Protein-mediated transbilayer movement of lipids in eukaryotes and prokaryotes: the relevance of ABC transporters Astrid Tannert, Antje Pohl, Thomas Pomorski, Andreas Herrmann * Institut fu ¨ r Biologie, Molekulare Biophysik, Humboldt-Universita ¨ t Berlin, Invalidenstr. 42, D-10115 Berlin, Germany Abstract Lipid distribution across cellular membranes is regulated by specific membrane proteins controlling transbilayer movement of lipids. Flippases facilitate flip /flop of lipids and allow them to equilibrate between the two membrane leaflets independent of ATP. Distinct P-Type-ATPases transport specific lipids unidirectionally across the membrane at the expense of ATP. A group of ATP- dependent lipid transporters, the ATP-binding cassette (ABC) transporter family, was identified in studies originally related to multidrug resistance (MDR) in cancer cells. Meanwhile, lipid transport activity has been shown for full and half size ABC proteins in eukaryotic and prokaryotic cells. This activity may not only modify the organisation of lipids in membranes, but could also be of significant consequence for cell homeostasis. The various types of lipid movement mediating proteins and their cellular localisation in eukaryotes and prokaryotes are reviewed. # 2003 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Lipid; Distribution; Flip  /flop; Proteins; ABC transporters 1. Introduction Biological membranes consist of bilayers of lipids (mainly phospholipids, glycolipids and cholesterol) in which proteins are embedded. However, lipids have more functions than forming the backbone of the membrane. The distribution of lipids within the bilayer influences important physiological functions such as cell viability (phosphatidylserine (PS) becomes exposed to the exoplasmic leaflet of the plasma membrane (PM) of apoptotic cells), membrane fusion and cell  /cell recogni- tion. Asymmetric distribution of phospholipids differing in their shapes due to head-group and fatty acid chain composition may induce membrane curvature, which might also be the result of a different number of lipids in both leaflets (see Fig. 1). Among others, ATP binding cassette (ABC) proteins play a role in lipid transport across cellular membranes. Proteins belonging to this large superfamily found ubiquitously in prokaryotes and eukaryotes are respon- sible for the transport of a variety of substances across cellular membranes under the consumption of ATP. In the past three decades, multidrug resistance (MDR) proteins belonging to the ABC transporter superfamily have been studied intensely for their ability to transport cytotoxic drugs (antibiotics) out of the cell, thereby making the transporters targets for chemotherapy. To understand how ABC proteins affect lipid orga- nisation, one has to consider general aspects and mechanisms of lipid transport. This review will first summarise current knowledge of lipid transport across cellular membranes, and will then focus on the role of ABC transporters in the general picture of lipid trans- port. The composition of different membranes is quite specific, with a lipid-to-protein ratio varying from 0.2 to 0.8 depending on the cell type and its function. In Fig. 2, the composition of the endoplasmic reticulum (ER) and PM of eukaryotes is shown and compared. Even within one membrane the lipid composition may be different between separate domains such as basolateral and apical domains of the PM which are found in polarised cells. These domains are separated by tight junctions at the exoplasmic leaflet. Even smaller do- * Corresponding author. Tel.:  /49-30-2093-8830; fax:  /49-30- 2093-8585. E-mail address: andreas.herrmann@rz.hu-berlin.de (A. Herrmann). International Journal of Antimicrobial Agents 22 (2003) 177  /187 www.ischemo.org 0924-8579/03/$30 # 2003 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/S0924-8579(03)00217-6