Discovery and characterization of the first known biological lanthanide chelator
Many bacteria secrete metallophores, low-molecular weight organic compounds that bind ions with high selectivity and affinity, in order to access essential metals from the environment. The biosynthetic machinery to produce metallophores as well as their structures have been elucidated for iron, zinc, nickel, molybdenum, and copper specific molecules. No lanthanide-specific metallophore has been discovered despite the knowledge that lanthanide metals (Ln) have recently been revealed to be essential cofactors for certain alcohol dehydrogenases across a diverse range of phyla. Here, we report the biosynthetic machinery for, the structure of, and the physiological relevance of the first known lanthanophore, methylolanthanin. The structure of methylolanthanin exhibits a unique 4-hydroxybenzoate moiety which has not previously been described in other metallophores. We find that production of methylolanthanin is required for normal levels of Ln accumulation in the methylotrophic bacterium Methylobacterium extorquens AM1, while overexpression of the molecule greatly increases bioaccumulation. Our results provide a clearer understanding of how Ln-utilizing bacteria sense, scavenge, and store Ln; essential processes in the environment where Ln are poorly bioavailable. Beyond Ln, we anticipate our study to be a starting point for understanding how organisms acquire other f-block metals, the actinides. More broadly, the discovery of a lanthanophore opens doors for study of how biosynthetic gene clusters are repurposed for new functions, how metallophores acquire their metal specificity, and the complex relationship between metal homeostasis and fitness. Overall design: To better understand the impacts of Ln solubility on methylotrophy in M. extorquens AM1, we assessed the growth and transcriptomic changes of a mutant lacking the lanthanide-dependent methanol dehydrogenase MxaFI (dmxaF) when grown with methanol and either soluble NdCl3 or poorly soluble Nd2O3. Gene expression profiling analysis was perfomed on two strains (WT, mxaF) with data from RNA-seq of each condition (NdCl3 or Nd2O3) with three biological replicates per condition, with the WT strain serving as a reference.