Ketoacidosis - Where Do the Protons Come From? Green Allan,Bishop Ronald E Trends in biochemical sciences In extreme conditions ketosis can progress to ketoacidosis, a dangerous and potentially life-threatening condition. Ketoacidosis is most common in new or poorly treated type 1 diabetes. The acidosis is usually attributed to the 'acidic' nature of the ketone bodies (acetoacetate, 3-hydroxybutyrate, and acetone). However, acetoacetate and 3-hydroxybutyrate are produced not as acids but as their conjugate bases, and acetone is neither an acid nor a base. This raises the question of why severe ketosis is accompanied by acidosis. Here, we analyze steps in ketogenesis and identify four potential sources: adipocyte lipolysis, hydrolysis of inorganic pyrophosphate generated during synthesis of fatty acyl-coenzyme A (CoA), the reaction catalyzed by an enzyme in the β-oxidation pathway (3-hydroxyacyl-CoA dehydrogenase), and increased synthesis of CoA. 10.1016/j.tibs.2019.01.005

Development of a synthetic live bacterial therapeutic for the human metabolic disease phenylketonuria. Isabella Vincent M,Ha Binh N,Castillo Mary Joan,Lubkowicz David J,Rowe Sarah E,Millet Yves A,Anderson Cami L,Li Ning,Fisher Adam B,West Kip A,Reeder Philippa J,Momin Munira M,Bergeron Christopher G,Guilmain Sarah E,Miller Paul F,Kurtz Caroline B,Falb Dean Nature biotechnology Phenylketonuria (PKU) is a genetic disease that is characterized by an inability to metabolize phenylalanine (Phe), which can result in neurotoxicity. To provide a potential alternative to a protein-restricted diet, we engineered Escherichia coli Nissle to express genes encoding Phe-metabolizing enzymes in response to anoxic conditions in the mammalian gut. Administration of our synthetic strain, SYNB1618, to the Pah PKU mouse model reduced blood Phe concentration by 38% compared with the control, independent of dietary protein intake. In healthy Cynomolgus monkeys, we found that SYNB1618 inhibited increases in serum Phe after an oral Phe dietary challenge. In mice and primates, Phe was converted to trans-cinnamate by SYNB1618, quantitatively metabolized by the host to hippurate and excreted in the urine, acting as a predictive biomarker for strain activity. SYNB1618 was detectable in murine or primate feces after a single oral dose, permitting the evaluation of pharmacodynamic properties. Our results define a strategy for translation of live bacterial therapeutics to treat metabolic disorders. 10.1038/nbt.4222