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Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme that catalyzes the transfer of a methyl group from the co-factor S-adenosyl-L-methionine (SAM) onto the substrate, nicotinamide (NA) to form 1-methyl-nicotinamide (MNA). Higher NNMT expression and MNA concentrations have been associated with obesity and type-2 diabetes. Here we report a small molecule analog of NA, JBSNF-000088, that inhibits NNMT activity, reduces MNA levels and drives insulin sensitization, glucose modulation and body weight reduction in animal models of metabolic disease. In mice with high fat diet (HFD)-induced obesity, JBSNF-000088 treatment caused a reduction in body weight, improved insulin sensitivity and normalized glucose tolerance to the level of lean control mice. These effects were not seen in NNMT knockout mice on HFD, confirming specificity of JBSNF-000088. The compound also improved glucose handling in ob/ob and db/db mice albeit to a lesser extent and in the absence of weight loss. Co-crystal structure analysis revealed the presence of the N-methylated product of JBSNF-000088 bound to the NNMT protein. The N-methylated product was also detected in the plasma of mice treated with JBSNF-000088. Hence, JBSNF-000088 may act as a slow-turnover substrate analog, driving the observed metabolic benefits.

We study a potential surface for the tetramethylene diradical, CH2CH2CH2CH2, a likely intermediate in the nonconcerted fragmentation of cyclobutane to two ethylenes. Outside a clearly defined region of a distorted cyclobutane we find two apparent minima, in geometry close to trans and gauche conformations of a model «-butane. These minima appear to be unstable with respect to fragmentation to two ethylenes. In fact, a motion in any degree of freedom away from the distorted cyclobutane region leads to a level crossing and a tetramethylene species whose orbitals resemble those of two interacting ethylenes. If by the term "intermediate" is meant a true minimum in the many dimensional potential surface then our calculations imply there is no such species intervening between cyclobutane and two ethylenes. We suggest that a large energetically flat region of a potential surface will in the context of modern collision theory have the same operational consequences as a true intermediate, and that such a region, termed a "twixtyl," may be a common feature of nonconcerted reactions.

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