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START HERE — how to read acetyl-CoA + 7 malonyl-CoA + 14 NADPH → palmitate
A one-cycle FAS cartoon on the human FASN frame that actually exists: 8VF7 (3.20 Å EM) chain B, modifying region with ACP at ER, crystal 4HH (PPant-Ser2156) and crystal NDP (NADPH). Occupancy is 4HH + NDP, not acetyl, not malonyl, not palmitate, not NADP⁺ — never copy a MAT/KS ternary as occupancy. Title “ACP at the ER” is this snapshot. Ser2156 ★ is the ACP phosphopantetheine serine. UniProt KS Cys161 / MAT Ser581 / TE Ser2308 are absent on this mesh — named, not starred, not geomClaims. Teaching NADPH is ER NDP B2601 (Thr1654 OG1⋯C4N = 3.39 Å). KR NDP B2602 is ~44 Å away — named, not extracted. 2CG5 human ACP overlay is named, not extracted (SEQADV Ala2156 engineered — Ppant serine absent there). White is CO₂ leave, not hydride. Blue is hydride. n=7 named, one C2 cycle shown. 4HH stays prosthetic. Type-II bacterial FAS is another set of genes. Measured Å are deposited 8VF7-B pairs only.
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Crystal / EM structures
PDB 8VF7 — human FASN modifying region ACP@ER + NADPH, 3.20 Å cryo-EM, EMD-43187 (Schultz 2025). Coordinates are public. Occupancy is 4HH + NDP. Human FASN UniProt P49327. PDB 2CG5 is a human ACP overlay (P49327 2119–2207) — named, not this mesh; its SEQADV Ala2156 (engineered) leaves the Ppant site empty.
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Mechanism — Ser2156-PPant; one C2 cycle
UniProt P49327 EC 2.3.1.85: acetyl-CoA + n malonyl-CoA + 2n NADPH + 2n H⁺ → palmitate + (n+1) CoA + n CO₂ + 2n NADP⁺. Teaching n = 7 (C2 → C16), one cycle shown. Schultz et al., Nature 2025, PMID:39979457. Type-II bacterial FAS is another set of genes. Source: UniProt P49327 · Schultz 2025
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0 — Setup: empty ACP@ER pocket
8VF7 occupancy is 4HH + NDP (PPant-Ser2156 and NADPH), not acetyl, not malonyl, not palmitate, not NADP⁺. The title says ACP at the ER — that is this snapshot, not a MAT/KS ternary. Prosthetic 4HH stays. Opaque, run:null (no autoplay). Ser2156 ★ is the ACP serine. Cys161 / Ser581 / Ser2308 are absent. 2CG5 is a human overlay, not this mesh. Cα 859–2194 with gaps 1151–1172 / 2067–2080 / 2114–2124 / 2156.Source: PDB 8VF7 (3.20 Å EM)
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① — Acetyl-CoA loads
[schematic] acetyl-CoA docks on the 4HH thiol — not deposited. 8VF7 holds PPant-Ser2156, not acetyl. MAT Ser581 is absent on this mesh. Never label 4HH as acetyl-CoA.Source: compiled MAT load on 8VF7 4HH pose
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② — Malonyl-CoA loads
Schematic malonyl-CoA docks on the 4HH pose — [schematic], not deposited. Asp2155 C ⋯ 4HH N = 1.34 Å is the deposited backbone LINK, not a malonyl geomClaim. Cys161 is absent (KS not on this mesh). Never label 4HH as malonyl-CoA.Source: 8VF7 4HH pose rebuilt as malonyl seat
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③ — KS condensation → β-ketoacyl-ACP + CO₂
(hypothetical, lit.-based) Schematic malonyl C3 leaves as CO₂ — no arrow, this is a departure not an attack: the white ball IS the leaving fragment, riding outward and growing into CO₂ around it; malonyl's own C3+O3A+O3B retire for the flight (never doubled), and the malonyl remainder dissolves into the product fade instead of blinking out. Acetyl-CoA + malonyl-CoA fade in place to schematic β-ketoacyl-ACP; CO₂ leaves. Never label 4HH as substrate. KS Cys161 is absent — condensation is compiled on this ACP@ER pose. Slow-motion on purpose. White = CO₂, not hydride. n=7 named, this is one cycle.Source: compiled FASN KS · Schultz 2025
