Sestrin-2 also known as Hi95 is a protein that in humans is encoded by the SESN2 gene. [5] [6] [7]
Sestrin-2 also known as Hi95 is a protein that in humans is encoded by the SESN2 gene. [5] [6] [7]
This gene encodes a member of the sestrin family of PA26-related proteins. The encoded protein may function in the regulation of cell growth and survival. This protein may be involved in cellular response to different stress conditions. [7] [8] The Sestrins constitute a family of evolutionarily-conserved stress-inducible proteins that suppress oxidative stress and regulate adenosine monophosphate-dependent protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling. By virtue of these activities, the Sestrins serve as important regulators of metabolic homeostasis. [9] Accordingly, inactivation of Sestrin genes in invertebrates resulted in diverse metabolic pathologies, including oxidative damage, fat accumulation, mitochondrial dysfunction and muscle degeneration that resemble accelerated tissue aging. [7] [10]
The NMDA receptor antagonist ketamine has been found to activate the mammalian target of rapamycin complex 1 (mTORC1) pathway in the medial prefrontal cortex (mPFC) of the brain as an essential downstream mechanism in the mediation of its rapid-acting antidepressant effects. [11] NV-5138 is a ligand and modulator of sestrin2, a leucine amino acid sensor and upstream regulatory pathway of mTORC1, and is under development for the treatment of depression. [11] The drug has been found to directly and selectively activate the mTORC1 pathway, including in the mPFC, and to produce rapid-acting antidepressant effects similar to those of ketamine. [11]
Regulatory-associated protein of mTOR also known as raptor or KIAA1303 is an adapter protein that is encoded in humans by the RPTOR gene. Two mRNAs from the gene have been identified that encode proteins of 1335 and 1177 amino acids long.
DNA-damage-inducible transcript 4 (DDIT4) protein also known as protein regulated in development and DNA damage response 1 (REDD1) is a protein that in humans is encoded by the DDIT4 gene.
60S ribosomal protein L28 is a protein that in humans is encoded by the RPL28 gene.
DnaJ homolog subfamily B member 9 is a protein that in humans is encoded by the DNAJB9 gene.
Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) is a protein that in humans is encoded by the RICTOR gene.
Ubiquitin carboxyl-terminal hydrolase 1 is an enzyme that in humans is encoded by the USP1 gene.
NUAK family SNF1-like kinase 2 also known as SNF1/AMP kinase-related kinase (SNARK) is an enzyme that in humans is encoded by the NUAK2 gene. Its deficiency in humans causes anencephaly, a severe form of anterior neural tube defect that curtails brain development.
Single-stranded DNA-binding protein 2 is a protein that in humans is encoded by the SSBP2 gene.
39S ribosomal protein L15, mitochondrial is a protein that in humans is encoded by the MRPL15 gene.
Tyrosine-protein kinase STYK1 is an enzyme that in humans is encoded by the STYK1 gene.
Neurensin-2 is a protein that in humans is encoded by the NRSN2 gene.
Peroxisomal NADH pyrophosphatase NUDT12 is an enzyme that in humans is encoded by the NUDT12 gene.
Immediate early response 3-interacting protein 1 is a protein that in humans is encoded by the IER3IP1 gene.
Solute carrier family 25 member 39 is a protein that in humans is encoded by the SLC25A39 gene. The protein has been shown to be necessary for the import of the major antioxidant glutathione into the mitochondria.
KATNBL1 is a protein that in humans is encoded by the KATNBL1 gene.
Autophagy-related protein 13 also known as ATG13 is a protein that in humans is encoded by the KIAA0652 gene.
Sestrin 1, also known as p53-regulated protein PA26, is a protein that in humans is encoded by the SESN1 gene. This gene encodes a member of the sestrin family. Sestrins are induced by the p53 tumor suppressor protein and play a role in the cellular response to DNA damage and oxidative stress. The encoded protein mediates p53 inhibition of cell growth by activating AMP-activated protein kinase, which results in the inhibition of the mammalian target of rapamycin protein. The encoded protein also plays a critical role in antioxidant defense by regenerating overoxidized peroxiredoxins, and the expression of this gene is a potential marker for exposure to radiation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.
Target of rapamycin complex subunit LST8, also known as mammalian lethal with SEC13 protein 8 (mLST8) or TORC subunit LST8 or G protein beta subunit-like, is a protein that in humans is encoded by the MLST8 gene. It is a subunit of both mTORC1 and mTORC2, complexes that regulate cell growth and survival in response to nutrient, energy, redox, and hormonal signals. It is upregulated in several human colon and prostate cancer cell lines and tissues. Knockdown of mLST8 prevented mTORC formation and inhibited tumor growth and invasiveness.
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
NV-5138 is an orally and centrally active small-molecule drug which is under development by Navitor Pharmaceuticals for the treatment of major depressive disorder (MDD). It directly and selectively activates the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway by binding to and modulating sestrin2, a leucine amino acid sensor and upstream regulatory pathway. The mTORC1 pathway is the same signaling pathway that the NMDA receptor antagonist ketamine activates in the medial prefrontal cortex (mPFC) to mediate its rapid-acting antidepressant effects. A single oral dose of NV-5138 has been found to increase mTORC1 signaling and produce synaptogenesis in the mPFC and to induce rapid antidepressant effects in multiple animal models of depression. Like those of ketamine, these actions require the signaling of brain-derived neurotrophic factor (BDNF). The antidepressant effects following a single dose of NV-5138 are long-lasting, with a duration of up to 7 days, and are similar to those of ketamine. Based on these promising preclinical findings, efforts are underway to assess NV-5138 in clinical trials with human subjects. By November 2019, NV-5138 had completed three phase I studies for the treatment of MDD. In these studies, preliminary evidence of efficacy, tolerability, safety, and pharmacokinetics was observed, and as of 2021 it was into Phase II trials.
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