RESUMEN
Alkene functionalization has garnered significant attention due to the versatile reactivity of C=C bonds. A major challenge is the selective conversion of isomeric alkenes into chiral products. Researchers have devised various biocatalytic strategies to transform isomeric alkenes into stereopure compounds; while selective, the enzymes often specifically convert one alkene isomer, thereby diminishing overall yield. To increase the overall yield, scientists have introduced additional driving forces to interconvert alkene isomers. This improves the yield of biocatalytic alkene functionalization at the cost of increased energy consumption and chemical waste. Developing a stereoconvergent enzyme for alkene functionalization offers an ideal solution, although such catalysts are rarely reported. Here we present engineered hemoproteins derived from a bacterial cytochrome P450 that efficiently catalyze the stereoconvergent α-carbonyl alkylation of isomeric silyl enol ethers, producing stereopure products. Through screening and directed evolution, we generated P450BM3 variant SCA-G2, which catalyzes stereoconvergent carbene transfer in E. coli, with high efficiency and stereoselectivity toward various Z/E mixtures of silyl enol ethers. In contrast to established stereospecific transformations that leave one isomer unreacted, SCA-G2 converts both isomers to a stereopure product. This biocatalytic approach simplifies the synthesis of chiral α-branched ketones by eliminating the need for stoichiometric chiral auxiliaries, strongly basic alkali-metal enolates, and harsh conditions, delivering products with high efficiency and excellent chemo- and stereoselectivities.
RESUMEN
La enfermedad cardiovascular constituye una serie de entidades patológicas que tienen tratamientos médicos diferentes. La terapia celular es un enfoque del siglo Xxi para abordar el tratamiento de la enfermedad cardiovascular y se aplica en todo el mundo. Sin embargo, no se ha abordado de manera adecuada la definición de la mejor población celular a utilizar ni las mejores condiciones de tratamiento. Sería ingenuo creer que se pueda encontrar un tratamiento único (ni siquiera con células madre) que permita tratar todo el espectro de las enfermedades cardiovasculares. Describimos el espectro de la cardiopatía isquémica, los posibles usos de células para su tratamiento adecuado y las cuestiones básicas que hay que abordar al contemplar la terapia celular cardiovascular. El objetivo clínico es la regeneración cardiaca y vascular, pero todavía está por determinar si las células pueden conseguir estos efectos. La elección de la célula correcta, la ventana terapéutica ideal y el paciente «adecuado» también son cuestiones abiertas al debate. Este artículo se ha diseñado para aportar una perspectiva respecto a las fases inicial, media y avanzada de la enfermedad cardiovascular y describir cómo podrían usarse las células de un modo diferenciado para el tratamiento de cada fase (AU)
Cardiovascular disease represents a continuum of disease entities whose medical treatments differ. Cell therapy is a 21st century approach to treating cardiovascular disease and is being applied worldwide. However, no concerted approach exists for defining the best cell population(s) to use, or the best treatment conditions. It is naïve to believe that a single treatment-even a stem cellcan be found to treat the entire spectrum of cardiovascular disease. We describe the continuum of ischemic heart disease, the potential uses of cells for treating this continuum, and the basic issues that must be considered when contemplating cardiovascular cell therapy. The clinical goal is cardiac and vascular regeneration. Whether cells can deliver this remains to be determined. The correct cell, the ideal therapeutic window, and the “right” patient likewise are open to debate. This article is designed to provide insights into the early, middle, and later stages of cardiovascular disease and how cells might be used differently for treatment at each stage (AU)