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)
Putative fatty acid transporter, FatP4 (Hall et al., 2005). See TC# 4.C.1.1.10 for details of the human ortholog.
Animals, yeast, plants, bacteria
FatP4 of Mus musculus (O88562)
Long-chain fatty acid transport protein 4 (FATP-4) (Fatty acid transport protein 4) (EC 6.2.1.-) (Solute carrier family 27 member 4). FATP4 is one of a family of six transmembrane proteins that facilitate long- and very long-chain fatty acid uptake. FATP4 is expressed in several tissues, including skin. Mutations in human SLC27A4, which encodes FATP4, cause ichthyosis prematurity syndrome, characterized by a thick desquamating epidermis and premature birth (PMID 23271751). There is an inverse correlation between fatty acid transport protein 4 and vision in Leber congenital amaurosis-associated with the RPE65 mutation (Li et al. 2020). Emodin influences expression of its structural gene (Cheng et al. 2021).
SLC27A4 of Homo sapiens
Long-chain fatty acid transport protein 6 (FATP-6) (Fatty acid transport protein 6) (Fatty-acid-coenzyme A ligase, very long-chain 2) (Solute carrier family 27 member 6) (Very long-chain acyl-CoA synthetase homologue 1) (VLCSH1) (hVLCS-H1)
SLC27A6 of Homo sapiens
Long-chain fatty acid transport protein 3 (FATP-3) (Fatty acid transport protein 3) (EC 6.2.1.-) (Solute carrier family 27 member 3) (Very long-chain acyl-CoA synthetase homologue 3) (VLCS-3)
SLC27A3 of Homo sapiens
Bile acyl-CoA synthetase (BACS) (EC 18.104.22.168) (Bile acid-CoA ligase) (BA-CoA ligase) (BAL) (Cholate--CoA ligase) (Fatty acid transport protein 5) (FATP-5) (Fatty-acid-coenzyme A ligase, very long-chain 3) (Solute carrier family 27 member 5) (Very long-chain acyl-CoA synthetase homologue 2) (VLCS-H2) (VLCSH2) (Very long-chain acyl-CoA synthetase-related protein) (VLACS-related) (VLACSR)
SLC27A5 of Homo sapiens
Long chain fatty acyl-CoA ligase (synthetase) (E.C. 22.214.171.124) (Pulsifer et al., 2012).
LCFA ligase of Arabidopsis thaliana (Q9XIA9)
Long chain fatty acyl-CoA ligase 2 of 744 aas. May play a role in lauric acid transport and thioesterification (Visser et al. 2007).
Faa2 of Saccharomyces cerevisiae
Bifunctional protein, Aas of 719 aas and 3 - 5 TMSs. Plays a role in lysophospholipid acylation. Transfers fatty acids to the 1-position via an enzyme-bound acyl-ACP intermediate in the presence of ATP and magnesium. Its physiological function is to regenerate phosphatidylethanolamine from 2-acyl-glycero-3-phosphoethanolamine (2-acyl-GPE) formed by transacylation reactions or degradation by phospholipase A1.
Aas of E. coli
The fatty acid transport protein-1, FATP-1 of 646 aas and from 1 to several TMSs. Expression levels of the encoding gene occurs in a tissue and gender-specific fashon (Song et al. 2008).
FatP1 of Gallus gallus
Hybrid PKS-NRPS synthetase of 1561 aas and as many as ~12 moderately hydrophobic peaks that may be TMSs (Armitage et al. 2019).
PKS-NRPS synthetase of Alternaria gaisen
Hybrid PKS-NRPS synthetase; part of the gene cluster that mediates the biosynthesis of the toxin tenuazonic acid (TeA), an inhibitor of protein biosynthesis on ribosomes by suppressing the release of new protein (Yun et al. 2015, Ninomiya et al. 2020, Yun et al. 2020). TAS1 alone is sufficient for TeA synthesis via the condensation of isoleucine (Ile) with acetoacetyl-CoA by the N-termainal NRPS module and subsequent cyclization conducted by the C-terminal KS domain (Yun et al. 2015, Yun et al. 2020).
PLS-NRPS synthetase of Magnaporthe oryzae (Rice blast fungus) (Pyricularia oryzae)
Long chain fatty acid transporter, Fat1 of 669 aa and 2 TMSs with an Nin-Cin topology. Obermeyer et al. 2007 proposed that Fat1p has a third region, which binds to the membrane and separates the highly conserved residues comprising the two halves of the ATP/AMP motif. The proposed topology places the ATP/AMP and FATP/VLACS domains on the inner face of the plasma membrane. The carboxyl-terminal region of Fat1p, which interacts with ACSL, is likewise positioned on the inner face of the plasma membrane (Obermeyer et al. 2007).
Fat1 of Saccharomyces cerevisiae (P38225)
Peroxysomal fatty acyl CoA synthase (ligase) or long chain fatty acid transporter-2, FATP2, of 620 aas and 2 TMSs. FATP2 may be a major apical proximal tubule nonesterified fatty acid transporter that regulates lipoapoptosis and may be an amenable target for the prevention of CKD progression (Khan et al. 2017).
SLC27A2 of Homo sapiens
Long-chain fatty acid trans-plasma membrane translocase or trapping enzyme, FATP1 (Insulin regulated). FATP1 has acyl-CoA ligase activity. (Martin et al., 2000; Hatch et al., 2002). FATP1 plays a role in porcine intramuscular preadipocytes proliferation and differentiation (Chen et al. 2017).
SLC27A1 of Homo sapiens