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④ — KR + DH compiled (ACP is at ER, not KR)
(hypothetical, lit.-based) KR hydride and DH water loss are compiled on this ACP@ER pose — ACP is not at KR. A short interstitial: the deposited 4HH backbone LINK line rides the step. 4HH C ⋯ Leu2157 N = 1.33 Å is the deposited backbone LINK. KR NDP B2602 is ~44 Å from 4HH SU — named, not a geomClaim. Tyr2034 is KR, not this ER NADPH. 2CG5 human overlay is not this mesh.Source: PDB 8VF7 ACP@ER occupancy
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⑤ — ER hydride → saturated acyl-ACP
(hypothetical, lit.-based) Crystal NADPH docks first, then its C4N (blue ball + blue arrow) delivers hydride onto C3 — never fired from a still-moving pose. Thr1654 OG1 ⋯ NDP C4N = 3.39 Å is deposited ER NADPH. 4HH SU⋯C4N = 6.72 Å is named, not a geomClaim. This NDP is ER, not KR. NDP is NADPH, not NADP⁺. Slow-motion on purpose. Blue = hydride, not oxygen nucleophile.Source: PDB 8VF7 NDP B2601
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⑥ — Palmitate leaves — 4HH stays
Schematic palmitate (C16 teaching product) departs. Prosthetic 4HH stays. TE Ser2308 is absent on this mesh — hydrolysis is compiled. n=7 is named, not animated 7×. C18 TE activity is named, not shown. 8VF7 occupancy is 4HH + NDP, not palmitate. Cys161 is absent. Type-II bacterial FAS is another set of genes.Source: FAS bookkeeping · EC 2.3.1.85
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How to read this page — a first-pass primer
First pass: Setup (empty pocket, Ser2156 ★, 4HH stays, occupancy is 4HH + NDP) → ① schematic acetyl-CoA docks → ② schematic malonyl-CoA docks → ③ white CO₂ leave, fade to β-ketoacyl-ACP → ④ KR+DH compiled (ACP@ER, not KR) → ⑤ blue ER hydride from crystal NDP → ⑥ palmitate leaves; 4HH stays. Second pass: 1.34 / 1.33 / 3.39 Å are crystal facts on 8VF7-B occupancy; acetyl, malonyl, ketoacyl, palmitate, CO₂ are [schematic]. Cys161 / 6.72 / 44 Å are not geomClaims. Third pass: open “Disagreements” for occupancy vs MAT/KS ternary, Ser2156 ★ vs Cys161, ER vs KR NADPH, 2CG5 human overlay, and n=7.
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Chemistry primer — one C2 cycle on ACP@ER
FASN elongates acetyl by malonyl C2 units. MAT loads acetyl then malonyl onto ACP PPant. KS condenses and CO₂ leaves. KR / DH / ER saturate the β-keto. TE hydrolyses palmitate (C16). This mesh is ACP at ER with NADPH — KS, MAT, TE domains are not deposited. White = CO₂. Blue = hydride. This is not ACC1 and not type-II bacterial FAS.
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Words used on screen — 4HH prosthetic · Ser2156 ★ · Cys161 absent · NDP ≠ NADP⁺
4HH prosthetic — PPant-Ser2156, not a substrate and not acetyl-CoA. Ser2156 ★ — ACP phosphopantetheine serine (this PDB = UniProt). Cys161 absent — KS is not on this modifying-region mesh. NDP ≠ NADP⁺ — occupancy is NADPH. 2CG5 — human ACP overlay, not this mesh.
Legend & Fidelity
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Mechanism fidelity — measured vs. inferred
The measured layer: 8VF7 (3.20 Å EM) human FASN modifying region ACP@ER + 4HH + NDP; Asp2155 C ⋯ 4HH N = 1.34 Å; 4HH C ⋯ Leu2157 N = 1.33 Å; Thr1654 OG1 ⋯ NDP C4N = 3.39 Å. The inferred layer ([schematic]): acetyl-CoA, malonyl-CoA, β-ketoacyl-ACP, palmitate, CO₂, transferring CO₂ / hydride spheres, product leave. Binding order is compiled staging, not a kinetic fit. The protein mesh is static. Schematic Å are not geomClaims. Cys161 / 6.72 / 44 Å are not geomClaims. Title “ACP at the ER” is this snapshot, not a MAT/KS ternary.
