Molecule Information

General Information of the Molecule (ID: Mol00075)

• Name: L-glutamine amidohydrolase (GLS) ,Homo sapiens
• Synonyms: GLS; K-glutaminase; L-glutamine amidohydrolase; GLS1; KIAA0838
• Molecule Type: Protein
• Gene Name: GLS
• Gene ID: 2744
• Location: chr2:190880821-190965552[+]
• Sequence:
  MMRLRGSGMLRDLLLRSPAGVSATLRRAQPLVTLCRRPRGGGRPAAGPAAAARLHPWWGG
  GGWPAEPLARGLSSSPSEILQELGKGSTHPQPGVSPPAAPAAPGPKDGPGETDAFGNSEG
  KELVASGENKIKQGLLPSLEDLLFYTIAEGQEKIPVHKFITALKSTGLRTSDPRLKECMD
  MLRLTLQTTSDGVMLDKDLFKKCVQSNIVLLTQAFRRKFVIPDFMSFTSHIDELYESAKK
  QSGGKVADYIPQLAKFSPDLWGVSVCTVDGQRHSTGDTKVPFCLQSCVKPLKYAIAVNDL
  GTEYVHRYVGKEPSGLRFNKLFLNEDDKPHNPMVNAGAIVVTSLIKQGVNNAEKFDYVMQ
  FLNKMAGNEYVGFSNATFQSERESGDRNFAIGYYLKEKKCFPEGTDMVGILDFYFQLCSI
  EVTCESASVMAATLANGGFCPITGERVLSPEAVRNTLSLMHSCGMYDFSGQFAFHVGLPA
  KSGVAGGILLVVPNVMGMMCWSPPLDKMGNSVKGIHFCHDLVSLCNFHNYDNLRHFAKKL
  DPRREGGDQRVKSVINLLFAAYTGDVSALRRFALSAMDMEQRDYDSRTALHVAAAEGHVE
  VVKFLLEACKVNPFPKDRWNNTPMDEALHFGHHDVFKILQEYQVQYTPQGDSDNGKENQT
  VHKNLDGLL
• 3D-structure: PDB ID: 8GWR; Classification: Oncoprotein; Method: X-ray diffraction; Resolution: 2.80 Å
• Function: Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate, the main excitatory neurotransmitter in the brain.
• Uniprot ID: GLSK_HUMAN
• Ensembl ID: ENSG00000115419
• HGNC ID: HGNC:4331

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

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.10] [1]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Intrahepatic cholangiocarcinoma [ICD-11: 2C12.10]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Intrahepatic cholangiocarcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.33E-18; Fold-change: 5.84E-01; Z-score: 9.68E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SCK-R cells; Liver; Homo sapiens (Human); CVCL_M271
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The observed elevation in GLS1 expression, which is important in glutaminolysis, and intracellular glutamine and glutamate levels in SCK-R cells, revealed that glutaminolysis was associated with metabolic reprogramming represented by cisplatin resistance in SCK-R cells. Indeed, treatment with CB-839 led to reduced L1CAM, AXL, and ZEB2 expression. Combination treatment with DRB18 and CB-839 reduced SCK-R cell proliferation. Based on these results, we speculate that inhibiting glucose and glutamine metabolism re-sensitized SCK-R cells to cisplatin.

Disease Class: Chondrosarcoma [ICD-11: 2B50.0] [5]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Chondrosarcoma [ICD-11: 2B50.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: JJ012 cells; Bone; Homo sapiens (Human); CVCL_D605
• In Vitro Model: SW-1353 cells; Brain; Homo sapiens (Human); CVCL_0543
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell colony formation assay
• Mechanism Description: The MEK, ERK, and NrF2 signaling pathways were shown to regulate AR-mediated alanine-serine-cysteine transporter 2 (ASCT2; also called SLC1A5) and glutaminase (GLS) expression as well as glutamine metabolism in cisplatin-resistant chondrosarcoma. The knockdown of AR expression in cisplatin-resistant chondrosarcoma cells was shown to reduce the expression of SLC1A5 and GLS in vivo. These results indicate that AR and glutamine metabolism are worth pursuing as therapeutic targets in dealing with cisplatin-resistant human chondrosarcoma.

Docetaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Prostate cancer [ICD-11: 2C82.0] [2]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.08E-01; Fold-change: 5.66E-02; Z-score: 1.67E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 293 T cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC-3 cells; Bone; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Mechanistically, Gln deprivation reduced OXPHOS and ATP levels, causing a disturbance in cell cycle progression. Genetic and chemical inhibition of the Gln-metabolism key protein GLS1 could validate the Gln deprivation results, thereby representing a valid therapeutic target. Moreover, immunohistological investigation of GLS1 revealed a high-expressing GLS1 subgroup post-docetaxel failure, exhibiting low overall survival. This subgroup presents an intriguing opportunity for targeted therapy focusing on glutamine metabolism.

Sorafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.02] [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Liver cancer
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.74E-22; Fold-change: 1.39E-01; Z-score: 1.12E+01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: NGS and real-time PCR demonstrated the downregulated expression of miR-23b-3p in sorafenib-resistant cells compared to parental cells. In silico analysis showed that miR-23b-3p specifically targeted autophagy through ATG12 and glutaminolysis through GLS1. In transfection assays, mimics of miR-23b-3p demonstrated reduced gene expression for both ATG12 and GLS1, decreased cell viability, and increased cell apoptosis of sorafenib-resistant HepG2 cells, whereas the antimiRs of miR-23b-3p demonstrated contrasting results.

Temozolomide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [ICD-11: 2C30.0] [4]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Sensitive Drug: Temozolomide
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Melanoma [ICD-11: 2C30]
• The Specified Disease: Melanoma
• The Studied Tissue: Skin
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.27E-01; Fold-change: -3.92E-02; Z-score: -6.41E-01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT144 cells; Skin; Homo sapiens (Human); CVCL_0318
• In Vitro Model: SkMEL5 cells; Skin; Homo sapiens (Human); CVCL_0527
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis; Immunohistochemistry assays
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR203 sensitizes MM cells to TMZ by targeting GLS.

Fluorouracil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [6]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Four-to-six-week-old female BALB/c mice, with CT26 cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor weight assay
• Mechanism Description: In the TME of CRC-PC, tumor cells outcompete adipocytes for Gln, leading to Gln deficiency. We show that this change in the TME induces GS upregulation in adipocytes, increasing the production of Gln, which promotes resistance of tumor cells to 5FU chemotherapy, a process mediated by mTOR activation. We also show that abnormal methionine metabolism in adipocytes may lead to altered H3k4me2 expression, which contributes to GS upregulation and chemoresistance to 5FU

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Melanoma [ICD-11: 2C30]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Skin
• The Specified Disease: Melanoma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.27E-01; Fold-change: 1.54E-01; Z-score: 1.07E-01

References

• Ref 1: Regulation of glucose and glutamine metabolism to overcome cisplatin resistance in intrahepatic cholangiocarcinoma. BMB Rep. 2023 Nov;56(11):600-605.
• Ref 2: Targeting the glutamine metabolism to suppress cell proliferation in mesenchymal docetaxel-resistant prostate cancer. Oncogene. 2024 Jun;43(26):2038-2050.
• Ref 3: miR-23b-3p Modulating Cytoprotective Autophagy and Glutamine Addiction in Sorafenib Resistant HepG2, a Hepatocellular Carcinoma Cell Line. Genes (Basel). 2022 Aug 1;13(8):1375.
• Ref 4: Sensitization of melanoma cells to temozolomide by overexpression of microRNA 203 through direct targeting of glutaminase-mediated glutamine metabolism. Clin Exp Dermatol. 2017 Aug;42(6):614-621. doi: 10.1111/ced.13119. Epub 2017 Jun 9.
• Ref 5: Glutamine metabolism controls amphiregulin-facilitated chemoresistance to cisplatin in human chondrosarcoma. Int J Biol Sci. 2023 Oct 9;19(16):5174-5186.
• Ref 6: Adipocytic Glutamine Synthetase Upregulation via Altered Histone Methylation Promotes 5FU Chemoresistance in Peritoneal Carcinomatosis of Colorectal Cancer. Front Oncol. 2021 Oct 12;11:748730.