GSTP1

Official Full Name

glutathione S-transferase pi 1

Organism

Homo sapiens

GeneID

2950

Background

Glutathione S-transferases (GSTs) are a family of enzymes that play an important role in detoxification by catalyzing the conjugation of many hydrophobic and electrophilic compounds with reduced glutathione. Based on their biochemical, immunologic, and structural properties, the soluble GSTs are categorized into 4 main classes: alpha, mu, pi, and theta. This GST family member is a polymorphic gene encoding active, functionally different GSTP1 variant proteins that are thought to function in xenobiotic metabolism and play a role in susceptibility to cancer, and other diseases. [provided by RefSeq, Jul 2008]

Synonyms

PI; DFN7; GST3; GSTP; FAEES3; HEL-S-22;

Bio Chemical Class

Alkyl aryl transferase

Protein Sequence

MPPYTVVYFPVRGRCAALRMLLADQGQSWKEEVVTVETWQEGSLKASCLYGQLPKFQDGDLTLYQSNTILRHLGRTLGLYGKDQQEAALVDMVNDGVEDLRCKYISLIYTNYEAGKDDYVKALPGQLKPFETLLSQNQGGKTFIVGDQISFADYNLLDLLLIHEVLAPGCLDAFPLLSAYVGRLSARPKLKAFLASPEYVNLPINGNGKQ

Open

Disease

Myelodysplastic syndrome, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

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Detailed Information

A vital family of enzymes in the body, glutathione S-transferases (GSTs) help to detoxify many toxic substances. Of these, GSTP1 (Glutathione S-Transferase Pi 1) is especially important for cellular detoxification and oxidative stress prevention. To help xenobiotics be metabolized, GSTP1 accelerates the conjugation of reduced glutathione (GSH) to different hydrophobic and electrophobic molecules.

The Discovery and Structural Insights into GSTP1

The trip to GSTP1 started in the middle of the 1980s. First to separate a neutral form of glutathione S-transferase from rat placental cytosol were Sato K and colleagues. Their results revealed a special enzymatic activity for this recently identified protein they termed GSTP1. Unlike other GST family members, GSTP1 has shown unique immunological characteristics that spurred further research on its function as a tumor marker in chemically caused liver cancer. Later research revealed that GSTP1 was upregulated in the early stages of hepatocellular carcinoma, thereby suggesting its possible tumor biomarker in cancer development.

Human GSTP1 is structurally found on chromosome 11q13.2 in seven exons and six introns. With the 5' promoter region rich in CpG islands, suggesting possible epigenetic control, the gene spans around 2.8 kilobases. Though it has been seen in the cytoplasm, nucleus, and endoplasmic reticulum of cells, the protein product of GSTP1 comprises 210 amino acids and is mostly located in this organelle.

The N-terminal domain and the C-terminal domain define two primary molecular regions for the structure of GSTP1. Whereas the C-terminal domain is in charge of fitting hydrophobic substrates at the H-site, the N-terminal domain comprises the G-site, a binding pocket for GSH. By conjugating GSH to a broad range of substrates, including medicines, carcinogens, and endogenous metabolites, this bipartite structure enables GSTP1 to conduct its enzymatic activity.

GSTP1 in Cellular Detoxification and Antioxidant Defense

GSTP1's main role is to neutralize electrophilic compounds that can induce oxidative stress, therefore shielding cells from harmful effects. Key to the enzyme's detoxifying function is its capacity to conjugate GSH to hydrophobic electrophiles, generating less toxic conjugates eliminated from the body. In cells suffering oxidative damage or in tissues exposed to environmental pollutants, this pathway is especially crucial.

