Molecule Information

General Information of the Molecule (ID: Mol00398)

• Name: Glutathione synthetase (GSH) ,Homo sapiens
• Synonyms: GSH synthetase; GSH-S; Glutathione synthase
• Molecule Type: Protein
• Gene Name: GSS
• Gene ID: 2937
• Location: chr20:34928432-34956027[-]
• Sequence:
  MATNWGSLLQDKQQLEELARQAVDRALAEGVLLRTSQEPTSSEVVSYAPFTLFPSLVPSA
  LLEQAYAVQMDFNLLVDAVSQNAAFLEQTLSSTIKQDDFTARLFDIHKQVLKEGIAQTVF
  LGLNRSDYMFQRSADGSPALKQIEINTISASFGGLASRTPAVHRHVLSVLSKTKEAGKIL
  SNNPSKGLALGIAKAWELYGSPNALVLLIAQEKERNIFDQRAIENELLARNIHVIRRTFE
  DISEKGSLDQDRRLFVDGQEIAVVYFRDGYMPRQYSLQNWEARLLLERSHAAKCPDIATQ
  LAGTKKVQQELSRPGMLEMLLPGQPEAVARLRATFAGLYSLDVGEEGDQAIAEALAAPSR
  FVLKPQREGGGNNLYGEEMVQALKQLKDSEERASYILMEKIEPEPFENCLLRPGSPARVV
  QCISELGIFGVYVRQEKTLVMNKHVGHLLRTKAIEHADGGVAAGVAVLDNPYPV
• 3D-structure: PDB ID: 2HGS; Classification: Amine/carboxylate ligase; Method: X-ray diffraction; Resolution: 2.10 Å
• Function: Catalyzes the production of glutathione from gamma-glutamylcysteine and glycine in an ATP-dependent manner. Glutathione (gamma-glutamylcysteinylglycine, GSH) is the most abundant intracellular thiol in living aerobic cells and is required for numerous processes including the protection of cells against oxidative damage, amino acid transport, the detoxification of foreign compounds, the maintenance of protein sulfhydryl groups in a reduced state and acts as a cofactor for a number of enzymes.
• Uniprot ID: GSHB_HUMAN
• Ensembl ID: ENSG00000100983
• HGNC ID: HGNC:4624

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

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

Drug Resistance Data Categorized by Drug

Approved Drug(s) 7 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Disease Class: Lung cancer [ICD-11: 2C25.5] [1]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.67E-68; Fold-change: 8.32E-02; Z-score: 2.09E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Vi-cell cell viability analyzer assay
• Mechanism Description: miR-21 achieves the drug resistance effect through three mechanisms: Increasing MDR1 and MPR1 expression levels, and enhancing drug efflux from the cells; increasing GSH, superoxide dismutase and GST-Pi expression levels and promoting drug inactivation; and inhibiting the PI3k signaling pathway and in turn inhibiting apoptotic signaling.

Idebenone

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: mitochondrial refractory epilepsy [ICD-11: 8A60.A] [2]

• Sensitive Disease: mitochondrial refractory epilepsy [ICD-11: 8A60.A]
• Sensitive Drug: Idebenone
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: Swiss albino mice model; Mus musculus
• Experiment for Molecule Alteration: Ellman assay
• Experiment for Drug Resistance: Pre-treatment resistance testing; Post-treatment resistance testing
• Mechanism Description: IDB had successful control over drug resistance in the rotenone corneal kindled model by bypassing blocked complex I. IDB has a good safety profile and can be considered an adjuvant along with standard antiseizure drugs in drug-resistant patients.

