Human cytochrome P450 (CYP) enzymes play an important role in the metabolism of drugs, steroids, fatty acids and xenobiotics. Microsomal CYPs are anchored in the ER membrane by an N-terminal transmembrane (TM) helix that is connected to the globular catalytic domain by a flexible linker sequence. However, the structural and functional importance of the TM-helix is unclear since it has been shown that CYPs can still associate with the membrane and have enzymatic activity in reconstituted systems after truncation or modification of the N-terminal sequence.