FAA2 (YER015W; also FAM1) encodes the peroxisomal medium- and long-chain fatty acyl-CoA synthetase of Saccharomyces cerevisiae (ATP-dependent AMP-binding enzyme family, EC 6.2.1.3). Purified Faa2p has the broadest chain-length range of the yeast Faa enzymes, preferring C9:0-C13:0 and tolerating C7:0-C17:0 fatty acids, and it is the main (probably exclusive) octanoate/decanoate/laurate-CoA ligase. Faa2p is oleate-induced, imported by the PTS1 pathway and associates peripherally with the matrix side of the peroxisomal membrane. There it activates medium-chain fatty acids that enter peroxisomes as free acids, and it re-esterifies long-chain and very-long-chain fatty acids released by the Pxa1p/Pxa2p ABC transporter, which hydrolyses acyl-CoAs during transport. It thereby supplies acyl-CoA substrates directly to the peroxisomal beta-oxidation enzymes (Pox1p, Fox2p, Pot1p). When overexpressed it can also activate endogenous myristate pools for protein N-myristoylation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001676 long-chain fatty acid metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for long-chain fatty acid metabolic process from node PTN001945066 (yeast Faa2p and mammalian ACSL donors). Faa2p activates C13-C17 (long-chain by GO's definition) as well as medium-chain fatty acids. Supporting Evidence: PMID:8206942 Faa2p can accommodate a wider range of acyl chain lengths: C9:0-C13:0 are preferred and have equivalent activities, although C7:0-C17:0 fatty acids are tolerated as substrates with no greater than a 2-fold variation in specific activity |
| GO:0001676 long-chain fatty acid metabolic process | IGI PMID:7962057 Saccharomyces cerevisiae contains four fatty acid activation... | ACCEPT | Summary: IGI (Johnson et al. 1994; with SGD:S000004185): overexpressed Faa2p rescues the nmt1-181 N-myristoyltransferase mutant by activating an endogenous myristate (C14:0) pool, a long-chain fatty acid metabolic role. Supporting Evidence: PMID:7962057 Overexpression of Faa2p can rescue nmt1-181 cells due to activation of an endogenous pool of C14:0 |
| GO:0001676 long-chain fatty acid metabolic process | IMP PMID:7962057 Saccharomyces cerevisiae contains four fatty acid activation... | ACCEPT | Summary: IMP (Johnson et al. 1994): genetic analysis of the four FAA genes shows Faa2p activates endogenous long-chain fatty acid pools. Supporting Evidence: PMID:7962057 Overexpression of Faa2p can rescue nmt1-181 cells due to activation of an endogenous pool of C14:0 |
| GO:0004467 long-chain fatty acid-CoA ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for long-chain fatty acid-CoA ligase from the broad ACSL node; Faa2p has experimental activity on long-chain substrates. Supporting Evidence: PMID:8206942 Faa2p can accommodate a wider range of acyl chain lengths: C9:0-C13:0 are preferred and have equivalent activities, although C7:0-C17:0 fatty acids are tolerated as substrates with no greater than a 2-fold variation in specific activity PMID:8206942 The myristoyl-CoA synthetase activities of Faa1p and Faa2p are 2 orders of magnitude greater than that of Faa3p in vitro |
| GO:0004467 long-chain fatty acid-CoA ligase activity | IDA PMID:8206942 Biochemical studies of three Saccharomyces cerevisiae acyl-C... | ACCEPT | Summary: IDA (Knoll et al. 1994): purified Faa2p activates C7-C17 fatty acids including myristate at high specific activity. Supporting Evidence: PMID:8206942 We have expressed Faa1p, Faa2p, and Faa3p in a strain of Escherichia coli that lacks its own endogenous acyl-CoA synthetase (FadD) PMID:8206942 Faa2p can accommodate a wider range of acyl chain lengths: C9:0-C13:0 are preferred and have equivalent activities, although C7:0-C17:0 fatty acids are tolerated as substrates with no greater than a 2-fold variation in specific activity PMID:8206942 The myristoyl-CoA synthetase activities of Faa1p and Faa2p are 2 orders of magnitude greater than that of Faa3p in vitro |
| GO:0004467 long-chain fatty acid-CoA ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA from ARBA/InterPro/Rhea/EC mappings for long-chain acyl-CoA synthetase; consistent with experimental data. Supporting Evidence: file:yeast/FAA2/FAA2-uniprot.txt Reaction=a long-chain fatty acid + ATP + CoA = a long-chain fatty acyl- |
