Metformin hydrolase is a recently evolved nickel-dependent heteromeric ureohydrolase.

The anti-diabetic drug metformin is one of the most widely prescribed medicines in the world. Together with its degradation product guanylurea, it is a major pharmaceutical pollutant in wastewater treatment plants and surface waters. An operon comprising two genes of the ureohydrolase family in Pseudomonas and Aminobacter species has recently been implicated in metformin degradation. However, the corresponding proteins have not been characterized. Here we show that these genes encode a Ni2+-dependent enzyme that efficiently and specifically hydrolyzes metformin to guanylurea and dimethylamine. The active enzyme is a heteromeric complex of α- and ß- subunits in which only the α-subunits contain the conserved His and Asp residues for the coordination of two Ni2+ ions in the active site. A crystal structure of metformin hydrolase reveals an α2ß4 stoichiometry of the hexameric complex, which is unprecedented in the ureohydrolase family. By studying a closely related but more widely distributed enzyme, we find that the putative predecessor specifically hydrolyzes dimethylguanidine instead of metformin. Our findings establish the molecular basis for metformin hydrolysis to guanylurea as the primary pathway for metformin biodegradation and provide insight into the recent evolution of ureohydrolase family proteins in response to an anthropogenic compound.

Larch arabinogalactan effects on reducing incidence of upper respiratory infections.

OBJECTIVE: Larch arabinogalactan (ResistAid * ) may prevent cold infections due to its immune-stimulatory properties. In a placebo-controlled, double-blind, randomized clinical trial, the effect of a proprietary larch arabinogalactan preparation on the incidences of common colds and its effect on cold symptoms, as a well established model for immune function, was compared to placebo. RESEARCH DESIGN AND METHODS: A total of 199 healthy participants who had a self reported cold infection rate of three in 6 months were randomly assigned to receive a total of either 4.5 g of an arabinogalactan preparation (n = 101) or placebo (n = 98) over a period of 12 weeks. MAIN OUTCOME MEASURES: The participants documented each common cold episode in a diary, and rated 10 predefined infection symptoms on a 4 point rating scale during an infection period, resulting in an infection score. The common cold episodes were confirmed by medical doctors. CLINICAL TRIAL REGISTRATION: ISRCTN41183655. RESULTS: In the full analysis set (FAS), arabinogalactan tended to decrease the incidence of common cold (p = 0.055). The number of participants affected by a cold was significantly reduced by arabinogalactan supplementation (p = 0.038). Concerning the per protocol (PP) collective, the incidences of common cold (p = 0.040) and the number of participants affected by the infection (p = 0.033) were significantly fewer after arabinogalactan compared to placebo consumption. The severity of symptoms at episode start as experienced by the participants was significantly higher after arabinogalactan supplementation (p = 0.028). The treatment was well tolerated with no significant differences between the study groups. CONCLUSION: The present study demonstrated that larch arabinogalactan increased the body's potential to defend against common cold infection. While the immunomodulatory effect of arabinogalactan can be assumed, its mechanism of action remains to be elucidated.