Mirror, mirror on the wall: which microbiomes will help heal them all?

BACKGROUND: Clinicians have known for centuries that there is substantial variability between patients in their response to medications—some individuals exhibit a miraculous recovery while others fail to respond at all. Still others experience dangerous side effects. The hunt for the factors responsible for this variation has been aided by the ability to sequence the human genome, but this just provides part of the picture. Here, we discuss the emerging field of study focused on the human microbiome and how it may help to better predict drug response and improve the treatment of human disease. DISCUSSION: Various clinical disciplines characterize drug response using either continuous or categorical descriptors that are then correlated to environmental and genetic risk factors. However, these approaches typically ignore the microbiome, which can directly metabolize drugs into downstream metabolites with altered activity, clearance, and/or toxicity. Variations in the ability of each individual’s microbiome to metabolize drugs may be an underappreciated source of differences in clinical response. Complementary studies in humans and animal models are necessary to elucidate the mechanisms responsible and to test the feasibility of identifying microbiome-based biomarkers of treatment outcomes. SUMMARY: We propose that the predictive power of genetic testing could be improved by taking a more comprehensive view of human genetics that encompasses our human and microbial genomes. Furthermore, unlike the human genome, the microbiome is rapidly altered by diet, pharmaceuticals, and other interventions, providing the potential to improve patient care by re-shaping our associated microbial communities

Cu^I and H₂O₂ inactivate and Fe^II inhibits [Fe]-hydrogenase at very low concentrations

[Fe]-Hydrogenase (Hmd) catalyzes reversible hydride transfer from H2. It harbors an iron-guanylylpyridinol as cofactor with an FeII that is ligated with one thiolate, two CO, one acyl-C, one pyridinol-N, and a solvent. Here, we report that CuI and H2O2 inactivate Hmd, half maximal rates being observed at 1 µM CuI and 20 µM H2O2 and that FeII inhibits the enzyme with very high affinity (Ki of 40 nM). Infrared and EPR studies together with competitive inhibition studies with isocyanide indicated that CuI exerts its inhibitory effect most probably by binding to the active site iron-thiolate ligand. Using the same methods, it was found that H2O2 binds to the active site iron at the solvent-binding site and oxidizes FeII to FeIII. Also it was shown that FeII reversibly binds distant to the active site iron, binding being competitive to the organic hydride acceptor; this inhibition is specific for FeII reminiscent to the second iron in [FeFe]-hydrogenases that specifically interacts with H2