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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 or more regions of hydrophobicity that may be TMSs.  These proteins may be over 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). Some of these proteins have TMSs, up to 5, with one at the N-terminus, and two sets of two putative TMSs in the middles of these proteins.  These hydrophobic regions could either associate with the membrane or be TMSs.

Faergeman et al. (2001) have presented evidence that the fatty acyl-CoA synthetase functions as components of a 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 proteins function 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. n-Hexadecane may cross the yeast cell plasm membrane in an energy-dependent manner with kinetics that follow saturation properties and exhibit a defined affinity for the cell transport system (Li et al. 2020).

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). However, lipophagy-derived fatty acids undergo extracellular efflux via lysosomal exocytosis (Cui et al. 2020). Liipophagy provides energy and essential building blocks for liver functions (Filali-Mouncef et al. 2021).

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)

References associated with 4.C.1 family:

Black, P.N., and C.C. DiRusso. (2007). Vectorial acylation: linking fatty acid transport and activation to metabolic trafficking. Novartis Found Symp 286: 127-38; discussion 138-41, 162-3, 196-203. 18269179
Chen, X., Y. Luo, R. Wang, B. Zhou, Z. Huang, G. Jia, H. Zhao, and G. Liu. (2017). Effects of fatty acid transport protein 1 on proliferation and differentiation of porcine intramuscular preadipocytes. Anim Sci J 88: 731-738. 27616431
Cui, W., A. Sathyanarayan, M. Lopresti, M. Aghajan, C. Chen, and D.G. Mashek. (2020). Lipophagy-derived fatty acids undergo extracellular efflux via lysosomal exocytosis. Autophagy 1-16. [Epub: Ahead of Print] 32070194
DiRusso, C.C., D. Darwis, T. Obermeyer, and P.N. Black. (2008). Functional domains of the fatty acid transport proteins: studies using protein chimeras. Biochim. Biophys. Acta. 1781: 135-143. 18258213
Faergeman, N.J., C.C. DiRusso, A. Elberger, J. Knudsen, and P.N. Black. (1997). Disruption of the Saccharomyces cerevisiae homologue to the murine fatty acid transport protein impairs uptake and growth on long-chain fatty acids. J. Biol. Chem. 272: 8531-8538. 9079682
Faergeman, N.J., P.N. Black, X.D. Zhao, J. Knudsen, and C.C. DiRusso. (2001). The Acyl-CoA synthetases encoded within FAA1 and FAA4 in Saccharomyces cerevisiae function as components of the fatty acid transport system linking import, activation, and intracellular Utilization. J. Biol. Chem. 276: 37051-37059. 11477098
Filali-Mouncef, Y., C. Hunter, F. Roccio, S. Zagkou, N. Dupont, C. Primard, T. Proikas-Cezanne, and F. Reggiori. (2021). The ménage à trois of autophagy, lipid droplets and liver disease. Autophagy 1-24. [Epub: Ahead of Print] 33794741
Gimeno, R.E. (2007). Fatty acid transport proteins. Curr. Opin. Lipidol. 18: 271-276. 17495600
Hall, A.M., B.M. Wiczer, T. Herrmann, W. Stremmel, and D.A. Bernlohr. (2005). Enzymatic properties of purified murine fatty acid transport protein 4 and analysis of acyl-CoA synthetase activities in tissues from FATP4 null mice. J. Biol. Chem. 280: 11948-11954. 15653672
Hatch, G.M., A.J. Smith, F.Y. Xu, A.M. Hall, and D.A. Bernlohr. (2002). FATP1 channels exogenous FA into 1,2,3-triacyl-sn-glycerol and down-regulates sphingomyelin and cholesterol metabolism in growing 293 cells. J Lipid Res 43: 1380-1389. 12235169
Hill, F.F. and D. Angelmaier. (1972). Specific enrichment of mutants of Escherichia coli with an altered acyl CoA synthetase by tritium suicide. Mol. Gen. Genet. 117: 143-152. 4561424
