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Open Enzyme Concept Graph

A visual map of how all Open Enzyme research domains relate to each other. Use the interactive diagram below to understand dependencies, synergies, and the full therapeutic stack.

Interactive Concept Map

graph TB
    subgraph Core["CORE PATHOLOGY"]
        A1["Gout"]
        A2["Enzyme Deficits"]
        A3["EPI"]
        A4["Hyperuricemia"]
    end

    subgraph Problem["PROBLEM MECHANISMS"]
        B1["Uric Acid Accumulation"]
        B2["MSU Crystal Formation"]
        B3["Gut Barrier Damage"]
        B4["SIBO/Dysbiosis"]
        B5["Brush Border Erosion"]
    end

    subgraph Immune["IMMUNE CASCADE"]
        C1["MSU Crystals"]
        C2["NLRP3 Inflammasome"]
        C3["ASC Speck Formation"]
        C4["IL-1β / IL-18 Release"]
        C5["Acute Flare"]
    end

    subgraph Host_Enzyme["HOST ENZYMES"]
        D1["Uricase Lost"]
        D2["Lipase Deficit"]
        D3["Protease Deficit"]
        D4["Amylase Deficit"]
    end

    subgraph Platform["ENGINEERED PLATFORMS"]
        E1["Saccharomyces cerevisiae"]
        E2["Aspergillus oryzae"]
        E3["GRAS Certification"]
    end

    subgraph Delivery["DELIVERY TARGETS"]
        F1["Uricase Gene"]
        F2["Lipase Gene"]
        F3["Protease Gene"]
        F4["Amylase Gene"]
        F5["Fermentation Protocol"]
        F6["Dosing Strategy"]
        F7["Shio-Koji Marinade"]
        F8["Amazake Drink"]
        F9["Wild-Type Baseline"]
        F10["Koji-Kin spore inoculum"]
        F11["Koji Rice colonized substrate"]
        F12["OTC PERT Benchmark (BoulderBio 40k FIP)"]
        F13["PERT Dose-Timing Framework (n=1)"]
    end

    subgraph Mechanism["THERAPEUTIC MECHANISM"]
        G1["Gut-Lumen Sink"]
        G2["Enzymatic Degradation"]
        G3["Uric Acid ↓ in Lumen"]
        G4["Re-absorption Prevention"]
    end

    subgraph Barrier["BARRIER REPAIR"]
        H1["Tight Junctions"]
        H2["Intestinal Permeability"]
        H3["TEER"]
    end

    subgraph Peptides["IMMUNOMODULATORY PEPTIDES"]
        I1["BPC-157"]
        I2["KPV Tripeptide"]
        I3["Barrier Integrity"]
        I4["IL-10 Promotion"]
    end

    subgraph Inhibitors["NLRP3 INHIBITORS"]
        J1["Oridonin"]
        J2["Disulfiram"]
        J3["ASC Block"]
        J4["Gasdermin D Block"]
        J5["Colchicine — CP2 P2X7 + CP3 ASC speck"]
        J6["Colchicine — ULT-initiation prophylaxis + CV repositioning (Lodoco FDA 2023)"]
        J7["Anakinra SC — off-label gout acute flare (IL-1R1 antagonist, same CP5a as canakinumab, ~$900/flare)"]
        J8["Topical CBD+THC 1:1 — CB2 NLRP3 suppression + TRPV1 analgesia (adjunct, jurisdiction-dependent)"]
        J9["BHB/Ketosis — contraindicated during active flare (transient UA rise compounds flare)"]
    end

    subgraph Parallel_Path["PARALLEL FLARE PATHWAYS (CP6a)"]
        N1["5-LOX"]
        N2["LTB4"]
        N3["Neutrophil Chemotaxis"]
        N4["Quercetin — 5-LOX IC50 300 nM"]
        N5["AKBA (Boswellia) — allosteric 5-LOX ~2.7 μM"]
        N6["EPA substrate competition → RvE1"]
    end

