Cpt1a (rat, UniProt P32198) - manual literature synthesis

No deep-research API was available for this session; this summary was written by hand
from the cached publications in publications/ and the UniProt record. Most cached
papers are abstract-only; full text was available for PMID:19136561, PMID:19332540,
PMID:21990363, PMID:31639005 and PMID:31748600.

Identity

• Carnitine O-palmitoyltransferase 1, liver isoform (L-CPT1, CPT1A), 773 aa, RGD:2396,
  GeneID 25757. Member of the carnitine/choline acetyltransferase family (UniProt
  SIMILARITY; InterPro IPR000542).

Catalytic activity

• Converts long-chain acyl-CoA plus L-carnitine to acylcarnitine plus CoA (EC 2.3.1.21,
  RHEA:12661), the first committed step of the carnitine shuttle that moves long-chain
  fatty acids into mitochondria for beta-oxidation [UniProt P32198 FUNCTION, ECO:0000269
  PubMed:16908527, 21990363, 24222496; PMID:24222496 "The enzyme carnitine
  palmitoyltransferase 1 (CPT1) catalyzes the transfer of an acyl group from acyl-CoA to
  carnitine to form acylcarnitine"].
• Catalytic residues His473 and Asp477 were assigned from a structural model based on
  carnitine acetyltransferase and confirmed by mutagenesis PMID:14711372. Glu-590 and Glu-603 are also needed for activity [PMID:12826662;
  PMID:12540837].
• Kinetics of expressed rat CPT1A: KM 46.5 uM palmitoyl-CoA, 184 uM carnitine
  (UniProt, PubMed:16908527).

Regulation by malonyl-CoA

• Inhibited by malonyl-CoA (UniProt ACTIVITY REGULATION). Determinants: Met593
  PMID:12499375, the N-terminal 18 residues interacting with the C-terminal domain
  PMID:11790778, the intermembrane-space loop/TM2 boundary PMID:16908527, and an
  N-terminal Nalpha/Nbeta structural switch responding to membrane curvature
  PMID:21990363. CK2 phosphorylation of Ser741/Ser747
  increases activity and changes malonyl-CoA inhibition PMID:15247243.
• Malonyl-CoA-insensitive M593S CPT1A sustains beta-oxidation of de novo fatty acids in
  hepatocytes under high glucose/insulin PMID:19302064.

Location and topology

• Polytopic integral protein of the mitochondrial outer membrane, two TM segments, both
  termini cytosolic, loop in the intermembrane space [PMID:9169604 "CPT I adopts a bitopic
  topology within the mitochondrial outer membrane"; PMID:16908527]. Import uses a
  noncleavable signal (residues 123-147) downstream of TM2 PMID:11087756.
• Not targeted to the ER; microsomal CPT activity is mitochondrial contamination
  PMID:12401113.
• Exists as hexamer/trimer via TM2 GXXXG motifs PMID:19136561. Found in an outer-membrane
  complex with ACSL1 and VDAC PMID:21622568.

Physiology (rat perturbation studies)

• Adenoviral overexpression in rat hepatocytes and liver raises beta-oxidation and
  lowers triglyceride content and secretion PMID:18349115.
• Overexpression in INS1E beta-cells lowers glucose-stimulated insulin secretion
  PMID:11988095.
• Hypothalamic CPT1 knockdown/inhibition lowers food intake and hepatic glucose
  production PMID:12754501 - systemic consequences of altered neuronal lipid
  oxidation, not a direct role in these processes.
• Many expression studies (diet, drugs, ethanol, CCl4, hypoxia) show Cpt1a mRNA/protein
  changes [e.g. PMID:33310031, PMID:31953200, PMID:31748600, PMID:19332540]; these are
  expression responses, not functions.

Activities known only from the human ortholog

• Lysine succinyltransferase activity (ENO1) and ZDHHC4 recruitment to MAVS for type I
  IFN signalling are reported for human CPT1A (UniProt By similarity, P50416); not tested
  in rat.