| GO:0004467 long-chain fatty acid-CoA ligase activity | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways RCA (YEAST-FAO-PWY) for the fatty acid activation step (EC 6.2.1.3). Correct: Faa2p is the acyl-CoA synthetase that acts inside peroxisomes, directly supplying beta-oxidation. Supporting Evidence: PMID:8670886 Medium-chain fatty acids are activated inside peroxisomes hby the acyl-CoA synthetase Faa2p file:yeast/FAA2/FAA2-uniprot.txt Also esterifies LCFAs in the peroxisome matrix |
| GO:0005737 cytoplasm | EXP PMID:7988550 Subcellular relocalization of a long-chain fatty acid CoA li... | KEEP AS NON CORE | Summary: EXP from Harington et al. 1994 (FAM1-1 suppressor). The paper inferred that wild-type Fam1p/Faa2p is cytosolic because it lacks a mitochondrial presequence; later work showed it is peroxisomal. Cytoplasm is a parent of peroxisome, so the term is not wrong, but it is uninformative. Supporting Evidence: PMID:7988550 we hypothesize that the suppressor acts by changing the subcellular localization of the protein and relocating at least some of the enzyme from the cytosol to the mitochondria PMID:8670886 Medium-chain fatty acids are activated inside peroxisomes hby the acyl-CoA synthetase Faa2p |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA from UniProt subcellular location 'Cytoplasm' (SL-0086), itself based on Harington et al. 1994. True only in the broad sense that peroxisomes are part of the cytoplasm. Supporting Evidence: file:yeast/FAA2/FAA2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:7988550} |
| GO:0005739 mitochondrion | HDA PMID:14576278 The proteome of Saccharomyces cerevisiae mitochondria. | MARK AS OVER ANNOTATED | Summary: HDA from the mitochondrial proteome of Sickmann et al. 2003. Wild-type Faa2p lacks a mitochondrial targeting sequence (only the FAM1-1 suppressor allele gains one) and is peroxisomal; detection in mitochondrial fractions most likely reflects peroxisome co-purification. Supporting Evidence: PMID:7988550 we hypothesize that the suppressor acts by changing the subcellular localization of the protein and relocating at least some of the enzyme from the cytosol to the mitochondria PMID:8670886 Medium-chain fatty acids are activated inside peroxisomes hby the acyl-CoA synthetase Faa2p |
| GO:0005739 mitochondrion | HDA PMID:16823961 Toward the complete yeast mitochondrial proteome: multidimen... | MARK AS OVER ANNOTATED | Summary: HDA from the PROMITO mitochondrial proteome (Reinders et al. 2006); same caveat as the other mitochondrial proteomics row for this peroxisomal enzyme. Supporting Evidence: PMID:8670886 Medium-chain fatty acids are activated inside peroxisomes hby the acyl-CoA synthetase Faa2p |
| GO:0005777 peroxisome | IDA PMID:8670886 The ABC transporter proteins Pat1 and Pat2 are required for ... | ACCEPT | Summary: IDA (Hettema et al. 1996): Faa2p is the intraperoxisomal acyl-CoA synthetase activating medium-chain fatty acids. Supporting Evidence: PMID:8670886 Medium-chain fatty acids are activated inside peroxisomes hby the acyl-CoA synthetase Faa2p |
| GO:0005778 peroxisomal membrane | EXP PMID:8670886 The ABC transporter proteins Pat1 and Pat2 are required for ... | ACCEPT | Summary: EXP (Hettema et al. 1996): Faa2p is a peripheral protein on the matrix side of the peroxisomal membrane (UniProt). Supporting Evidence: file:yeast/FAA2/FAA2-uniprot.txt Peroxisome membrane {ECO:0000269|PubMed:8670886}; Peripheral membrane file:yeast/FAA2/FAA2-uniprot.txt protein {ECO:0000269|PubMed:8670886}; Matrix side |
| GO:0005778 peroxisomal membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular location (SL-0203, peroxisome membrane), based on Hettema et al. 1996. Supporting Evidence: file:yeast/FAA2/FAA2-uniprot.txt Peroxisome membrane {ECO:0000269|PubMed:8670886}; Peripheral membrane |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA for ER (is_active_in) from the broad ACSL node seeded by plant, fly and mammalian ER ACSLs. Faa2p is a PTS1-imported peroxisomal enzyme and there is no evidence for ER localisation; the location does not transfer to this peroxisomal subfamily member. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Supporting Evidence: PMID:8670886 Medium-chain fatty acids are activated inside peroxisomes hby the acyl-CoA synthetase Faa2p file:yeast/FAA2/FAA2-uniprot.txt Peroxisome membrane {ECO:0000269|PubMed:8670886}; Peripheral membrane |