    subgraph Complement["COMPLEMENT PRIMING (CP0 — NEW)"]
        O1["Complement C5a"]
        O2["C5aR1"]
        O3["ROS Burst (non-transcriptional priming)"]
        O4["Avacopan (C5aR1 antagonist, FDA ANCA)"]
        O5["S100A8/A9 DAMP (2025 flare driver)"]
        O6["C1-INH (SERPING1) — EcN-LBP luminal CP0 candidate"]
        O7["DAF SCR1-4 — koji-secreted CP0 candidate"]
        O8["Houttuynia cordata polysaccharides — dietary CP0 (comp-018 Phase 2)"]
    end

    subgraph Resolution["ACTIVE RESOLUTION (CP5b — NEW)"]
        P1["ALX/FPR2 Resolution Receptor"]
        P2["RvD1 / RvD2 (DHA-derived)"]
        P3["MaR1 (Maresin, DHA-derived)"]
        P4["Neutrophil Infiltration (resolved)"]
        P5["aggNET (resolution form)"]
        P6["Lactoferrin (fermentable, partial overlap)"]
    end

    subgraph TNFSF14_arm["CP1a AMPLIFIER"]
        Q1["TNFSF14 / LIGHT"]
        Q2["NF-κB Priming"]
    end

    subgraph MultiCP["MULTI-CHOKEPOINT PROTEINS / COMPOUNDS"]
        R1["Lactoferrin — CP1a + CP4/CP6b (GSDMD mitophagy) + CP5b"]
        R2["EGCG — 20S proteasome 86 nM → CP1a + CP4 + CP5"]
        R3["Zileuton — FDA 5-LOX inhibitor (CP6a), never tested in gout"]
        R4["Koji Uricase — upstream crystal elimination (removes trigger)"]
        R5["Theaflavins — NLRP3-NEK7 disruption (CP2/CP3) + URAT1/GLUT9 down + TF3 TNFSF14/HVEM (CP1a)"]
    end

    subgraph Cannabinoids["CANNABINOIDS / TERPENES"]
        M1["CBD"]
        M2["Beta-Caryophyllene"]
        M3["CBG"]
        M4["THCV"]
        M5["Limonene — Nrf2 + TLR4 — MSU rat gout 2025"]
    end

    subgraph Metabolic["METABOLIC MODULATION"]
        K1["Beta-Hydroxybutyrate"]
        K2["Ketogenic State"]
        K3["HDAC Inhibition"]
        K4["Probiotic Fitness"]
    end

    subgraph Clinical["CLINICAL PRECEDENT"]
        L1["ALLN-346 (terminated 2022)"]
        L2["Rasburicase"]
        L3["PULSE Probiotic"]
        L4["PRX-115 Phase 2 (2025)"]
        L5["SSS11 Phase 1 (C. utilis uricase)"]
        L6["Canakinumab FDA 2023 (gout)"]
        L7["TNFSF14 / LIGHT — emerging target"]
    end

