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FOLH1

Official Full Name
folate hydrolase 1
Organism
Homo sapiens
GeneID
2346
Background
This gene encodes a type II transmembrane glycoprotein belonging to the M28 peptidase family. The protein acts as a glutamate carboxypeptidase on different alternative substrates, including the nutrient folate and the neuropeptide N-acetyl-l-aspartyl-l-glutamate and is expressed in a number of tissues such as prostate, central and peripheral nervous system and kidney. A mutation in this gene may be associated with impaired intestinal absorption of dietary folates, resulting in low blood folate levels and consequent hyperhomocysteinemia. Expression of this protein in the brain may be involved in a number of pathological conditions associated with glutamate excitotoxicity. In the prostate the protein is up-regulated in cancerous cells and is used as an effective diagnostic and prognostic indicator of prostate cancer. This gene likely arose from a duplication event of a nearby chromosomal region. Alternative splicing gives rise to multiple transcript variants encoding several different isoforms. [provided by RefSeq, Jul 2010]
Synonyms
PSM; FGCP; FOLH; GCP2; PSMA; mGCP; GCPII; NAALAD1;
Bio Chemical Class
Peptidase
Protein Sequence
MWNLLHETDSAVATARRPRWLCAGALVLAGGFFLLGFLFGWFIKSSNEATNITPKHNMKAFLDELKAENIKKFLYNFTQIPHLAGTEQNFQLAKQIQSQWKEFGLDSVELAHYDVLLSYPNKTHPNYISIINEDGNEIFNTSLFEPPPPGYENVSDIVPPFSAFSPQGMPEGDLVYVNYARTEDFFKLERDMKINCSGKIVIARYGKVFRGNKVKNAQLAGAKGVILYSDPADYFAPGVKSYPDGWNLPGGGVQRGNILNLNGAGDPLTPGYPANEYAYRRGIAEAVGLPSIPVHPIGYYDAQKLLEKMGGSAPPDSSWRGSLKVPYNVGPGFTGNFSTQKVKMHIHSTNEVTRIYNVIGTLRGAVEPDRYVILGGHRDSWVFGGIDPQSGAAVVHEIVRSFGTLKKEGWRPRRTILFASWDAEEFGLLGSTEWAEENSRLLQERGVAYINADSSIEGNYTLRVDCTPLMYSLVHNLTKELKSPDEGFEGKSLYESWTKKSPSPEFSGMPRISKLGSGNDFEVFFQRLGIASGRARYTKNWETNKFSGYPLYHSVYETYELVEKFYDPMFKYHLTVAQVRGGMVFELANSIVLPFDCRDYAVVLRKYADKIYSISMKHPQEMKTYSVSFDSLFSAVKNFTEIASKFSERLQDFDKSNPIVLRMMNDQLMFLERAFIDPLGLPDRPFYRHVIYAPSSHNKYAGESFPGIYDALFDIESKVDPSKAWGEVKRQIYVAAFTVQAAAETLSEVA
Open
Disease
Adenocarcinoma, Bladder cancer, Cervical cancer, Diagnostic imaging, General pain disorder, Influenza, Intracranial injury, Non-small-cell lung cancer, Prostate cancer, Solid tumour/cancer
Approved Drug
3 +
Clinical Trial Drug
41 +
Discontinued Drug
1 +

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Detailed Information

The FOLH1 gene encodes a type II transmembrane glycoprotein known as folate hydrolase 1 (FOLH1), also referred to as prostate-specific membrane antigen (PSMA). This enzyme belongs to the M28 peptidase family and has a key role in several physiological processes, particularly in the intestine and brain. The protein it produces is involved in glutamate carboxypeptidase activity, hydrolyzing compounds like the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) and folate. The gene is expressed in various tissues, including the prostate, central and peripheral nervous systems, and kidneys. Importantly, mutations in FOLH1 are linked to impaired folate absorption and a range of associated health issues.

The Function of FOLH1 in Different Tissues

1. In the Intestine: FOLH1 plays a critical role in folate absorption. Folate exists in the diet as polyglutamated forms, which must be converted into monoglutamated forms to be absorbed by the small intestine. FOLH1 catalyzes this conversion, making the folate bioavailable for the body. In individuals with mutations in FOLH1, folate absorption is impaired, leading to low blood folate levels and potentially contributing to hyperhomocysteinemia, a condition marked by elevated levels of homocysteine in the blood, which is a risk factor for cardiovascular diseases.