| GO:0005829 cytosol | RCA GO_REF:0000123 | REMOVE | Summary: YeastPathways RCA (YEAST-FAO-PWY) placing fatty acid oxidation in the cytosol. Faa2p acts inside peroxisomes, the exclusive site of beta-oxidation in yeast. Supporting Evidence: PMID:8670886 Peroxisomes of Saccharomyces cerevisiae are the exclusive site of fatty acid beta-oxidation PMID:8670886 Medium-chain fatty acids are activated inside peroxisomes hby the acyl-CoA synthetase Faa2p |
| GO:0006631 fatty acid metabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO IEA (IPR045311) for fatty acid metabolic process. Appropriately general for an enzyme that activates both medium- and long-chain fatty acids. Supporting Evidence: PMID:8206942 Faa2p can accommodate a wider range of acyl chain lengths: C9:0-C13:0 are preferred and have equivalent activities, although C7:0-C17:0 fatty acids are tolerated as substrates with no greater than a 2-fold variation in specific activity |
| GO:0006635 fatty acid beta-oxidation | IMP PMID:18757502 The human peroxisomal ABC half transporter ALDP functions as... | ACCEPT | Summary: IMP (van Roermund et al. 2008). The abstract describes the free-fatty-acid route into peroxisomes that requires intraperoxisomal activation, the step performed by Faa2p (Hettema et al. 1996); the curator's IMP from the full text is consistent with Faa2p's established role. Core process for Faa2p. Supporting Evidence: PMID:18757502 uptake of fatty acids into peroxisomes may occur via two routes, either as free fatty acids thus requiring intraperoxisomal activation into acyl-CoA esters or as long-chain acyl-CoA esters PMID:8670886 Medium-chain fatty acids are activated inside peroxisomes hby the acyl-CoA synthetase Faa2p |
| GO:0015910 long-chain fatty acid import into peroxisome | IGI PMID:18757502 The human peroxisomal ABC half transporter ALDP functions as... | KEEP AS NON CORE | Summary: IGI with FOX2 (van Roermund et al. 2008). Faa2p does not translocate fatty acids, but its intraperoxisomal activation traps free fatty acids that enter peroxisomes, and re-esterifies those delivered by Pxa1p/Pxa2p; the curator scored this as involvement in long-chain fatty acid import into peroxisome. Plausible contributory role, not a core transport function. Supporting Evidence: PMID:18757502 uptake of fatty acids into peroxisomes may occur via two routes, either as free fatty acids thus requiring intraperoxisomal activation into acyl-CoA esters or as long-chain acyl-CoA esters |
| GO:0015916 fatty-acyl-CoA transport | IGI PMID:18757502 The human peroxisomal ABC half transporter ALDP functions as... | UNDECIDED | Summary: IGI with FOX2 (van Roermund et al. 2008) for fatty-acyl-CoA transport. The abstract attributes acyl-CoA transport to the Pxa1p/Pxa2p heterodimer; how Faa2p participates in acyl-CoA transport (rather than in activating free fatty acids) cannot be assessed from the available abstract. Supporting Evidence: PMID:18757502 uptake of fatty acids into peroxisomes may occur via two routes, either as free fatty acids thus requiring intraperoxisomal activation into acyl-CoA esters or as long-chain acyl-CoA esters |
| GO:0016020 membrane | IBA GO_REF:0000033 | TOO GENERAL | Summary: IBA for membrane (is_active_in) from the ACSL family; Faa2p is peripherally associated with the peroxisomal membrane. Correct but less specific than peroxisomal membrane. Supporting Evidence: file:yeast/FAA2/FAA2-uniprot.txt Peroxisome membrane {ECO:0000269|PubMed:8670886}; Peripheral membrane |
| GO:0019395 fatty acid oxidation | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways RCA for fatty acid oxidation; Faa2p is the activating enzyme inside peroxisomes and belongs in this process. Supporting Evidence: PMID:8670886 Medium-chain fatty acids are activated inside peroxisomes hby the acyl-CoA synthetase Faa2p PMID:8670886 Peroxisomes of Saccharomyces cerevisiae are the exclusive site of fatty acid beta-oxidation |
| GO:0031956 medium-chain fatty acid-CoA ligase activity | IDA PMID:8206942 Biochemical studies of three Saccharomyces cerevisiae acyl-C... | ACCEPT | Summary: IDA (Knoll et al. 1994): purified Faa2p prefers C9:0-C13:0 substrates. Medium-chain activation is the distinctive function of Faa2p among yeast ligases. Supporting Evidence: PMID:8206942 Faa2p can accommodate a wider range of acyl chain lengths: C9:0-C13:0 are preferred and have equivalent activities, although C7:0-C17:0 fatty acids are tolerated as substrates with no greater than a 2-fold variation in specific activity |
