Natural products from microbes have provided humans with beneficial antibiotics for millennia. However, a decline in the pace of antibiotic discovery exerts pressure on human health as antibiotic resistance spreads, a challenge that may better faced by unveiling chemical diversity produced by microbes. Current microbial genome mining approaches have revitalized research into antibiotics, but the empirical nature of these methods limits the chemical space that is explored.Here, we address the problem of finding novel pathways by incorporating evolutionary principles into genome mining. We recapitulated the evolutionary history of twenty-three enzyme families previously uninvestigated in the context of natural product biosynthesis in Actinobacteria, the most proficient producers of natural products. Our genome evolutionary analyses where based on the assumption that expanded—repurposed enzyme families—from central metabolism, occur frequently and thus have the potential to catalyze new conversions in the context of natural products biosynthesis. Our analyses led to the discovery of biosynthetic gene clusters coding for hidden chemical diversity, as validated by comparing our predictions with those from state-of-the-art genome mining tools; as well as experimentally demonstrating the existence of a biosynthetic pathway for arseno-organic metabolites in Streptomyces coelicolor and Streptomyces lividans, Using a gene knockout and metabolite profile combined strategy.As our approach does not rely solely on sequence similarity searches of previously identified biosynthetic enzymes, these results establish the basis for the development of an evolutionary-driven genome mining tool termed EvoMining that complements current platforms. We anticipate that by doing so real ‘chemical dark matter’ will be unveiled.

Purpose We aimed to examine the prospective association between manganese, iron, copper, zinc, iodine, selenium, selenoprotein P, free zinc, and their interplay, with incident type 2 diabetes (T2D), cardiovascular disease (CVD) and colorectal cancer (CRC). Methods Serum trace element (TE) concentrations were measured in a case-cohort study embedded within the EPIC-Potsdam cohort, consisting of a random sub-cohort (n = 2500) and incident cases of T2D (n = 705), CVD (n = 414), and CRC (n = 219). TE patterns were investigated using principal component analysis. Cox proportional hazard models were fitted to examine the association between TEs with T2D, CVD and CRC incidence. Results Higher manganese, zinc, iodine and selenium were associated with an increased risk of developing T2D (HR Q5 vs Q1: 1.56, 1.09–2.22; HR per SD, 95% CI 1.18, 1.05–1.33; 1.09, 1.01–1.17; 1.19, 1.06–1.34, respectively). Regarding CVD, manganese, copper and copper-to-zinc ratio were associated with an increased risk (HR per SD, 95% CI 1.13, 1.00–1.29; 1.22, 1.02–1.44; 1.18, 1.02–1.37, respectively). The opposite was observed for higher selenium-to-copper ratio (HR Q5 vs Q1, 95% CI 0.60, 0.39–0.93). Higher copper and zinc were associated with increasing risk of developing CRC (HR per SD, 95% CI 1.29, 1.05–1.59 and 1.14, 1.00–1.30, respectively). Selenium, selenoprotein P and selenium-to-copper-ratio were associated to decreased risk (HR per SD, 95% CI 0.82, 0.69–0.98; 0.81, 0.72–0.93; 0.77, 0.65–0.92, respectively). Two TE patterns were identified: manganese–iron–zinc and copper–iodine–selenium. Conclusion Different TEs were associated with the risk of developing T2D, CVD and CRC. The contrasting associations found for selenium with T2D and CRC point towards differential disease-related pathways.

Purpose We aimed to evaluate age-dependent changes of six trace elements (TE) [manganese (Mn), iron (Fe), zinc (Zn), copper (Cu), iodine (I), and selenium (Se)] over a 20-year period. Methods TE concentrations were determined using repeated serum samples taken at baseline and after 20 years of follow-up from 219 healthy participants of the EPIC-Potsdam study, using inductively coupled plasma tandem mass spectrometry. For each TE, absolute and relative differences were calculated between the two time points, as well as the proportion of individuals within normal reference ranges. Interdependence between age-related TE differences was investigated using principal component analysis (PCA). Relationships between selected factors (lifestyle, sociodemographic, anthropometric factors, and hypertension) and corresponding TE longitudinal variability were examined using multivariable linear regression models.Results Median age of our study sample was 58.32 years (4.42) at baseline and 40% were females. Median Mn, Zn, Se concentrations and Se to Cu ratio significantly decreased during aging while median Fe, Cu, I concentrations and Cu to Zn ratio significantly increased. A substantial percentage of the participants, at both time points, had Zn concentrations below the reference range. The first PCA-extracted factor reflected the correlated decline in both Mn and Zn over time while the second factor reflected the observed (on average) increase in both Cu and I over time. Overall, none of the investigated factors were strong determinants of TE longitudinal variability, except possibly dietary supplement use, and alcohol use for Fe. Conclusions In conclusion, in this population-based study of healthy elderly, decrease in Mn, Zn, and Se concentrations and increase in Fe, Cu, and I concentrations were observed over 20 years of follow-up. Further research is required to investigate dietary determinants and markers of TE status as well as the relationships between TE profiles and the risk of age-related diseases.

Trace elements, like Cu, Zn, Fe, or Se, are important for the proper functioning of antioxidant enzymes. However, in excessive amounts, they can also act as pro-oxidants. Accordingly, trace elements influence redox-modulated signaling pathways, such as the Nrf2 pathway. Vice versa, Nrf2 target genes belong to the group of transport and metal binding proteins. In order to investigate whether Nrf2 directly regulates the systemic trace element status, we used mice to study the effect of a constitutive, whole-body Nrf2 knockout on the systemic status of Cu, Zn, Fe, and Se. As the loss of selenoproteins under Se-deprived conditions has been described to further enhance Nrf2 activity, we additionally analyzed the combination of Nrf2 knockout with feeding diets that provide either suboptimal, adequate, or supplemented amounts of Se. Experiments revealed that the Nrf2 knockout partially affected the trace element concentrations of Cu, Zn, Fe, or Se in the intestine, liver, and/or plasma. However, aside from Fe, the other three trace elements were only marginally modulated in an Nrf2-dependent manner. Selenium deficiency mainly resulted in increased plasma Zn levels. One putative mediator could be the metal regulatory transcription factor 1, which was up-regulated with an increasing Se supply and downregulated in Se-supplemented Nrf2 knockout mice.

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A decline of immune responses and dynamic modulation of the redox status are observed during aging and are influenced by trace elements such as copper, iodine, iron, manganese, selenium, and zinc. So far, analytical studies have focused mainly on single trace elements. Therefore, we aimed to characterize age-specific profiles of several trace elements simultaneously in serum and organs of adult and old mice. This allows for correlating multiple trace element levels and to identify potential patterns of age-dependent alterations. In serum, copper and iodine concentrations were increased and zinc concentration was decreased in old as compared to adult mice. In parallel, decreased copper and elevated iron concentrations were observed in liver. The age-related reduction of hepatic copper levels was associated with reduced expression of copper transporters, whereas the increased hepatic iron concentrations correlated positively with proinflammatory mediators and Nrf2-induced ferritin H levels. Interestingly, the age-dependent inverse regulation of copper and iron was unique for the liver and not observed in any other organ. The physiological importance of alterations in the iron/copper ratio for liver function and the aging process needs to be addressed in further studies.