Phosphoethanolamine transferases, including MCR, are enzymes of the Gram-negative inner membrane that consist a soluble periplasmic catalytic and a transmembrane domain (Figure ). The catalytic domain has been the subject of relatively extensive biochemical study and contains a zinc site (Zn1, comprised of three conserved amino acids, Glu246, Asp 465 and His466) adjacent to the threonine residue (Thr285) that is the likely site of formation of the covalent phosphointermediate formed when PEtN is transferred from a phosphatidyl ethanolamine donor to the lipid A acceptor substrate (Scheme 1). Two additional conserved "gating" histidine residues (His395 and His478) are observed in some structures to bind a second zinc equivalent (Zn2), but the physiological and mechanistic significance of this site remains unclear. The contribution of the transmembrane domain to MCR activity is also incompletely understood, although it is reasonable to assume involvement in binding both (lipdated) donor and acceptor substrates, and potentially in orienting these for PEtN transfer. Given that the majority of studies have investigated the isolated MCR catalytic domain, it is also an open question as to whether residues from the transmembrane domain, in particular Glu116 positioned on a short -helix that sits on the inner membrane surface, form part of the active site in the intact protein and hence are important in catalyzing the PEtN transfer reaction.