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Disagreements on record
(a) Occupancy vs MAT/KS ternary. 8VF7 holds 4HH + NDP, not acetyl, not malonyl, not palmitate. (b) 4HH vs substrate. 4HH is prosthetic PPant, not acetyl-CoA. (c) Ser2156 ★ vs Cys161. Screen star is the ACP serine. Cys161 / Ser581 / Ser2308 are absent — named, not starred. (d) KR+DH compiled on ACP@ER — ACP is not at KR. (e) Teaching NDP is ER B2601, not KR B2602 (~44 Å). (f) 2CG5 is a human ACP overlay (P49327 2119–2207), not this mesh — and its SEQADV Ala2156 (engineered) means the Ppant serine is absent there. (g) n=7 named, one cycle shown. (h) C18 TE activity named, not shown. (i) Type-II bacterial FAS / mito FAS = other genes. (j) Cα gaps 1151–1172 / 2067–2080 / 2114–2124 / 2156. (k) Chains A and B; teaching = chain B (ACP present).
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Regulation — phosphorylation · SREBP · type-II FAS
This cycle is cytosolic FASN only. Type-II bacterial FAS and mitochondrial FAS are other genes — not this mesh. Phosphorylation / SREBP transcriptional control are named, not animated. Cerulenin is a drawer inhibitor, not a ligand.Source: UniProt P49327 · PDB 8VF7 · Schultz 2025
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Kinetics scope (no measured timecourse on this page)
One acetyl-CoA + 7 malonyl-CoA + 14 NADPH → palmitate event is named; one C2 cycle is drawn, not a steady-state run. Compiled BRENDA values for EC 2.3.1.85 are not re-asserted here — no measured kcat/Km on this page [schematic]. Pair with a kinetics chapter.Source: BRENDA EC 2.3.1.85 — no kcat/Km re-asserted
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Sequence
Human FASN UniProt P49327 · NCBI Gene 2194. This screen uses 8VF7 numbering (Ser2156 = UniProt Ser2156; Cys161 named off-mesh). Chain B. Cα 859–2194 with gaps 1151–1172 / 2067–2080 / 2114–2124 / 2156.
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Simulation map — what you see is what is written
Setup = 8VF7 pocket empty, 4HH stays (opaque, no autoplay). ① schematic acetyl-CoA moves in. ② schematic malonyl-CoA moves in. ③ slow-mo: white CO₂ leave; fade to β-ketoacyl-ACP. ④ KR+DH compiled. ⑤ slow-mo: blue ER hydride from crystal NDP. ⑥ palmitate leaves; 4HH stays. Only these events move.
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Sources — bibliography of this page
S1 — PDB 8VF7: human FASN modifying region ACP@ER + 4HH + NDP, 3.20 Å EM — public coordinates; measured Asp2155 C⋯4HH N = 1.34 Å · 4HH C⋯Leu2157 N = 1.33 Å · Thr1654 OG1⋯NDP C4N = 3.39 Å
S2 — Schultz et al., Nature 2025, PMID:39979457 — ACP shuttling; ACP@ER snapshot
S3 — Sequence: UniProt P49327 · NCBI Gene 2194
S4 — Kinetics: BRENDA EC 2.3.1.85 — no kcat/Km re-asserted on this page
› Backbones and the 4HH / NDP poses are taken directly from the listed PDB entries,
superposed into one common frame. Where no crystalline state exists for a step
(e.g., acetyl-CoA, malonyl-CoA, β-ketoacyl, palmitate, CO₂, carboxyl/hydride flight, product leave), the pose is drawn
schematically and labeled as such in the narration. Occupancy is 4HH + NDP, not acetyl/malonyl/palmitate. Schematic Å are not geomClaims. Title ACP at the ER is this snapshot, not a MAT/KS ternary.