Within the framework of oxidative stress, GSTP1 both detoxifies damaging reactive oxygen species (ROS) and controls cellular responses to oxidative damage. Normal circumstances allow GSTP1 to bind to JNK (c-Jun N-terminal kinase) and stop its phosphorylation, therefore avoiding stress-induced death. However, the GSTP1-JNK complex separates under oxidative stress, permitting JNK phosphorylation—which causes death. This regulatory function emphasizes how important GSTP1 is in balancing cell survival and death in response to oxidative stress. Fascinatingly, investigations in animals lacking GSTP1 have shown higher JNK activity in the lungs and liver, therefore confirming the enzyme's role as a sensor of oxidative stress.

GSTP1 and Nitric Oxide Metabolism

The presence of GSTP1 in nitric oxide (NO) metabolism adds even another fascinating feature. Among other functions, NO is essential for cell signaling, immunological responses, and visual control. Important for the storage and movement of NO in cells, dinitrosyl-dithiol iron complexes (DNICs) are produced and transported under the direction of GSTP1. Using interactions with multidrug resistance-associated protein 1 (MRP1), GSTP1 helps DNICs migrate between cellular compartments, hence assuring appropriate control of NO levels.

Furthermore found to interact with inducible nitric oxide synthase (iNOS) is GSTP1, which, in certain circumstances reduces NO generation. This connection implies that GSTP1 not only contributes to detoxification but also helps to fine-tune NO-mediated signaling pathways, which are crucial for immunological responses and control of apoptosis.

Figure 1 illustrates how MRP1 and GSTP1 work together to transport and store nitric oxide (NO) as dinitrosyl iron complexes (DNICs), protecting cells from NO-induced toxicity. Figure 1. MRP1 and GSTP1-mediated transport and storage of NO as DNICs. (Russell TM, et al., 2023)

GSTP1 and its Role in Disease Susceptibility and Cancer

Particularly in cancer, the polymorphism character of the GSTP1 gene has been thoroughly investigated for consequences in disease susceptibility. Single nucleotide polymorphisms (SNPs) causing amino acid alterations in the protein produce GSTP1 variants. One well-known polymorphism that influences the catalytic efficiency of the enzyme and thus its capacity to detoxify carcinogens is the replacement of Ile105 with Val105. Those who possess this variation may therefore be more likely to get cancer, especially those linked to environmental toxicity like lung cancer in smokers.

Additionally linked to epigenetic control of cancer is GSTP1. Hypermethylation of the GSTP1 promoter region causes transcriptional silence of the gene in several malignancies, including prostate, breast, and liver cancer, which may help to initiate tumors early on. Because it increases tumorigenic potential and makes cells more sensitive to oxidative stress, this epigenetic inactivation of GSTP1 is often linked with poor prognosis. GSTP1 promoter hypermethylation has been linked, according to clinical research, to lymph node metastases, advanced tumor stage, and poor general survival in cancer patients.

Furthermore, GSTP1 is important for controlling the cell signaling channels linked to cancer development. GSTP1, for example, interacts with TNF receptor-associated factor 2 (TRAF2), therefore reducing its activity and so preventing the activation of downstream signaling molecules such as JNK and p38 MAPK. This inhibition helps cells survive and stops apoptosis from starting. On the other hand, the silence of GSTP1 causes hyperactivation of the TRAF2-ASK1 signaling axis, hence promoting dead cells. These results imply that GSTP1 not only shields cancer cells from oxidative damage but also controls important pro-survival pathways.

References:

Oshodi Y, Ojewunmi O, Oshodi TA, et al. Oxidative stress markers and genetic polymorphisms of glutathione S-transferase T1, M1, and P1 in a subset of children with autism spectrum disorder in Lagos, Nigeria. Niger J Clin Pract. 2017;20(9):1161-1167.
Russell TM, Richardson DR. The good Samaritan glutathione-S-transferase P1: An evolving relationship in nitric oxide metabolism mediated by the direct interactions between multiple effector molecules. Redox Biol. 2023;59:102568.
Shishido Y, Tomoike F, Kuwata K, et al. A Covalent Inhibitor for Glutathione S-Transferase Pi (GSTP1-1 ) in Human Cells. Chembiochem. 2019;20(7):900-905.

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