Mitochondrial HMG-CoA lyase - 3D Mechanism Simulator

Loading structural data… (3MP5)

References & Databases

START HERE — how to read (3S)-HMG-CoA → acetoacetate + acetyl-CoA A lyase cartoon on the human HMGCL frame that actually exists: 3MP5 (2.25 Å X-ray) chain B with crystal HMG-CoA substrate + Mg. Occupancy is substrate HMG-CoA on chain B only, not acetoacetate, not acetyl-CoA — never read HMG as product. 3MP5 is R41M — Arg41 is not this mesh (residue 41 is Met). Do not pin Arg41. Cys266 ★ is the UniProt ACT_SITE cysteine. His233 is a Mg²⁺ ligand (named, not starred); the general base is unassigned — compiled water-shuttle model (Fu 2010). Acetoacetate / acetyl-CoA are [schematic] on this HMG pose. Mg stays. HMGCLL1 is another gene. Gold is H⁺, not hydride. 2CW6 is WT+Mg companion. 3MP3 3HG analog is rejected. Measured Å are deposited 3MP5-B pairs only.
Crystal / X-ray structures PDB 3MP5 — human HMGCL R41M + HMG-CoA chain B + Mg, 2.25 Å X-ray (Fu 2010). Coordinates are public. Occupancy is substrate HMG-CoA on chain B only. PDB 2CW6 is WT+Mg companion. Human HMGCL UniProt P35914.
Mechanism — Cys266 ACT_SITE; general base unassigned UniProt P35914 EC 4.1.3.4: (S)-3-hydroxy-3-methylglutaryl-CoA = acetoacetate + acetyl-CoA. This page teaches lyase cleavage (ketogenesis). On this mesh the ACT_SITE cysteine is Cys266. His233 is named, not starred. This page does not draw a covalent Cys intermediate. HMGCLL1 is another gene. Source: UniProt P35914 · Fu 2010 · Fu 2006
0 — Setup: empty lyase pocket 3MP5 occupancy is substrate HMG-CoA on chain B only, not acetoacetate, not acetyl-CoA. The pocket is shown empty so binding can start; Mg stays. Opaque, run:null (no autoplay). 3MP5 is R41M — Arg41 is not this mesh. Cys266 ★ is ACT_SITE. His233 is named. Transit 1–27 is not this mesh (Cα 28–323). HMGCLL1 is another gene.Source: PDB 3MP5 (2.25 Å X-ray)
① — HMG-CoA binds Crystal HMG-CoA docks on chain B — real 3MP5 occupancy, the teaching substrate (unlike 2WYA product HMG). HMG is on chain B only (1 copy). His233 NE2 ⋯ HMG O7 = 3.94 Å is deposited 3MP5-B. Arg41 is not this mesh.Source: PDB 3MP5 chain B HMG
② — C3–OH proton leaves (compiled) (hypothetical, lit.-based) Gold ball + gold arrow: the C3-hydroxyl proton (HMG O7) leaves into the Mg-ordered water shuttle. The general base is unassigned — His233 is a Mg²⁺ ligand, not the base (Fu 2010: base/acid assignments await further studies; simplest model is an ordered-water shuttle with the Cys266 thiolate as relay partner). C2 receives a proton after C2–C3 scission; it is not the donor. Cys266 ★ is ACT_SITE; this page does not draw a covalent Cys intermediate. His233 NE2 ⋯ MG = 2.58 Å is deposited 3MP5-B. Slow-motion on purpose. Gold = H⁺, not hydride.Source: compiled HMGCL C3–OH → Mg–water shuttle · Fu 2006 / Fu 2010 · UniProt P35914 Cys266
③ — C2–C3 cleavage → acetoacetate + acetyl-CoA (hypothetical, lit.-based) Crystal HMG-CoA cross-fades to schematic acetoacetate + schematic acetyl-CoA — the C2–C3 linkage heats, thins and snaps at T.react while the products emerge in place through the swap beat. Occupancy is substrate HMG-CoA, not these products. Asp42 OD1 ⋯ MG = 2.36 Å is deposited 3MP5-B. Arg41 is not this mesh. Slow-motion on purpose.Source: compiled lyase cleavage · 3MP5 Asp42 / MG
④ — Acetoacetate leaves Schematic acetoacetate departs. Schematic acetyl-CoA stays for the opposite leave. Mg stays. Occupancy was substrate HMG-CoA, not these products. Arg41 is not this mesh.Source: ketogenesis bookkeeping · EC 4.1.3.4
⑤ — Acetyl-CoA leaves — BDH1 next Schematic acetyl-CoA departs the other way. Mg stays. This page does not run HMGCLL1. HMG on 3MP5-B is substrate, not product. His235 NE2 ⋯ MG = 2.41 Å is deposited 3MP5-B. BDH1 is next.Source: ketogenesis bookkeeping · EC 4.1.3.4

