title: Histone demethylase LSD1 is a folate-binding protein.
abstract: Methylation of lysine residues in histones has been known to serve a regulatory role in gene expression. Although enzymatic removal of the methyl groups was discovered as early as 1973, the enzymes responsible for their removal were isolated and their mechanism of action was described only recently. The first enzyme to show such activity was LSD1, a flavin-containing enzyme that removes the methyl groups from lysines 4 and 9 of histone 3 with the generation of formaldehyde from the methyl group. This reaction is similar to the previously described demethylation reactions conducted by the enzymes dimethylglycine dehydrogenase and sarcosine dehydrogenase, in which protein-bound tetrahydrofolate serves as an accepter of the formaldehyde that is generated. We now show that nuclear extracts of HeLa cells contain LSD1 that is associated with folate. Using the method of back-scattering interferometry, we have measured the binding of various forms of folate to both full-length LSD1 and a truncated form of LSD1 in free solution. The 6R,S form of the natural pentaglutamate form of tetrahydrofolate bound with the highest affinity (K(d) = 2.8 μM) to full-length LSD1. The fact that folate participates in the enzymatic demethylation of histones provides an opportunity for this micronutrient to play a role in the epigenetic control of gene expression.
authors.affiliation: Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Zigmund
authors.initials: Z
authors.lastname: Luka
authors.forename: Frank
authors.initials: F
authors.lastname: Moss
authors.forename: Lioudmila V
authors.initials: LV
authors.lastname: Loukachevitch
authors.forename: Darryl J
authors.initials: DJ
authors.lastname: Bornhop
authors.forename: Conrad
authors.initials: C
authors.lastname: Wagner
mesh_terms: D002850:Chromatography, Gel; D005492:Folic Acid / Q000378:metabolism*; D006367:HeLa Cells; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans
chemical_list: D005492:Folic Acid; D056466:Histone Demethylases; C495195:KDM1A protein, human