Molecule Information

General Information of the Molecule (ID: Mol04148)

• Name: Proline-rich Akt substrate 40 kDa (PRAS40) ,Homo sapiens
• Synonyms: 40 kDa proline-rich AKT substrate
• Molecule Type: Protein
• Gene Name: AKT1S1
• Gene ID: 84335
• Location: chr19:49869033-49878459[-]
• Sequence:
  MASGRPEELWEAVVGAAERFRARTGTELVLLTAAPPPPPRPGPCAYAAHGRGALAEAARR
  CLHDIALAHRAATAARPPAPPPAPQPPSPTPSPPRPTLAREDNEEDEDEPTETETSGEQL
  GISDNGGLFVMDEDATLQDLPPFCESDPESTDDGSLSEETPAGPPTCSVPPASALPTQQY
  AKSLPVSVPVWGFKEKRTEARSSDEENGPPSSPDLDRIAASMRALVLREAEDTQVFGDLP
  RPRLNTSDFQKLKRKY
• 3D-structure: PDB ID: 5WBL; Classification: Protein binding; Method: X-ray diffraction; Resolution: 3.35 Å
• Function: Negative regulator of the mechanistic target of rapamycin complex 1 (mTORC1), an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth (PubMed:17277771, PubMed:17386266, PubMed:17510057, PubMed:29236692). In absence of insulin and nutrients, AKT1S1 associates with the mTORC1 complex and directly inhibits mTORC1 activity by blocking the MTOR substrate- recruitment site (PubMed:29236692). In response to insulin and nutrients, AKT1S1 dissociates from mTORC1 (PubMed:17386266, PubMed:18372248). Its activity is dependent on its phosphorylation state and binding to 14-3-3 (PubMed:16174443, PubMed:18372248). May also play a role in nerve growth factor-mediated neuroprotection (By similarity). .
• Uniprot ID: AKTS1_HUMAN
• Ensembl ID: ENSG00000204673
• HGNC ID: HGNC:28426

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Bortezomib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Multiple myeloma [ICD-11: 2A83.0] [1]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Resistant Drug: Bortezomib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ANBL-6 cells; Blood; Homo sapiens (Human); CVCL_5425
• In Vitro Model: JJN-3 cells; Bone marrow; Homo sapiens (Human); CVCL_2078
• In Vitro Model: LP-1 cells; Blood; Homo sapiens (Human); CVCL_0012
• In Vitro Model: OPM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vitro Model: RPMI 8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_7353
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We found that PYCR1 and PYCR2 mRNA expression correlated with an inferior overall survival. MM cells from relapsed/refractory patients express significantly higher levels of PYCR1 mRNA. In line with the strong expression of PYCR1, we performed a tracer study in RPMI-8226 cells, which revealed an increased conversion of 13C-glutamine to proline in hypoxia. PYCR1 inhibition reduced MM viability and proliferation and increased apoptosis. Mechanistically, we found that PYCR1 silencing reduced protein levels of p-PRAS40, p-mTOR, p-p70, p-S6, p-4EBP1 and p-eIF4E levels, suggesting a decrease in protein synthesis, which we also confirmed in vitro. Pargyline and siPYCR1 increased bortezomib-mediated apoptosis.

References

• Ref 1: Pyrroline-5-Carboxylate Reductase 1: a novel target for sensitizing multiple myeloma cells to bortezomib by inhibition of PRAS40-mediated protein synthesis. J Exp Clin Cancer Res. 2022 Feb 1;41(1):45.