| GO:0031956 medium-chain fatty acid-CoA ligase activity | IEA GO_REF:0000116 | ACCEPT | Summary: IEA from Rhea medium-chain reactions (octanoate, decanoate, laurate); correct. Supporting Evidence: file:yeast/FAA2/FAA2-uniprot.txt Is the main if not exclusive MCFA (octanoate, decanoate and laureate) |
| GO:0031957 very long-chain fatty acid-CoA ligase activity | IGI PMID:9988704 The Saccharomyces cerevisiae FAT1 gene encodes an acyl-CoA s... | KEEP AS NON CORE | Summary: IGI with FAT1 (Choi and Martin 1999) for very long-chain fatty acid-CoA ligase. Fat1p provides most C24-CoA synthetase activity, leaving residual activity in fat1 cells; van Roermund et al. 2012 place Faa2p and/or Fat1p on the inner peroxisomal membrane re-esterifying VLCFAs released by Pxa1p/Pxa2p. Purified Faa2p is most active on medium chains, so this is at most a minor activity; deferring to the curator's genetic evidence. Supporting Evidence: PMID:9988704 Fat1p accounts for approximately 90% of the C24-specific acyl-CoA synthetase activity in glucose-grown cells and approximately 66% of the total activity in cells grown under peroxisomal induction conditions PMID:22493507 The Pxa1p-Pxa2p complex functionally interacts with the acyl-CoA synthetases Faa2p and/or Fat1p on the inner surface of the peroxisomal membrane for subsequent re-esterification of the VLCFAs |
| GO:0042760 very long-chain fatty acid catabolic process | IGI PMID:21145416 Differential substrate specificities of human ABCD1 and ABCD... | KEEP AS NON CORE | Summary: IGI with human ABCD1/ABCD2 (van Roermund et al. 2011): VLCFA beta-oxidation in yeast expressing human ABCD transporters depends on intraperoxisomal re-activation, which Faa2p can provide. Plausible contributory role. Supporting Evidence: PMID:21145416 Our earlier work showed that in yeast the uptake of fatty acids into peroxisomes may occur via two routes, either as (1.) free fatty acid or as (2.) acyl-CoA ester PMID:22493507 The Pxa1p-Pxa2p complex functionally interacts with the acyl-CoA synthetases Faa2p and/or Fat1p on the inner surface of the peroxisomal membrane for subsequent re-esterification of the VLCFAs |
| GO:0102391 decanoate-CoA ligase activity | EXP PMID:8206942 Biochemical studies of three Saccharomyces cerevisiae acyl-C... | ACCEPT | Summary: EXP (Knoll et al. 1994): decanoate (C10:0) is among the preferred substrates of purified Faa2p. Supporting Evidence: PMID:8206942 Faa2p can accommodate a wider range of acyl chain lengths: C9:0-C13:0 are preferred and have equivalent activities, although C7:0-C17:0 fatty acids are tolerated as substrates with no greater than a 2-fold variation in specific activity |
| GO:0102391 decanoate-CoA ligase activity | IEA GO_REF:0000116 | ACCEPT | Summary: IEA from Rhea RHEA:33627 (decanoate-CoA ligase); consistent with experimental data. Supporting Evidence: file:yeast/FAA2/FAA2-uniprot.txt Reaction=decanoate + ATP + CoA = decanoyl-CoA + AMP + diphosphate |
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Download this section (compressed HTML)Q: What fraction of residual peroxisomal very-long-chain acyl-CoA synthetase activity in fat1 mutants is due to Faa2p, and do Faa2p and Fat1p physically associate with Pxa1p/Pxa2p at the membrane?
Q: Is Faa2p's association with the peroxisomal membrane mediated by a protein partner (e.g. Pxa1p/Pxa2p) or by intrinsic lipid binding?
Experiment: Measure C16-C26 beta-oxidation and intraperoxisomal acyl-CoA formation (tandem MS) in faa2, fat1 and faa2 fat1 strains, with and without Pxa1p/Pxa2p, using isolated peroxisomes and intact cells.
Hypothesis: Faa2p and Fat1p together account for all intraperoxisomal re-esterification of fatty acids delivered by Pxa1p/Pxa2p.
Medium chain fatty acyl-CoA synthetase; activates imported fatty acids; accepts a wide range of fatty acid chain lengths with a preference for medium chains, C9:0-C13:0; localized to the peroxisome; comparative analysis suggests that a mitochondrially targeted form may result from translation starting at a non-canonical codon upstream of the annotated start codon
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