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The former annotated human pseudogene dihydrofolate reductase-like 1 (DHFRL1) is expressed and functional

Gráinne McEntee, Stefano Minguzzi, Kirsty O'Brien, Nadia Ben Larbi, Christine Loscher, Ciarán Ó'Fágáin and Anne Parle-McDermott
Proceedings of the National Academy of Sciences of the United States of America
Vol. 108, No. 37 (September 13, 2011), pp. 15157-15162
Stable URL: http://www.jstor.org/stable/41352062
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
The former annotated human pseudogene dihydrofolate reductase-like 1 (DHFRL1) is expressed and functional
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Abstract

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 DHFR 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 DHFRP4, located on chromosome 3. We demonstrate that the DHFRP4, or dihydrofolate reductase-like 1 (DHFRL1), gene is expressed and shares some commonalities with DHFR. Recombinant DHFRL1 can complement a DHFR-negative phenotype in bacterial and mammalian cells but has a lower specific activity than DHFR. The Km for NADPH is similar for both enzymes but DHFRL1 has a higher Km 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.

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