ArticleProceedings of the National Academy of Sciences of the United States of America2011
The former annotated human pseudogene dihydrofolate reductase-like 1 (DHFRL1) is expressed and functional.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 35 citations in OpenAlex.
- Fundamental origins of neural tube defects with a basis in genetics and nutrition.Experimental brain research · 2025Review
- DHFR2 RNA directly regulates dihydrofolate reductase and its expression level impacts folate one carbon metabolism.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Host Genome-Wide Association Study of Infant Susceptibility toInfection and immunity · 2021Article
- Methods to Study Translated Pseudogenes: Recombinant Expression and Complementation, Targeted Proteomics, and RNA Profiling.Methods in molecular biology (Clifton, N.J.) · 2021Article
- The Structural Basis for Nonsteroidal Anti-Inflammatory Drug Inhibition of Human Dihydrofolate Reductase.Journal of medicinal chemistry · 2020Article
- Knockout of dihydrofolate reductase in mice induces hypertension and abdominal aortic aneurysm via mitochondrial dysfunction.Redox biology · 2019Article
- A-to-I RNA Editing Up-regulates Human Dihydrofolate Reductase in Breast Cancer.The Journal of biological chemistry · 2017Article
- Reverse Chemical Genetics: Comprehensive Fitness Profiling Reveals the Spectrum of Drug Target Interactions.PLoS genetics · 2016Article
- Novel Role of 3'UTR-Embedded Alu Elements as Facilitators of Processed Pseudogene Genesis and Host Gene Capture by Viral Genomes.PloS one · 2016Article
- The Dihydrofolate Reductase 19 bp Polymorphism Is Not Associated with Biomarkers of Folate Status in Healthy Young Adults, Irrespective of Folic Acid Intake.The Journal of nutrition · 2015Article
- Impact of a novel homozygous mutation in nicotinamide nucleotide transhydrogenase on mitochondrial DNA integrity in a case of familial glucocorticoid deficiency.BBA clinical · 2015Article
- Adult vascular smooth muscle cells in culture express neural stem cell markers typical of resident multipotent vascular stem cells.Cell and tissue research · 2014Article
- Embryonic rat vascular smooth muscle cells revisited - a model for neonatal, neointimal SMC or differentiated vascular stem cells?Vascular cell · 2014Article
- Pseudogene-derived lncRNAs: emerging regulators of gene expression.Frontiers in genetics · 2014Article
- Insight into the molecular mechanism about lowered dihydrofolate binding affinity to dihydrofolate reductase-like 1 (DHFRL1).Journal of molecular modeling · 2013Article
- Not so pseudo: the evolutionary history of protein phosphatase 1 regulatory subunit 2 and related pseudogenes.BMC evolutionary biology · 2013Article
- RCPedia: a database of retrocopied genes.Bioinformatics (Oxford, England) · 2013Article
- Gene copy-number polymorphism caused by retrotransposition in humans.PLoS genetics · 2013Article
- GENCODE: the reference human genome annotation for The ENCODE Project.Genome research · 2012Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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 K(m) for NADPH is similar for both enzymes but DHFRL1 has a higher K(m) 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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