{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:36:47Z","timestamp":1787240207703,"version":"build-2736575974"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"37","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,9,13]]},"abstract":"<jats:p>\n                    Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. DHFR has been studied extensively from a number of perspectives because of its role in health and disease. Although the presence of a number of intronless\n                    <jats:italic>DHFR<\/jats:italic>\n                    pseudogenes has been known since the 1980s, it was assumed that none of these were expressed or functional. We show that humans do have a second dihydrofolate reductase enzyme encoded by the former pseudogene\n                    <jats:italic>DHFRP4<\/jats:italic>\n                    , located on chromosome 3. We demonstrate that the\n                    <jats:italic>DHFRP4<\/jats:italic>\n                    , or dihydrofolate reductase-like 1 (\n                    <jats:italic>DHFRL1<\/jats:italic>\n                    ), gene is expressed and shares some commonalities with DHFR. Recombinant DHFRL1 can complement a\n                    <jats:italic>DHFR<\/jats:italic>\n                    -negative phenotype in bacterial and mammalian cells but has a lower specific activity than DHFR. The\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>m<\/jats:italic>\n                    <\/jats:sub>\n                    for NADPH is similar for both enzymes but DHFRL1 has a higher\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>m<\/jats:italic>\n                    <\/jats:sub>\n                    for dihydrofolate when compared to DHFR. The need for a second reductase with lowered affinity for its substrate may fulfill a specific cellular requirement. The localization of DHFRL1 to the mitochondria, as demonstrated by confocal microscopy, indicates that mitochondrial dihydrofolate reductase activity may be optimal with a lowered affinity for dihydrofolate. We also found that DHFRL1 is capable of the same translational autoregulation as DHFR by binding to its own mRNA; with each enzyme also capable of replacing the other. The identification of DHFRL1 will have implications for previous research involving DHFR.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1103605108","type":"journal-article","created":{"date-parts":[[2011,8,27]],"date-time":"2011-08-27T01:27:03Z","timestamp":1314408423000},"page":"15157-15162","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":36,"title":["The former annotated human pseudogene dihydrofolate reductase-like 1 (\n                    <i>DHFRL1<\/i>\n                    ) is expressed and functional"],"prefix":"10.1073","volume":"108","author":[{"given":"Gr\u00e1inne","family":"McEntee","sequence":"first","affiliation":[{"name":"School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Minguzzi","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsty","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Ben Larbi","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Loscher","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciar\u00e1n","family":"\u00d3\u2019F\u00e1g\u00e1in","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Parle-McDermott","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,8,26]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.81.5.1484"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.81.16.5170"},{"key":"e_1_3_3_3_2","volume-title":"Vitamins and Hormones","author":"Litwack G","year":"2008","unstructured":", ed G Litwack (Elsevier, New York), Folic Acid and Folates. 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