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Carbohydrate digestion and metabolism break down simple and complex carbohydrates from food into saccharides (i.e., sugars) for the body to use as energy. Carbohydrate digestion starts in the mouth during mastication, or chewing. The masticated carbohydrates remain intact in the stomach. Digestion resumes in the duodenum of the small intestine, where pancreatic alpha-amylase and brush border enzymes of the microvilli convert complex carbohydrates to monosaccharides. Finally, the monosaccharides...
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α-glucosidase inhibitors, including acarbose (Precose), miglitol (Glyset), and voglibose (Voglib) (primarily available in Asia), are drugs that control blood sugar levels by delaying the digestion of starch and disaccharides. They achieve this by inhibiting α-glucosidase enzymes in the intestine, which slow the absorption of carbohydrates in the intestine, which in turn leads to a prolonged release of the glucoregulatory hormone GLP-1 from intestinal L-cells.
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Carbohydrates are polymers composed of molecules containing atoms of carbon, hydrogen and oxygen. One gram of carbohydrate can provide four kilo-calories of energy, which makes it the most efficient instant energy source.
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Polysaccharides such as glycogen and starch are synthesized from nucleoside diphosphate sugars, primarily uridine diphosphate glucose (UDPG) and adenosine diphosphate glucose (ADPG). These activated glucose donors act as key intermediates in carbohydrate metabolism and biosynthesis. UDPG primarily involves glycogen synthesis in animals and many bacteria, while ADPG plays a fundamental role in starch synthesis in plants and certain bacteria.UDPG is formed when glucose-1-phosphate reacts with...
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Carbohydrates, proteins, and fats are the primary macronutrients in the human diet. However, carbohydrates are the most favored source of energy in the body. They can be found in a wide variety of foods, including whole grains, fruit, and vegetables, in various forms, such as sugars, starch, and dietary fiber. Based on their structure, carbohydrates are classified into three main classes— monosaccharides, disaccharides, and polysaccharides. The body's cells can only utilize simple...
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Sugar (a simple carbohydrate) metabolism (chemical reactions) is a classic example of the many cellular processes that use and produce energy. Living things consume sugar as a major energy source because sugar molecules have considerable energy stored within their bonds. Consumed carbohydrates have their origins in photosynthesizing organisms like plants. During photosynthesis, plants use the energy of sunlight to convert carbon dioxide gas into sugar molecules, like glucose. Because this...
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Degradadores bifuncionales recubiertos de azúcar activados por enzimas

Qian Zhu1, Gerhard Fischer2, Steven S Cheng1

  • 1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.

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Los investigadores desarrollaron quimeras de proteólisis recubiertas de azúcar (SCP) que requieren la eliminación enzimática de una porción de azúcar para la degradación de proteínas específicas. Esta estrategia de control metabólico mejora la selectividad de los PROTAC mediante el control de su actividad a través de la modificación de O-GlcNAc y las enzimas O-GlcNAcase (OGA).

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Área de la Ciencia:

  • La bioquímica
  • Biología molecular
  • Biología Química

Sus antecedentes:

  • La degradación dirigida de proteínas utiliza quimeras dirigidas a la proteólisis (PROTAC) para dirigir las proteínas al sistema ubiquitina-proteasoma.
  • Las ligasas E3 de uso común como el cereblón (CRBN) se expresan ampliamente, lo que limita la selectividad de PROTAC.
  • El desarrollo de estrategias para el control metabólico de la actividad de PROTAC es crucial para mejorar la especificidad terapéutica.

Objetivo del estudio:

  • Desarrollar una nueva estrategia de activación enzimática para los PROTAC utilizando la modificación O-GlcNAc.
  • Para crear PROTAC recubiertos de azúcar (SCP) que se activan mediante la eliminación enzimática de la fracción O-GlcNAc.
  • Investigar el impacto de la modificación de O-GlcNAc en la unión de CRBN y la degradación de las proteínas objetivo.

Principales métodos:

  • Análisis estructurales de los degradantes ciclimídicos complejos con CRBN y BRD4.
  • Síntesis de ciclimidas modificados por O-GlcNAc (SCP).
  • Pruebas de unión bioquímica in vitro, pruebas de degradación celular y pruebas de viabilidad celular.

Principales resultados:

  • La glicosilación de ciclimidas redujo la unión de CRBN y la formación de complejos con BRD4.
  • La eliminación enzimática de la fracción O-GlcNAc por O-GlcNAcase (OGA) restauró la unión a CRBN y indujo la degradación de la proteína diana.
  • Necesidad demostrada de activación enzimática en líneas celulares modificadas y nativas.

Conclusiones:

  • La modificación de O-GlcNAc sirve como un mecanismo eficaz para la degradación de proteínas dirigidas metabólicamente.
  • Las estrategias de activación enzimática pueden mejorar la selectividad de los PROTAC.
  • Este enfoque motiva el desarrollo de estrategias similares utilizando otras modificaciones de proteínas para mejorar la selectividad.