unknown redox chemistry, establish biochemical responses to microaerobic conditions, and set the stage to interrogate the importance of these reactions in host-microbe interactions. The ultimate goal of this research program is to gain a molecular understanding of microbial adaptation to O2 limitation that can be leveraged to treat elusive drug-resistant bacterial pathogens.