Cyanide as a primordial reductant enables a protometabolic reductive glyoxylate pathway.

Investigation of prebiotic metabolic pathways is predominantly based on abiotically replicating the reductive citric acid cycle. While attractive from a parsimony point of view, attempts using metal/mineral-mediated reductions have produced complex mixtures with inefficient and uncontrolled reactions. Here we show that cyanide acts as a mild and efficient reducing agent mediating abiotic transformations of tricarboxylic acid intermediates and derivatives.

The Unexpected Base-Pairing Behavior of Cyanuric Acid in RNA and Ribose versus Cyanuric Acid Induced Helicene Assembly of Nucleic Acids: Implications for the Pre-RNA Paradigm.

The cyanuric acid (CA) heterocycle forms supramolecular structures with adenine nucleobases/nucleosides and oligonucleotides, leading to speculation that they can act as forerunners to RNA. Herein, the assembly behavior of RNA containing CA and CA-ribose nucleoside was studied. Contrary to previous reports, CA in RNA and the CA-ribonucleoside resulted in destabilization of supramolecular assemblies, which led to a reevaluation of the CA-adenine hexameric rosette structure.

Structural basis for the action of the drug trametinib at KSR-bound MEK.

The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology, and more recently in immunotherapy and ageing. However, many MEK inhibitors are limited owing to on-target toxicities and drug resistance. Accordingly, a molecular understanding of the structure and function of MEK within physiological complexes could provide a template for the design of safer and more effective therapies.

Linked cycles of oxidative decarboxylation of glyoxylate as protometabolic analogs of the citric acid cycle.

The development of metabolic approaches towards understanding the origins of life, which have focused mainly on the citric acid (TCA) cycle, have languished-primarily due to a lack of experimentally demonstrable and sustainable cycle(s) of reactions. We show here the existence of a protometabolic analog of the TCA involving two linked cycles, which convert glyoxylate into CO and produce aspartic acid in the presence of ammonia. The reactions proceed from either pyruvate, oxaloacetate or malonate in the presence of glyoxylate as the carbon source and hydrogen peroxide as the oxidant under neutral aqueous conditions and at mild temperatures.

Anchimeric-Assisted Spontaneous Hydrolysis of Cyanohydrins Under Ambient Conditions: Implications for Cyanide-Initiated Selective Transformations.

Nitrile/cyanide hydrolysis is of importance from the perspective of organic chemistry, especially, prebiotic chemistry. Herein we report that cyanohydrins, generated by the reaction of cyanide with β-keto acids and γ-keto-alcohols, spontaneously hydrolyze under ambient conditions (aqueous medium, RT, and a range of pH). The spontaneous hydrolysis is affected by an intramolecular proton transfer and an intramolecular 5-exo-dig attack, but with a twist.