base flipping was first observed in 1994 when researchers klimasauskas, kumar, roberts, and cheng used x-ray crystallography to view an intermediate step in the chemical reaction of a methyltransferase bound to dna. the methyltransferase they used was the c5-cytosine methyltransferase from "haemophilus haemolyticus" (m. hhai). this enzyme recognizes a specific sequence of the dna (5'-gcgc-3') and methylates the first cytosine base of the sequence at its c5 location. upon crystallization of the m. hhai-dna complex, they saw the target cytosine base was rotated completely out of the double helix and was positioned in the active site of the m. hhai. it was held in place by numerous interactions between the m. hhai and dna.