Long-chain acyl-CoA synthetase 1 - 3D Mechanism Simulator

Loading structural data… (1V26)

References & Databases

START HERE — how to read FA + ATP + CoA → acyl-CoA + AMP + PPi A two-half-reaction ANL cartoon on the bacterial ACS frame that actually exists: 1V26 (2.50 Å) T. thermophilus HB8 ACS with crystal AMP + myristate + Mg. Human ACSL1 (P33121) has no PDB — species hedge. Crystal AMP+MYR is an adenylation-product-like split, not intact acyl-AMP and not ATP. ATP, PPi, CoA-SH, and acyl-CoA are [schematic]. 1V25 ANP is a named overlay, not this ternary. Lys439 ★ is the compiled AMP-binding lysine on this Thermus mesh (human ACSL1 has no UniProt ACT_SITE). No covalent residue intermediate (A-page). White is nucleotidyl P-attack (FA-O → ATP PA). Blue is sulfur nucleophile (CoA-S → carbonyl), not hydride. Measured Å are deposited 1V26 pairs only. ACSL3–6 are other genes. Membrane anchor is not this cartoon.
Crystal structures PDB 1V26 — TT0168 long-chain-fatty-acid-CoA ligase from Thermus thermophilus HB8, 2.50 Å, AMP + MYR + MG (Hisanaga 2004). Coordinates are public. 1V25 is the same protein + ANP (AMP-PNP), 2.30 Å — named overlay, not this ternary. 1ULT is the apo companion. Human ACSL1 UniProt P33121 has no PDB.
Mechanism — two ANL half-reactions UniProt P33121 EC 6.2.1.3 / Rhea 15421: a long-chain fatty acid + ATP + CoA → a long-chain fatty acyl-CoA + AMP + diphosphate. (1) FA + ATP → acyl-AMP + PPi. (2) acyl-AMP + CoA → acyl-CoA + AMP. Hisanaga et al., JBC 2004, PMID:15145952. Also-EC 6.2.1.15 / 6.2.1.24 are not shown. Source: UniProt P33121 · Hisanaga 2004
0 — Setup: Mg present, pocket shown empty 1V26 holds AMP + myristate + Mg. The pocket is shown empty so ordered binding can start. Mg stays as a named occupant. Opaque, run:null (no autoplay). Human P33121 has no PDB; this mesh is T. thermophilus. Lys439 ★ is compiled AMP-binding lysine on this frame.Source: PDB 1V26 (2.50 Å)
① — Fatty acid binds Crystal myristate docks as a long-chain fatty-acid analog — real 1V26 occupancy; teaching chain is palmitate. Lys439 NZ ⋯ MYR O1 = 2.80 Å. Carboxylate faces the AMP phosphate / Mg. ACSL3–6 are other genes.Source: 1V26 MYR-A1001
② — ATP binds Schematic ATP docks as crystal AMP plus a teaching β/γ-phosphate opposite the fatty acid — [schematic], not deposited ATP. 1V25 ANP is a different crystal. AMP on 1V26 is not ATP. AMP O3P ⋯ Mg = 2.53 Å.Source: 1V26 AMP/MG; 1V25 named overlay
③ — FA-O attacks ATP α-P → acyl-AMP + PPi (hypothetical, lit.-based) White phosphoryl rides from fatty-acid carboxylate O to schematic ATP PA. FA + ATP fade in place to crystal AMP+MYR (acyl-AMP analog occupancy) and schematic PPi, which departs once formed (product release precedes CoA binding). This is not intact acyl-AMP. A-page. Slow-motion on purpose. White = nucleotidyl P-attack, not hydride.Source: compiled ANL adenylation · Hisanaga 2004
④ — CoA binds [schematic] CoA-SH (pantetheine stub, not full 3′-phospho-ADP-CoA) docks with thiol toward the acyl-AMP analog carbonyl. CoA is not deposited on 1V26. MYR O1 ⋯ AMP P = 2.83 Å is the deposited split, not a mixed-anhydride bond.Source: schematic CoA on 1V26 AMP+MYR
⑤ — CoA-S attacks carbonyl → acyl-CoA + AMP (hypothetical, lit.-based) Blue nucleophile rides from CoA thiol S to the acyl-AMP analog carbonyl. Acyl-AMP + CoA fade in place to schematic acyl-CoA and crystal AMP. Second ANL half-reaction. A-page. Slow-motion on purpose. Blue = sulfur nucleophile, not hydride.Source: compiled ANL thioesterification · UniProt P33121
⑥ — Acyl-CoA and AMP leave — CPT1A next [schematic acyl-CoA] Acyl-CoA and AMP depart opposite ways. Mg stays. PPi already left with the first half-reaction. Acyl-CoA is the substrate of CPT1A. This page does not transfer carnitine.Source: β-oxidation bookkeeping · EC 6.2.1.3