Hirsch, D., A. Stahl, and H.F. Lodish. (1998). A family of fatty acid transporters conserved from mycobacterium to man. Proc. Natl. Acad. Sci. U.S.A. 95: 8625-8629. 9671728
Jia, Z., Z. Pei, D. Maiguel, C.J. Toomer, and P.A. Watkins. (2007). The fatty acid transport protein (FATP) family: very long chain acyl-CoA synthetases or solute carriers? J. Mol. Neurosci. 33: 25-31. 17901542
Khan, S., P.D. Cabral, W.P. Schilling, Z.W. Schmidt, A.N. Uddin, A. Gingras, S.M. Madhavan, J.L. Garvin, and J.R. Schelling. (2017). Kidney Proximal Tubule Lipoapoptosis Is Regulated by Fatty Acid Transporter-2 (FATP2). J Am Soc Nephrol. [Epub: Ahead of Print] 28993506
Li, J., Y. Xu, Q. Song, S. Zhang, L. Xie, and J. Yang. (2020). Transmembrane transport mechanism of n-hexadecane by Candida tropicalis: Kinetic study and proteomic analysis. Ecotoxicol Environ Saf 209: 111789. [Epub: Ahead of Print] 33340957
Li, S., W.C. Gordon, N.G. Bazan, and M. Jin. (2020). Inverse correlation between fatty acid transport protein 4 and vision in Leber congenital amaurosis associated with RPE65 mutation. Proc. Natl. Acad. Sci. USA 117: 32114-32123. 33257550
Lin, M.H., F.F. Hsu, and J.H. Miner. (2013). Requirement of fatty acid transport protein 4 for development, maturation, and function of sebaceous glands in a mouse model of ichthyosis prematurity syndrome. J. Biol. Chem. 288: 3964-3976. 23271751
Martin, G., M. Nemoto, L. Gelman, S. Geffroy, J. Najib, J.C. Fruchart, P. Roevens, B. de Martinville, S. Deeb, and J. Auwerx. (2000). The human fatty acid transport protein-1 (SLC27A1; FATP-1) cDNA and gene: organization, chromosomal localization, and expression. Genomics 66: 296-304. 10873384
Obermeyer, T., P. Fraisl, C.C. DiRusso, and P.N. Black. (2007). Topology of the yeast fatty acid transport protein Fat1p: mechanistic implications for functional domains on the cytosolic surface of the plasma membrane. J Lipid Res 48: 2354-2364. 17679730
Saier, M.H., and J.M. Kollman. (1999). Is FatP a long-chain fatty acid transporter? Mol. Microbiol. 33: 670-672. 10417658
Schwenk, R.W., G.P. Holloway, J.J. Luiken, A. Bonen, and J.F. Glatz. (2010). Fatty acid transport across the cell membrane: regulation by fatty acid transporters. Prostaglandins Leukot Essent Fatty Acids 82: 149-154. 20206486
Song, Y., J. Feng, L. Zhou, G. Shu, X. Zhu, P. Gao, Y. Zhang, and Q. Jiang. (2008). Molecular cloning and ontogenesis expression of fatty acid transport protein-1 in yellow-feathered broilers. J Genet Genomics 35: 327-333. 18571120
Steinberg, G.R., D.J. Dyck, J. Calles-Escandon, N.N. Tandon, J.J. Luiken, J.F. Glatz, and A. Bonen. (2002). Chronic leptin administration decreases fatty acid uptake and fatty acid transporters in rat skeletal muscle. J. Biol. Chem. 277: 8854-8860. 11729182
Stuhlsatz-Krouper, S.M., N.E. Bennett, and J.E. Schaffer. (1998). Substitution of alanine for serine 250 in the murine fatty acid transport protein inhibits long chain fatty acid transport. J. Biol. Chem. 273: 28642-28650. 9786857
Stuhlsatz-Krouper, S.M., N.E. Bennett, and J.E. Schaffer. (1999). Molecular aspects of fatty acid transport: mutations in the IYTSGTTGXPK motif impair fatty acid transport protein function. Prostaglandins Leukot. Essent. Fatty Acids.  60: 285-289. 10471110
Visser, W.F., C.W. van Roermund, L. Ijlst, H.R. Waterham, and R.J. Wanders. (2007). Metabolite transport across the peroxisomal membrane. Biochem. J. 401: 365-375. 17173541
Zou, Z., C.C. DiRusso, V. Ctrnacta, and P.N. Black. (2002). Fatty acid transport in Saccharomyces cerevisiae. Directed mutagenesis of FAT1 distinguishes the biochemical activities associated with Fat1p. J. Biol. Chem. 277: 31062-31071. 12052836