How to read this page — a first-pass primer First pass: Setup (empty pocket, Mg stays, Cys266 ★, R41M, substrate HMG not product) → ① crystal HMG-CoA docks on chain B → ② gold C3–OH proton to Mg–water [schematic] → ③ fade to schematic acetoacetate + acetyl-CoA → ④ acetoacetate leaves → ⑤ acetyl-CoA leaves the other way; BDH1 next. Second pass: 2.58 / 2.36 / 2.41 / 3.94 Å are crystal facts on 3MP5-B; acetoacetate and acetyl-CoA are [schematic]; HMG is substrate, not product. Third pass: open “Disagreements” for R41M vs Arg41, His233 named not starred, and HMGCLL1 vs this gene.
Chemistry primer — HMG-CoA lyase HMGCL cleaves (3S)-HMG-CoA to acetoacetate + acetyl-CoA. His233 is a Mg²⁺ ligand (named, not starred); the general base is unassigned — compiled water-shuttle model; Cys266 is the UniProt ACT_SITE. This page does not draw a covalent Cys intermediate. Gold is H⁺, not hydride. This is not HMGCLL1.
Words used on screen — substrate HMG · Cys266 ★ · R41M · Mg stays Substrate HMG — 3MP5-B occupancy, not acetoacetate, not acetyl-CoA. Cys266 ★ — ACT_SITE on this PDB = UniProt. R41M — Arg41 is not this mesh (Met41). Mg stays — named occupant, not a leaving group.

Legend & Fidelity

Mechanism fidelity — measured vs. inferred The measured layer: 3MP5 (2.25 Å X-ray) human HMGCL R41M chain B + substrate HMG-CoA + Mg; His233 NE2 ⋯ MG = 2.58 Å; Asp42 OD1 ⋯ MG = 2.36 Å; His235 NE2 ⋯ MG = 2.41 Å; His233 NE2 ⋯ HMG O7 = 3.94 Å. The inferred layer ([schematic]): acetoacetate / acetyl-CoA on the HMG pose, transferring H⁺ spheres. Binding order is compiled staging, not a kinetic fit. The protein mesh is static. Substrate-complex Å are not product geomClaims.
Disagreements on record (a) Occupancy vs products. 3MP5-B holds substrate HMG-CoA, not acetoacetate, not acetyl-CoA. (b) R41M. Residue 41 is Met — Arg41 is not this mesh; do not pin Arg41. (c) His233 is named, not starred — Mg²⁺ ligand; general base unassigned. (d) Cys266 ★ is ACT_SITE; this page does not draw a covalent Cys intermediate. (e) HMGCLL1 is another gene. (f) Concerted vs split C3–OH deprotonation / C2–C3 cleavage — this page splits ② then ③ for 1-event/1-step. (g) 2CW6 is WT+Mg companion, not this ternary. (h) 3MP3 3HG analog is rejected. (i) Transit 1–27 is not this mesh (Cα 28–323). (j) Peroxisome location is drawer text, not a catalytic event. (k) Homodimer assembly is not this cartoon.
Regulation — isoforms · matrix · peroxisome This cleavage is monofunctional HMGCL only. HMGCLL1 is another gene — not this mesh. Matrix localization is assumed, not a catalytic event on this page. Peroxisome dual localization is drawer text, not animated.Source: UniProt P35914 · PDB 3MP5 · Fu 2010
Kinetics scope (no measured timecourse on this page) One (3S)-HMG-CoA → acetoacetate + acetyl-CoA event is drawn, not a steady-state run. Compiled BRENDA values for EC 4.1.3.4 are not re-asserted here — no measured k_cat/K_m on this page [schematic]. Pair with a kinetics chapter.Source: BRENDA EC 4.1.3.4 — no k_cat/K_m re-asserted
Sequence Human HMGCL UniProt P35914 · NCBI Gene 3155. This screen uses 3MP5 numbering (Cys266 = UniProt Cys266; residue 41 = Met). Chain B. Cα 28–323. Transit 1–27 is not this mesh.
Simulation map — what you see is what is written Setup = 3MP5 pocket empty, Mg stays (opaque, no autoplay). ① crystal HMG-CoA moves in. ② slow-mo: gold C3–OH proton to Mg–water. ③ slow-mo: fade to schematic acetoacetate + acetyl-CoA. ④ acetoacetate leaves. ⑤ acetyl-CoA leaves the other way. Only these events move.
Sources — bibliography of this page S1 — PDB 3MP5: human HMGCL R41M + HMG-CoA chain B + Mg, 2.25 Å X-ray — public coordinates; measured His233 NE2⋯MG = 2.58 Å · Asp42 OD1⋯MG = 2.36 Å · His235 NE2⋯MG = 2.41 Å · His233 NE2⋯HMG O7 = 3.94 Å S2 — Fu et al., 2010, PMID:20558737 — human HMGCL R41M + HMG-CoA S3 — Fu et al., 2006, PMID:16330550 — 2CW6 WT+Mg companion S4 — Sequence: UniProt P35914 · NCBI Gene 3155 S5 — Kinetics: BRENDA EC 4.1.3.4 — no k_cat/K_m re-asserted on this page

› Backbones and HMG poses are taken directly from the listed PDB entries, superposed into one common frame. Where no crystalline state exists for a step (e.g., acetoacetate on 3MP5, acetyl-CoA, C3–OH proton flight, product leave), the pose is drawn schematically and labeled as such in the narration. Occupancy is substrate HMG-CoA, not acetoacetate. Substrate-complex Å are not product geomClaims.

N-domainC-domainONH⁺ (gold)