2. In the Brain: FOLH1 is expressed in glial cells and plays a role in modulating neurotransmission. It does so by hydrolyzing NAAG, a neuropeptide, to release glutamate, an excitatory neurotransmitter. This process can impact conditions related to glutamate excitotoxicity, such as neurodegenerative diseases and brain injuries. The enzyme's activity may contribute to pathological conditions where excessive glutamate leads to neuronal damage.

3. In the Prostate: FOLH1 is particularly important in the prostate, where it is highly expressed in cancerous cells. Elevated levels of PSMA, the protein produced by FOLH1, have been observed in prostate cancer, making it an effective diagnostic marker. Furthermore, PSMA is used as a prognostic indicator for prostate cancer progression, as it is upregulated in cancerous tissues. This has led to the development of PSMA-targeted therapies for prostate cancer, aiming to target and eliminate cancer cells expressing this protein.

FOLH1 and Cancer

FOLH1's involvement in cancer is most notable in prostate cancer (PCa), where it is overexpressed in tumor cells. Studies have linked this overexpression to tumor progression and metastasis. The increased activity of PSMA (FOLH1's protein product) in cancer cells aids in the hydrolysis of polyglutamated folates, increasing folate uptake, which is crucial for tumor cell survival. Additionally, PSMA's ability to cleave neuropeptides such as NAAG to release glutamate further fuels cancer cell metabolism, supporting rapid cell division and growth.

PSMA-targeted therapies, such as PSMA PET imaging, are now used to detect and stage prostate cancer, offering a more sensitive and accurate method than traditional imaging. PSMA PET has been approved for use in clinical settings and is recommended by international guidelines for investigating prostate cancer. Its ability to detect lymph node and distant metastases, even at low prostate-specific antigen (PSA) levels, has significantly impacted clinical decision-making.

This figure illustrates the regulation of PSMA/GCPII expression in prostate cancer cells, showing how Ca2+ ions upregulate PSMA expression while androgens (AR) downregulate it through various molecular mechanisms.Figure 1. Schematic representation of PSMA/GCPII regulation in prostate cancer cells. (Evans JC, et al., 2016)

Genetic Insights: FOLH1 Mutations and Disease Associations

A mutation in the FOLH1 gene can lead to defects in the enzyme's function, particularly in the absorption of dietary folates. This condition can result in hyperhomocysteinemia, a state where elevated homocysteine levels in the blood are associated with an increased risk of cardiovascular diseases and neurological disorders. Additionally, FOLH1 mutations may contribute to various forms of cancer, particularly prostate cancer, due to their role in regulating cell growth and survival.

Research has also suggested that mutations or dysregulation of FOLH1 may be implicated in other diseases related to glutamate excitotoxicity. In the brain, excessive glutamate can lead to neuronal death and has been linked to several neurodegenerative diseases. Therefore, understanding the role of FOLH1 in these conditions is crucial for developing targeted treatments.

PSMA in Diagnostic and Therapeutic Applications

The upregulation of PSMA (encoded by FOLH1) in prostate cancer cells has made it a key target for both diagnostic and therapeutic strategies. The use of PSMA PET imaging has proven valuable in detecting prostate cancer, staging the disease, and guiding treatment decisions. Furthermore, PSMA is also targeted in radioligand therapy, such as 177Lu-PSMA therapy, to treat advanced prostate cancer by delivering targeted radiation directly to cancer cells expressing PSMA.

PSMA's role extends beyond prostate cancer. It has been implicated in several other cancers, such as breast cancer, lung cancer, and pancreatic cancer, where it is overexpressed in the tumor vasculature. Its presence in the neovasculature of these tumors has made PSMA a target for diagnostic imaging and therapeutic interventions aimed at inhibiting tumor growth and metastasis.

Future Directions

Given the central role of FOLH1 and its protein product, PSMA, in various diseases, including prostate cancer and neurological disorders, there is ongoing research to further explore their potential as therapeutic targets. A deeper understanding of how FOLH1 is regulated and its function in different tissues may lead to novel treatment strategies, improving the precision of current therapies and expanding their applicability to other types of cancers and neurological conditions.

References:

  1. Farolfi A, Calderoni L, et al. Current and Emerging Clinical Applications of PSMA PET Diagnostic Imaging for Prostate Cancer. J Nucl Med. 2021;62(5):596-604.
  2. Hofman MS, Hicks RJ, et al. Prostate-specific Membrane Antigen PET: Clinical Utility in Prostate Cancer, Normal Patterns, Pearls, and Pitfalls. Radiographics. 2018;38(1):200-217.
  3. Evans JC, Malhotra M, et al. The therapeutic and diagnostic potential of the prostate specific membrane antigen/glutamate carboxypeptidase II (PSMA/GCPII) in cancer and neurological disease. Br J Pharmacol. 2016;173(21):3041-3079.
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