{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T01:51:51Z","timestamp":1783043511553,"version":"3.54.6"},"reference-count":21,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T00:00:00Z","timestamp":1735603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Foundation","award":["DBI 2000296"],"award-info":[{"award-number":["DBI 2000296"]}]},{"name":"National Science Foundation","award":["HRD 2011933"],"award-info":[{"award-number":["HRD 2011933"]}]},{"name":"National Science Foundation","award":["2U54MD007597"],"award-info":[{"award-number":["2U54MD007597"]}]},{"DOI":"10.13039\/100006545","name":"National Institute on Minority Health and Health Disparities","doi-asserted-by":"publisher","award":["DBI 2000296"],"award-info":[{"award-number":["DBI 2000296"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006545","name":"National Institute on Minority Health and Health Disparities","doi-asserted-by":"publisher","award":["HRD 2011933"],"award-info":[{"award-number":["HRD 2011933"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006545","name":"National Institute on Minority Health and Health Disparities","doi-asserted-by":"publisher","award":["2U54MD007597"],"award-info":[{"award-number":["2U54MD007597"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Somatic and genetic mutations in glutathione peroxidases (GPxs), including GPx7 and GPx8, have been linked to intellectual disability, microcephaly, and various tumors. GPx7 and GPx8 evolved the latest among the GPx enzymes and are present in the endoplasmic reticulum. Although lacking a glutathione binding domain, GPx7 and GPx8 possess peroxidase activity that helps the body respond to cellular stress. However, the protein mutations in these peroxidases remain relatively understudied. Methods: By elucidating the structural and stability consequences of missense mutations, this study aims to provide insights into the pathogenic mechanisms involved in different cancers, thereby aiding clinical diagnosis, treatment strategies, and the development of targeted therapies. We performed saturated computational mutagenesis to analyze 2926 and 3971 missense mutations of GPx7 and GPx8, respectively. Results: The results indicate that G153H and G153F in GPx7 are highly destabilizing, while E93M and W142F are stabilizing. In GPx8, N74W and G173W caused the most instability while S70I and S119P increased stability. Our analysis shows that highly destabilizing somatic and genetic mutations are more likely pathogenic compared to stabilizing mutations. Conclusions: This comprehensive analysis of missense mutations in GPx7 and GPx8 provides critical insights into their impact on protein structure and stability, contributing to a deeper understanding of the roles of somatic mutations in cancer development and progression. These findings can inform more precise clinical diagnostics and targeted treatment approaches for cancers.<\/jats:p>","DOI":"10.3390\/cancers17010105","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T12:37:19Z","timestamp":1735648639000},"page":"105","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Computational Mutagenesis of GPx7 and GPx8: Structural and Stability Insights into Rare Genetic and Somatic Missense Mutations and Their Implications for Cancer Development"],"prefix":"10.3390","volume":"17","author":[{"given":"Adebiyi","family":"Sobitan","sequence":"first","affiliation":[{"name":"Department of Biology, Howard University, Washington, DC 20059, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nosimot","family":"Buhari","sequence":"additional","affiliation":[{"name":"Department of Biology, Howard University, Washington, DC 20059, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zainab","family":"Youssri","sequence":"additional","affiliation":[{"name":"Department of Biology, Howard University, Washington, DC 20059, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fayuan","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Biology, Howard University, Washington, DC 20059, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawit","family":"Kidane","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Howard University College of Medicine, Washington, DC 20059, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaolei","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Biology, Howard University, Washington, DC 20059, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Pei, J., Pan, X., Wei, G., and Hua, Y. 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