Molecule Information

General Information of the Molecule (ID: Mol04056)

• Name: Pyrroline-5-carboxylate reductase 1 (PYCR1) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: PYCR1
• Gene ID: 5831
• Location: chr17:81932384-81942412[-]
• Sequence:
  MSVGFIGAGQLAFALAKGFTAAGVLAAHKIMASSPDMDLATVSALRKMGVKLTPHNKETV
  QHSDVLFLAVKPHIIPFILDEIGADIEDRHIVVSCAAGVTISSIEKKLSAFRPAPRVIRC
  MTNTPVVVREGATVYATGTHAQVEDGRLMEQLLSSVGFCTEVEEDLIDAVTGLSGSGPAY
  AFTALDALADGGVKMGLPRRLAVRLGAQALLGAAKMLLHSEQHPGQLKDNVSSPGGATIH
  ALHVLESGGFRSLLINAVEASCIRTRELQSMADQEQVSPAAIKKTILDKVKLDSPAGTAL
  SPSGHTKLLPRSLAPAGKD
• 3D-structure: PDB ID: 6XP1; Classification: Oxidoreductase; Method: X-ray diffraction; Resolution: 1.75 Å
• Function: Oxidoreductase that catalyzes the last step in proline biosynthesis, which corresponds to the reduction of pyrroline-5- carboxylate to L-proline using NAD(P)H (PubMed:16730026, PubMed:19648921, PubMed:23024808, PubMed:28258219). At physiologic concentrations, has higher specific activity in the presence of NADH (PubMed:16730026, PubMed:23024808). Involved in the cellular response to oxidative stress (PubMed:16730026, PubMed:19648921). .
• Uniprot ID: P5CR1_HUMAN
• Ensembl ID: ENSG00000183010
• HGNC ID: HGNC:9721

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.