4.C.1 The Fatty Acid Group Translocation (FAT) Family
The FAT family includes hundreds of sequenced homologues which include fatty acyl CoA ligases (fatty acyl CoA synthases), carnitine CoA ligases, and putative fatty acid transporters (Hirsch et al., 1998). Animals yeast and bacteria have numerous paralogues which may exhibit 2-4 TMSs and may be up to 500-600 residues long (Black & DiRusso, 2007). The proteins with 2-4 TMSs may be transporters, but those with none are not likely to be. While some of the eukaryotic members of the family have been shown to increase the uptake of long chain fatty acids when expressed in mammalian cells, a Mycobacterium tuberculosis homologue increases the rate of uptake of long chain fatty acids when expressed in E. coli. It is thought that these proteins catalyze and energize transport using a carrier or channel mechanism, trapping the fatty acids in the cell cytoplasm as a result of covalent modification by this esterification (Saier and Kollman, 1999; DiRusso & Black, 2004).
Faergeman et al. (2001) have presented evidence that fatty acyl-CoA synthetase function as components of fatty acid uniport systems in yeast by linking import and activation of exogenous fatty acids. Further, Zou et al. (2002) isolated FAT1 mutants of S. cerevisiae that are deficient for either transport or acyl-CoA synthetase activity. The yeast functions in concert with acyl-coenzyme A synthetase (ACSL; either Faa1p or Faa4p) in vectorial acylation, which couples the transport of exogenous fatty acids with activation to CoA thioesters.
Loss of acyl-CoA synthetase activity in yeast or animal cells results in greatly reduced fatty acid uptake activity, suggesting that uptake and CoA esterification are linked (Stuhlsatz-Krouper et al., 1998, 1999). If transport is coupled to thioesterification, these systems function by a group translocation mechanism termed 'vectorial acylation'. Steinberg et al. (2002) have noted that chronic leptin administration decreases fatty acid uptake and fatty acid transporter (FAT/CD36; TC #9.B.39) mRNA in rat skeletal muscle. FAT/CD36 is not homologous to members of the FAT family. Humans have 6 paralogues, FATP1 - 6 (Schwenk et al. 2010).
FadD of E. coli (4.C.1.1.4) is associated with the plasma membrane where it is hypothesized to transport or abstract fatty acids from the membrane concomitant with acylation of CoA to form thioesters. Hill and Angelmaier (1972) identified a mutant that had wild type acyl-CoA synthetase activities yet was unable to incorporate exogenous fatty acids into total lipids. They proposed that the affected gene product participates in the uptake of LCFAs and facilitates the diffusion of oleate through the cytoplasma membrane (DiRusso & Black, 2004). Involvement of FatP in transport is controversial (Jia et al., 2007).
The proposed group translocation reaction catalyzed by some FAT family members is:
Fatty acid (out) + Coenzymes A (in) + ATP (in) → Fatty acyl-CoA (in) + AMP (in) + P2 (in)