Pmvk, or phosphomevalonate kinase, is an enzyme that catalyzes the conversion of mevalonate 5-phosphate to mevalonate 5-diphosphate in the mevalonate pathway [6]. This pathway is crucial for the synthesis of cholesterol and other isoprenoids, which are essential for various cellular functions, including cell membrane integrity, protein prenylation, and the synthesis of coenzymes [5,7].

In porokeratosis, a rare chronic progressive hypokeratotic skin disease, specific variants in Pmvk have been identified as causative factors. For example, a novel heterozygous missense variant, c.207G>T (p.Lys69Asn) in the PMVK gene, was found in all patients of a Chinese family with porokeratosis but not in normal individuals of the family or in 100 controls. In silico analysis indicated its pathogenicity [1]. Also, in linear porokeratosis, postzygotic somatic mutations in Pmvk were found in affected tissue, suggesting its role in the disease's development [4].

In addition, in hepatocellular carcinoma, depletion of PMVK in HCC cells was shown to facilitate CD8+ T cell activation, suppressing tumor growth. PMVK phosphorylates and stabilizes glutamate decarboxylase 1, increasing the synthesis of γ-aminobutyric acid, which is then converted to 4-acetaminobutyric acid that suppresses CD8+ T cell activation [2]. In lung cancer cells, knockdown of PMVK enhanced radiosensitivity through an impaired homologous recombination repair pathway by ubiquitination of the replication protein A1 [3].

In conclusion, Pmvk plays a vital role in the mevalonate pathway. Its mutations are associated with porokeratosis, and its functions are also linked to tumor immune escape in hepatocellular carcinoma and radiosensitivity in lung cancer. These findings from various disease-related studies, especially those on gene-associated diseases, help to understand the biological functions of Pmvk and its potential as a therapeutic target in these disease areas.

References:

1. Zhang, Wenjing, Nie, Xinmiao, Shi, Lei, Shao, Fengmin, Cao, Lihua. 2023. A Novel PMVK Variant Associated with Familial Porokeratosis. In Human heredity, 88, 50-57. doi:10.1159/000531120. https://pubmed.ncbi.nlm.nih.gov/37315547/

2. Zhou, Xinyi, Chen, Zhiqiang, Yu, Yijiang, Prochownik, Edward V, Li, Youjun. 2024. Increases in 4-Acetaminobutyric Acid Generated by Phosphomevalonate Kinase Suppress CD8+ T Cell Activation and Allow Tumor Immune Escape. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2403629. doi:10.1002/advs.202403629. https://pubmed.ncbi.nlm.nih.gov/39325640/

3. Park, Seok Soon, Kwon, Mi Ri, Ju, Eun Jin, Jeong, Seong-Yun, Choi, Eun Kyung. 2023. Targeting phosphomevalonate kinase enhances radiosensitivity via ubiquitination of the replication protein A1 in lung cancer cells. In Cancer science, 114, 3583-3594. doi:10.1111/cas.15896. https://pubmed.ncbi.nlm.nih.gov/37650703/

4. Atzmony, Lihi, Khan, Habib M, Lim, Young H, Leventhal, Jonathan S, Choate, Keith A. . Second-Hit, Postzygotic PMVK and MVD Mutations in Linear Porokeratosis. In JAMA dermatology, 155, 548-555. doi:10.1001/jamadermatol.2019.0016. https://pubmed.ncbi.nlm.nih.gov/30942823/

5. Blicharz, Leszek, Czuwara, Joanna, Rudnicka, Lidia, Torrelo, Antonio. 2023. Autoinflammatory Keratinization Diseases-The Concept, Pathophysiology, and Clinical Implications. In Clinical reviews in allergy & immunology, 65, 377-402. doi:10.1007/s12016-023-08971-3. https://pubmed.ncbi.nlm.nih.gov/38103162/

6. Wang, Jiuxiang, Liu, Ying, Liu, Fei, Guo, An-Yuan, Liu, Mugen. 2016. Loss-of-function Mutation in PMVK Causes Autosomal Dominant Disseminated Superficial Porokeratosis. In Scientific reports, 6, 24226. doi:10.1038/srep24226. https://pubmed.ncbi.nlm.nih.gov/27052676/

7. Saito, Sonoko, Saito, Yuki, Sato, Showbu, Nakabayashi, Kazuhiko, Kubo, Akiharu. 2024. Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis. In American journal of human genetics, 111, 896-912. doi:10.1016/j.ajhg.2024.03.017. https://pubmed.ncbi.nlm.nih.gov/38653249/