    subgraph DiscoveryEngine["DISCOVERY ENGINE (methodology)"]
        DE1["Chokepoint Cascade Map"]
        DE2["Repurposing Surface"]
        DE3["Zileuton — CP6a 5-LOX (FDA asthma)"]
        DE4["Disulfiram — CP6b GSDMD (FDA alcohol)"]
        DE5["Avacopan — CP0 C5aR1 (FDA ANCA)"]
        DE6["Strain Library (synthesis output)"]
        DE7["Modality × Target Matrix — exploration surface"]
        DE8["Paperclip GXL — 11M full-text papers + 150M abstracts MCP"]
        DE9["TCM × Modern Rigor — empirical-prior re-mining lens"]
        DE10["Si Miao San / Si Miao Wan — 4-herb gout formula (ChiCTR RCTs)"]
        DE11["Smilax glabra (Tu Fu Ling) — primary TCM gout herb"]
        DE12["Global Lab Access — Maruyama Tokyo / Jiangnan / DTU parallel paths"]
        DE13["comp-013 TCM Gout Compound Triage — 4 GUT-LUMINAL VIABLE"]
        DE14["comp-014 Medicinal Mushroom Compound Mapping — Phase 2 complete"]
        DE15["ADA — adenosine deaminase (chokepoint candidate)"]
        DE16["PINK1/mitophagy — NLRP3-priming-adjacent (chokepoint candidate)"]
        DE17["comp-019 — Gut-Lumen Uricase × ABCG2 Genotype Flux Model"]
        DE18["comp-018/comp-020 — Upstream Complement Modulator Sweep (dietary CP0)"]
        DE19["Compounding Pharmacy Track — 503A/503B delivery for repurposing surface"]
        DE20["Ginkgo Cloud Lab — cell-free $39/protein pre-gate + strain-engineering eval"]
        DE21["Delivery Route × Compound Class Matrix — companion exploration surface (route axis)"]
        DE22["Gout Kill Chain Delivery Route Analysis — chokepoint × route per-node grid"]
        DE23["GSDMD Pore Self-Delivery Paradox — pore as size-selective delivery window"]
        DE24["Purine-Degrading Bacteria (PDB) — gut as independent urate disposal organ"]
        DE25["Chassis-Pending Interventions — index of interventions awaiting chassis"]
        DE26["comp-030 DAF SCR1-4 Cassette Ranking — 43,200 candidates, top cluster confirms §1.25 baseline"]
        DE27["comp-023 Cordycepin Burden FBA — GREEN verdict; <1% carbon, 1,000× Jeennor breakpoint"]
        DE28["comp-032 ABCG2 Q141K Chaperone Screen — GREEN; 5 FDA-approved candidates ranked"]
        DE29["comp-035 IA Uricase H₂O₂ Reaction-Diffusion — GREEN across all 3 architectures"]
        DE30["comp-029 Combined CP0 Systems Model — YELLOW; RA gut-luminal + DAF SCR1-4"]
        DE31["comp-033/036 Inhaled mRNA-IL-1RA — RED single-dose / YELLOW repeat-dose"]
        DE32["comp-037 C1-INH Protease Stability + Glycosylation in EcN — MODERATE (kinetic-competition gated)"]
    end

    subgraph PlatformArch["PLATFORM ARCHITECTURE (NEW)"]
        PA1["Catalase Capacity Principle — route-agnostic H₂O₂ safety (delivery-route-matrix)"]
        PA2["Substrate Engineering Principle 9 — first-class eng. lever (open-source-platform)"]
        PA3["Closed-Loop Pharmacogenomics Pipeline — genotype→selection→QC→dose→track (open-source-platform)"]
        PA4["Protease-Vulnerability-to-Redesign Workflow — 4-step pattern (lactoferrin, DAF)"]
    end

    subgraph MushroomTrack["MEDICINAL MUSHROOM COMPLEMENT TRACK (Phase 7 — NEW)"]
        MT1["Ganoderma lucidum / lingzhi — GLPP polysaccharide-peptide"]
        MT2["Cordyceps militaris — cordycepin + native pentostatin ADA-inhibitor pairing"]
        MT3["Pleurotus citrinopileatus — ergothioneine (7.0 mg/g DW, highest fungal producer)"]
        MT4["Lentinula edodes / shiitake — eritadenine"]
        MT5["Hericium erinaceus / lion's mane — erinacines"]
        MT6["Trametes versicolor / turkey tail — PSK/PSP"]
        MT7["Inonotus obliquus / chaga — inotodiol"]
        MT8["comp-014 — breadth aggregation (6,798 compounds, 55 species)"]
        MT9["H06 — track viability falsification card (stub)"]
        MT10["Extract Characterization SOPs — GLPP / cordycepin / EGT"]
    end
        PR1["PRPS — phosphoribosyl pyrophosphate synthetase"]
        PR2["PRPP — central purine/pyrimidine substrate"]
        PR3["De novo purine biosynthesis"]
        PR4["Eurycomanol (tongkat ali) — PRPS suppression (In Vitro, PMID 34785103)"]
        PR5["Fructose → ATP depletion → PRPS disinhibition (canonical pathological pathway)"]
        PR6["Tongkat Ali Physta — SUA ↓7-11% (2021 RCT, n=105)"]
    end

