ACSL1 (P33121) curation notes

Provenance note: provider deep research (Falcon) failed with HTTP 402 Payment
Required, and perplexity is not configured in this environment. No
ACSL1-deep-research-*.md file exists. This manual synthesis, built from the UniProt
record, the cached publications in publications/, and targeted PubMed searches (papers
fetched into the cache with just fetch-pmid), replaces it.

Identity and family

• Long-chain-fatty-acid--CoA ligase 1, EC 6.2.1.3; ANL superfamily (AMP-binding domain),
  one of five ACSL isoforms (ACSL1, 3, 4, 5, 6). Three isoforms by alternative splicing.
• Mg2+-dependent; reaction: long-chain fatty acid + ATP + CoA = long-chain acyl-CoA + AMP +
  PPi [file:human/ACSL1/ACSL1-uniprot.txt "Reaction=a long-chain fatty acid + ATP + CoA = a long-chain fatty acyl-"].
• Tissue: high in liver, heart, skeletal muscle, kidney, adipose; erythroid cells.

Activity and substrate range

• UniProt: "Catalyzes the conversion of long-chain fatty acids to their active form
  acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation";
  human ACSL1 "Preferentially uses palmitoleate, oleate and linoleate" (PMID:24269233).
• Human ACSL1 complements the yeast faa1 faa4 acyl-CoA synthetase mutant in the
  sphingosine-1-phosphate to glycerophospholipid pathway (activation of
  trans-2-hexadecenoic acid and palmitate) [PMID:24269233 "in addition to the previously
  identified ACSL family members (ACSL1, 3, 4, 5, and 6), we found that ACSVL1, ACSVL4, and
  ACSBG1 also restored metabolism"; PMID:22633490 "mammalian ACSL family members are
  acyl-CoA synthetases involved in the sphingolipid-to-glycerolipid metabolic pathway"].
• Overexpression in hepatoma cells increases ACS activity PMID:22022213.
• Arachidonate, EETs/HETEs, phytanate and pristanate activities are inferred from the rat
  ortholog (P18163; rat IDA annotations exist in QuickGO) — "By similarity" in UniProt.

Subcellular location

• Mitochondrial outer membrane (rat IDA; human hepatoma IF) [PMID:22022213 "ACSL1 was
  located at mitochondria in both cell lines"; PMID:24503477 "intracellular localization of
  FATP4 to the endoplasmic reticulum, and of ACSL1 to mitochondria"].
• ER membrane (human, HeLa expression) PMID:24269233. In liver ~50% of ACSL1 is on ER
  PMID:30190326.
• Peroxisomal membrane: rat IDA only; not shown for human.
• Lipid droplet: NOT experimentally established for ACSL1 protein. BioID in mouse
  hepatocytes found lipid-droplet proteins among ACSL1 proximity partners
  PMID:30190326, which is proximity, not residency. Haney et al. 2024
  call ACSL1 "the lipid droplet-associated enzyme" and a regulator of LD biogenesis, but
  their data are expression (snRNA-seq, IF of ACSL1 in IBA1+ microglia), a CRISPR screen and
  triacsin C inhibition — none shows ACSL1 protein on the LD surface
  PMID:38480892. The
  canonical LD-resident ACSL is ACSL3. No GO lipid droplet (GO:0005811) annotation exists for
  ACSL1 in human, mouse or rat in GOA.

Physiological roles (mostly mouse knockouts)

• Partitioning FAs toward beta-oxidation:
• Adipose KO: PMID:20620995; cold intolerance.
• Heart KO: PMID:21245374.
• Liver KO: 50% loss of hepatic ACSL activity, lower TAG incorporation in hepatocytes and
  lower beta-oxidation PMID:19648649.
• Glycerolipid (TAG) synthesis / lipid droplet accumulation: in hepatocytes ACSL1 loss
  reduces oleate incorporation into TAG PMID:19648649; in human iPSC microglia, fibrillar
  amyloid-beta induces ACSL1 and TAG synthesis, and triacsin C reverses LD accumulation
  PMID:38480892. ACSL1 here supplies acyl-CoA substrate for TAG synthesis
  (participation in triglyceride biosynthesis); LD formation itself is downstream.
• Fatty acid uptake: ACSL1 enhances uptake indirectly by metabolic trapping
  PMID:24503477.
• Inflammation: myeloid ACSL1 promotes inflammatory macrophage phenotype in diabetic mice
  PMID:22308341. ACSL1-high microglia (LDAM) in APOE4/4 Alzheimer disease brain
  PMID:38480892.

Curation decisions summary

• Core: GO:0004467 long-chain fatty acid-CoA ligase activity at MOM (GO:0005741) and ER
  membrane (GO:0005789); process GO:0035338 / GO:0001676; supply of acyl-CoA to TAG synthesis
  (GO:0019432).
• Uptake/transport terms kept as non-core (indirect, metabolic trapping).
• IEP-derived "response to" IEA terms removed.
• No NEW lipid droplet / lipid droplet organization annotations: localization not shown;
  LD formation is a downstream consequence of TAG synthesis (fails participation test as a
  direct LD-organization actor; comparator genes like GPAT/DGAT carry TAG synthesis).