How to read this page — a first-pass primer First pass: Setup (Mg present, pocket empty, Lys439 ★, Thermus mesh) → ① myristate docks → ② schematic ATP docks → ③ white FA-O → ATP PA, fade to AMP+MYR analog + PPi → ④ schematic CoA docks → ⑤ blue CoA-S → carbonyl, fade to acyl-CoA + AMP → ⑥ acyl-CoA and AMP leave opposite ways; Mg stays. Second pass: 2.80 / 3.72 / 2.53 / 2.83 Å are crystal facts on 1V26; ATP, PPi, CoA, and acyl-CoA are [schematic]. White = nucleotidyl P-attack. Blue = CoA-S. Third pass: open “Disagreements” for species hedge, AMP ≠ ATP, split occupancy vs intact acyl-AMP, and 1V25 overlay vs this ternary.
Chemistry primer — ANL adenylation then thioester ACSL1 activates a long-chain fatty acid in two half-reactions. The carboxylate attacks ATP α-P; PPi leaves and an acyl-AMP mixed anhydride forms. CoA-SH then attacks that carbonyl; AMP leaves and the product is acyl-CoA, the substrate of CPT1A. Gold is unused on this page (no catalytic H⁺ sphere). White = nucleotidyl P-attack (FA-O → ATP PA). Blue = sulfur nucleophile (CoA-S → carbonyl), not hydride. This is not CPT1A (carnitine transfer) and not ACSL3–6.
Words used on screen — species hedge · AMP analog · ANL Species hedge — the mesh is T. thermophilus TT0168; human ACSL1 has no PDB. AMP analog — deposited AMP+MYR is an adenylation-product-like split, not intact acyl-AMP and not ATP. ANL — adenylate-forming superfamily (two half-reactions). CoA stub — pantetheine cartoon, not full 3′-phospho-ADP-CoA.

Legend & Fidelity

Mechanism fidelity — measured vs. inferred The measured layer: 1V26 (2.50 Å) T. thermophilus ACS with AMP, MYR, MG; Lys439 NZ ⋯ MYR O1 = 2.80 Å; Lys439 NZ ⋯ AMP P = 3.89 Å; Thr327 OG1 ⋯ AMP P = 3.72 Å; AMP O3P ⋯ Mg = 2.53 Å; AMP P ⋯ Mg = 3.77 Å; MYR O1 ⋯ AMP P = 2.83 Å. The inferred layer ([schematic]): ATP β/γ, PPi, CoA-SH stub, acyl-CoA, transferring nucleophile spheres, product leave. Binding order is compiled staging, not a kinetic fit. The protein mesh is static. 1V25 ANP overlay Å are not geomClaims.
Disagreements on record (a) Species. Human P33121 has no PDB; 1V26 is T. thermophilus TT0168. (b) AMP ≠ ATP ≠ acyl-AMP. Crystal AMP+MYR is a split occupancy, not a Michaelis ATP·FA ternary and not intact acyl-AMP. (c) 1V25 vs 1V26. ANP is a different crystal; ATP on this mesh is schematic. (d) Concerted vs split. Compiled ANL writes two half-reactions; this page splits them (③ then ⑤) for 1-event/1-step teaching. (e) ACSL3–6 are other genes. (f) Also-EC 6.2.1.15 / 6.2.1.24 are not shown. (g) No UniProt ACT_SITE on human ACSL1; Lys439 is compiled on this Thermus mesh.
Regulation — isoforms · membrane This mesh is ACSL1 (long-chain, liver/OMM teaching). ACSL3–6 are other genes. Preferentially palmitoleate/oleate/linoleate is drawer, not motion. Membrane type-III anchor is not this cartoon. Malonyl-CoA gating is CPT1A, not this page.Source: UniProt P33121
Kinetics scope (no measured timecourse on this page) One FA + ATP + CoA → acyl-CoA + AMP + PPi event is drawn, not a steady-state run. Compiled BRENDA values for EC 6.2.1.3 are not re-asserted here — no measured k_cat/K_m on this page [schematic]. Pair with a kinetics chapter.Source: BRENDA EC 6.2.1.3 — no k_cat/K_m re-asserted
Sequence Human ACSL1 UniProt P33121 · NCBI Gene 2180 (no human PDB). This screen uses T. thermophilus TT0168 numbering (Lys439 on 1V26). Chain A. Cα 8–539.
Simulation map — what you see is what is written Setup = 1V26 pocket empty, Mg visible (opaque, no autoplay). ① crystal myristate moves in. ② schematic ATP moves in. ③ slow-mo: white FA-O → ATP PA; FA+ATP fade to AMP+MYR analog + PPi; PPi leaves. ④ schematic CoA moves in. ⑤ slow-mo: blue CoA-S → carbonyl; analog+CoA fade to acyl-CoA + AMP. ⑥ acyl-CoA and AMP leave opposite ways; Mg stays. Only these events move.
Sources — bibliography of this page S1 — PDB 1V26: TT0168 ACS, T. thermophilus, 2.50 Å, AMP + MYR + MG — public coordinates; measured NZ⋯O1 = 2.80 Å · O3P⋯Mg = 2.53 Å S2 — Hisanaga et al., J Biol Chem 2004, PMID:15145952 — two-step ANL mechanism; companion 1V25 ANP S3 — Sequence: UniProt P33121 (human ACSL1, no PDB) · NCBI Gene 2180 · Rhea 15421 S4 — Kinetics: BRENDA EC 6.2.1.3 — no k_cat/K_m re-asserted on this page

› Backbones and ligand poses are taken directly from the listed PDB entries, superposed into one common frame. Where no crystalline state exists for a step (e.g., ATP, PPi, CoA, acyl-CoA, nucleophile flight, product release), the pose is drawn schematically and labeled as such in the narration.

N-domainC-domainONphosphoryl (white)nucleophile (blue)