| Category | Key property | Summary | Evidence |
|---|---|---|---|
| Gene/protein identity | Human target verification | **CPT2** encodes **carnitine O-palmitoyltransferase 2, mitochondrial** (CPT II), the inner-mitochondrial-membrane enzyme of the carnitine shuttle; it is distinct from CPT1 isoforms despite historical naming confusion in some resources. | (pqac-00000017, pqac-00000049, pqac-00000053) |
| Protein family | Family membership | CPT2 belongs to the **carnitine/choline acyltransferase family** and is evolutionarily distinct from CPT1 proteins, despite their complementary function in the shuttle. | (pqac-00000024, pqac-00000036, pqac-00000037) |
| Isoforms/expression | Tissue distribution | CPT2 is reported as a **single, ubiquitously expressed isoform**, with comparatively high functional importance in energy-demanding tissues such as heart, liver, and skeletal muscle. | (pqac-00000003, pqac-00000022, pqac-00000049) |
| Core biochemical function | Enzymatic role | CPT2 catalyzes the **final step of the carnitine shuttle**, regenerating mitochondrial **acyl-CoA** from **acylcarnitine** and releasing **free L-carnitine**, thereby enabling long-chain fatty acid β-oxidation. | (pqac-00000001, pqac-00000017, pqac-00000018) |
| Reaction | Catalyzed chemistry | The reaction is reversible and can be written as **acylcarnitine + CoA ⇌ acyl-CoA + carnitine**; under some experimental conditions CPT2 can also catalyze the reverse direction with acyl-CoA + carnitine. | (pqac-00000002, pqac-00000005, pqac-00000007) |
| Physiologic substrates | Main substrate class | CPT2 primarily handles **medium- to long-chain fatty acyl groups**, especially those entering mitochondria for oxidation after CPT1/CACT-mediated transport. | (pqac-00000001, pqac-00000006, pqac-00000020) |
| Substrate specificity | Chain-length preference | Human CPT2 shows activity across about **C8-C20**, with **C10-C14** reported as preferred and robust activity for common long-chain substrates such as C12 and C16 species. | (pqac-00000000, pqac-00000002, pqac-00000021) |
| Specificity limits | Poor/negative substrates | CPT2 has **very low activity toward short-chain and very-long-chain substrates**, poor activity toward **trans-2-enoyl-CoA** intermediates, and does **not** significantly process branched-chain amino acid oxidation intermediates. | (pqac-00000001, pqac-00000002, pqac-00000021) |
| Pathway role | Carnitine shuttle | CPT2 works with **CPT1** on the outer mitochondrial membrane and **CACT/SLC25A20** on the inner membrane to move long-chain fatty acid equivalents into the matrix for oxidation. | (pqac-00000018, pqac-00000019, pqac-00000020) |
| Cellular localization | Organelle/subcompartment | CPT2 is localized to the **inner mitochondrial membrane** and functions on the **matrix side/intramitochondrial space**, consistent with regeneration of β-oxidation-competent acyl-CoA inside mitochondria. | (pqac-00000010, pqac-00000013, pqac-00000014) |
| Membrane topology | Membrane association | Structural studies indicate CPT2 is **monomeric** and associated with the inner membrane through a **membrane-anchoring insertion** that inserts into the **inner leaflet** rather than spanning the membrane like CPT1. | (pqac-00000011, pqac-00000024, pqac-00000025) |
| Precursor processing | Mitochondrial targeting | CPT2 is synthesized as a **precursor protein** with an **N-terminal targeting sequence** that is cleaved during mitochondrial import/localization. | (pqac-00000019, pqac-00000012) |
| Structural organization | Domain architecture | CPT2 has **N-terminal and C-terminal domains**, each built around a **six-stranded antiparallel β-sheet** surrounded by α-helices, with the active site located at the domain interface. | (pqac-00000023, pqac-00000024) |
| Active-site architecture | Ligand-binding tunnel | The enzyme contains a **Y-shaped tunnel** accommodating **CoA**, **acyl**, and **carnitine** moieties; this architecture helps explain chain-length selectivity and acyltransferase chemistry. | (pqac-00000023, pqac-00000024) |
| Catalytic residues | Key residues/mechanism | Important structural/catalytic residues include **His372**, **Ser590**, and carnitine-binding residues such as **Tyr486, Ser488, Thr499**, with **Arg498** helping position active-site elements. | (pqac-00000023) |
| Regulation vs CPT1 | Malonyl-CoA sensitivity | Unlike CPT1, CPT2 is generally described as **not allosterically inhibited by malonyl-CoA** and is **not the main rate-limiting regulatory step** of fatty acid entry into mitochondria. | (pqac-00000049, pqac-00000050, pqac-00000052) |
| Evolution | Relationship to CPT1 | CPT2 and CPT1 are functionally linked but **evolutionarily distant** within the acyltransferase family; CPT2 appears to have undergone a distinct evolutionary trajectory without the isoform-expanding duplications seen for CPT1. | (pqac-00000036, pqac-00000037, pqac-00000039) |
| Human disease | Deficiency syndrome | **CPT2 deficiency** is a rare autosomal recessive long-chain fatty acid oxidation disorder with three major forms: **neonatal lethal**, **severe infantile hepatocardiomuscular**, and **adult/myopathic**. | (pqac-00000026, pqac-00000028, pqac-00000029) |
| Clinical manifestations | Major phenotypes | Severe forms feature **hypoketotic hypoglycemia, liver dysfunction/failure, cardiomyopathy, renal/cerebral anomalies**, whereas the common myopathic form causes **exercise-induced myalgia, rhabdomyolysis, and myoglobinuria** with normal intervals between attacks. | (pqac-00000026, pqac-00000027, pqac-00000031) |
| Disease epidemiology | Recent summary statistics | Literature summaries report **>300 described patients** and newborn-screening-based incidence estimates around **1:750,000 to 1:2,000,000**, although ascertainment is incomplete. | (pqac-00000030, pqac-00000031) |
| Mutational landscape | Common variants | More than **60 CPT2 mutations** have been reported; **p.S113L** is the most common mutation in the myopathic form, accounting for roughly **64% of variant alleles** in one 2024 literature summary and up to **90%** in older cohorts/reviews. | (pqac-00000032, pqac-00000042, pqac-00000043) |
| Variant mechanism | S113L effect | The common **S113L** variant is often **thermolabile** rather than catalytically dead at baseline, showing reduced stability and increased inhibition susceptibility under metabolic stress, helping explain attacks during fever, exercise, fasting, or cold exposure. | (pqac-00000042, pqac-00000044, pqac-00000045) |
| Recent research directions | 2023-2024 developments | Recent work links CPT2 dysfunction or altered expression to **NAFLD/MAFLD and hepatocarcinogenesis**, and cancer literature describes **context-dependent roles** for CPT2, acting as either tumor-promoting or tumor-suppressive depending on tissue context. | (pqac-00000009, pqac-00000033, pqac-00000034) |


*Table: This table summarizes the main molecular, biochemical, structural, and clinical properties of human CPT2. It is useful as a compact reference for functional annotation and for distinguishing CPT2’s core mitochondrial fatty-acid-oxidation role from disease and emerging cancer-related findings.*