Lamotrigine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: mitochondrial refractory epilepsy [ICD-11: 8A60.A] [2]

• Resistant Disease: mitochondrial refractory epilepsy [ICD-11: 8A60.A]
• Resistant Drug: Lamotrigine
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: Swiss albino mice model; Mus musculus
• Experiment for Molecule Alteration: Ellman assay
• Experiment for Drug Resistance: Pre-treatment resistance testing; Post-treatment resistance testing
• Mechanism Description: The involvement of complex I in drug resistance is well established in epilepsy; therefore, the model chosen for this study was rotenone corneal kindled model of drug resistance using rotenone as a selective irreversible inhibitor of complex I, which have shown resistance to drugs such as valproate, levetiracetam, lamotrigine, pregabalin, carbamazepine, zonisamide, topiramate, gabapentin and their combinations

Levetiracetam

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: mitochondrial refractory epilepsy [ICD-11: 8A60.A] [2]

• Resistant Disease: mitochondrial refractory epilepsy [ICD-11: 8A60.A]
• Resistant Drug: Levetiracetam
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: Swiss albino mice model; Mus musculus
• Experiment for Molecule Alteration: Ellman assay
• Experiment for Drug Resistance: Pre-treatment resistance testing; Post-treatment resistance testing
• Mechanism Description: The involvement of complex I in drug resistance is well established in epilepsy; therefore, the model chosen for this study was rotenone corneal kindled model of drug resistance using rotenone as a selective irreversible inhibitor of complex I, which have shown resistance to drugs such as valproate, levetiracetam, lamotrigine, pregabalin, carbamazepine, zonisamide, topiramate, gabapentin and their combinations

Phenytoin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: mitochondrial refractory epilepsy [ICD-11: 8A60.A] [2]

• Resistant Disease: mitochondrial refractory epilepsy [ICD-11: 8A60.A]
• Resistant Drug: Phenytoin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: Swiss albino mice model; Mus musculus
• Experiment for Molecule Alteration: Ellman assay
• Experiment for Drug Resistance: Pre-treatment resistance testing; Post-treatment resistance testing
• Mechanism Description: The involvement of complex I in drug resistance is well established in epilepsy; therefore, the model chosen for this study was rotenone corneal kindled model of drug resistance using rotenone as a selective irreversible inhibitor of complex I, which have shown resistance to drugs such as valproate, levetiracetam, lamotrigine, pregabalin, carbamazepine, zonisamide, topiramate, gabapentin and their combinations

Pregabalin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: mitochondrial refractory epilepsy [ICD-11: 8A60.A] [2]

• Resistant Disease: mitochondrial refractory epilepsy [ICD-11: 8A60.A]
• Resistant Drug: Pregabalin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: Swiss albino mice model; Mus musculus
• Experiment for Molecule Alteration: Ellman assay
• Experiment for Drug Resistance: Pre-treatment resistance testing; Post-treatment resistance testing
• Mechanism Description: The involvement of complex I in drug resistance is well established in epilepsy; therefore, the model chosen for this study was rotenone corneal kindled model of drug resistance using rotenone as a selective irreversible inhibitor of complex I, which have shown resistance to drugs such as valproate, levetiracetam, lamotrigine, pregabalin, carbamazepine, zonisamide, topiramate, gabapentin and their combinations

Valproic acid

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: mitochondrial refractory epilepsy [ICD-11: 8A60.A] [2]

• Resistant Disease: mitochondrial refractory epilepsy [ICD-11: 8A60.A]
• Resistant Drug: Valproic acid
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: Swiss albino mice model; Mus musculus
• Experiment for Molecule Alteration: Ellman assay
• Experiment for Drug Resistance: Pre-treatment resistance testing; Post-treatment resistance testing
• Mechanism Description: The involvement of complex I in drug resistance is well established in epilepsy; therefore, the model chosen for this study was rotenone corneal kindled model of drug resistance using rotenone as a selective irreversible inhibitor of complex I, which have shown resistance to drugs such as valproate, levetiracetam, lamotrigine, pregabalin, carbamazepine, zonisamide, topiramate, gabapentin and their combinations

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.67E-68; Fold-change: 4.98E-01; Z-score: 2.03E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 5.04E-48; Fold-change: 4.94E-01; Z-score: 2.13E+00

References

• Ref 1: Effect of microRNA-21 on multidrug resistance reversal in A549/DDP human lung cancer cells. Mol Med Rep. 2015 Jan;11(1):682-90. doi: 10.3892/mmr.2014.2662. Epub 2014 Oct 15.
• Ref 2: Attenuation of mitochondrial refractory epilepsy in rotenone corneal kindling model of drug resistance by idebenone: An approach to bypass mitochondrial complex I. Epilepsy Res. 2024 Nov;207:107458.