Nutrient Sensors

mTORC1 integrates four major signals – nutrients, growth factors, energy and redox status – to regulate many core processes that are involved in cellular metabolism. We are applying proprietary insights into a new and growing class of proteins that serve as specific nutrient sensors to discover new drugs to selectively modulate mTORC1 activity.

Nutrient sensors are specialized, intracellular proteins that enable the cell to sense and respond to the availabilities of amino acids, glucose, and other biomolecules. In tissues throughout the body, the availabilities of certain amino acids – the building blocks of proteins – are continuously monitored by amino acid sensors that specifically regulate mTORC1 activity to initiate cellular processes that maintain metabolic balance or homeostasis.

The roles of several critical amino acid sensors have recently been elucidated by Navitor’s scientific founder, David M. Sabatini, MD, PhD.  We are rapidly translating these findings into drugs that selectively regulate mTORC1 activity to treat disease.

  • Sestrin2 is a sensor for the amino acid leucine, an important branched chain amino acid involved in many aspects of mammalian physiology mainly through its ability to impact mTORC1 activity. In most tissues, leucine binding to Sestrin2 triggers a series of events resulting in the activation of mTORC1.
  • CASTOR is a sensor for the amino acid arginine, another amino acid that plays diverse roles in mammals including immune cell activation, insulin secretion, and muscle growth. Similar to the binding of leucine to Sestrin2, the specific binding of arginine to CASTOR triggers a series of events resulting in the activation of mTORC1.
  • SAMTOR is a sensor for S-adenosylmethionine (SAM) which is an important metabolite of the amino acid methionine that has been associated with improved insulin sensitivity and extended lifespan in rodents. The discovery of SAMTOR opens up a broader understanding of the role mTORC1 plays in cellular metabolism by linking the activity of this complex to the one carbon metabolic pathway that is critical for the survival of many cancers and possibly longevity.

 

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