    subgraph Androgens["ANDROGEN-URATE AXIS (NEW)"]
        S1["Testosterone (endogenous or exogenous)"]
        S2["Estradiol"]
        S3["SHBG (liver-produced, binds T)"]
        S4["URAT1 (apical reabsorption)"]
        S5["ABCG2 (apical secretion, kidney + gut)"]
        S6["Insulin sensitivity"]
        S7["Clomid / SERMs"]
        S8["Aromatase Inhibitors"]
    end

    subgraph ABCG2Mod["ABCG2 MODULATORS (NEW)"]
        AM1["Butyrate / SCFA from fermentable fiber"]
        AM2["Sulforaphane (Nrf2)"]
        AM3["TNFα / chronic inflammation"]
        AM4["Q141K polymorphism (gout-causing variant)"]
        AM5["Curcumin / Quercetin / EGCG (functional inhibitors)"]
    end

    subgraph KojiEndgame["KOJI ENDGAME STRAIN (NEW)"]
        KE1["Ward 1995 dual-cassette gate (A. awamori glucoamylase-KEX2 hLf >2 g/L)"]
        KE2["Uricase cassette (PamyB + uaZ, primary)"]
        KE3["Lactoferrin cassette (glucoamylase-KEX2-hLf, secondary)"]
        KE4["Carnosine cassette (CarnS + panD, optional third)"]
        KE5["Native kojic acid (3-5 g/L, free)"]
        KE6["Native ergothioneine (~20 mg/g, free)"]
        KE7["Format constraint: shio-koji unsuitable for peptide payloads"]
        KE8["Dried koji powder (heat-inactivated, default for peptides)"]
        KE9["H01 Killshot 1 SURVIVED 2026-05-05 — architecture validated submerged; solid-state remains open"]
        KE10["NSlD-dP10 protease-deletion host — default for Lf cassette (Huynh 2020)"]
        KE11["NSAR1 5-marker platform — 5 integration slots (Oikawa 2020)"]
        KE12["comp-010 cassette compatibility — LOW overall risk; KEX2 pos 579 moderate; uricase SKL PTS1 verify"]
        KE13["comp-022 uricase cassette ranking — 43,200 candidates; top cluster confirms PamyB+amyB SP+direct-secretion"]
        KE14["comp-023 cordycepin cassette burden — GREEN FBA verdict; breakpoint ~1,000× Jeennor titer"]
    end

    subgraph Chaperones["ER CHAPERONE SUBSYSTEMS (NEW)"]
        CH1["BiP/Kar2 — generic HSP70 ER chaperone"]
        CH2["PDI/ERO1 — disulfide bond formation"]
        CH3["Calnexin/Calreticulin — N-glycoprotein QC"]
        CH4["HacA UPR — transcriptional capacity expansion"]
        CH5["Chaperone-orthogonal stacking framework — predict synergy from non-overlapping load classes"]
        CH6["Pairwise expression matrix — falsifiable test of framework"]
        CH7["Wakai 2019 3-cellulase 40× synergy — direct A. oryzae evidence (light-class stacking)"]
        CH8["Huynh 2020 39.7 mg/L mAb ceiling — 2 PDI-heavy cassettes, NSlD-dP10 required"]
        CH9["Zhou 2016 — constitutive HacA in koji REDUCES amylase via RESS feedback"]
        CH10["Cross-class helper combinations (Pichia, 6.5-8.7×) — highest-leverage capacity expansion"]
        CH11["Per-architecture PDI residence time (α coefficients) — CCP 0.3-0.6, Ig-like 1.0, transferrin-lobe 1.5-2.5"]
        CH12["DAF SCR1-4 single-cassette routing — triple-cassette synergy 0.35-0.65 below 0.6 decision gate"]
    end

    subgraph EnzymeQC["ENZYME QUANTIFICATION (NEW)"]
        EQ1["Enzyme Quantification Protocol — Tier 1 kitchen → Tier 4 outsourced"]
        EQ2["Lipase p-NPP assay — Creon-cap-equivalent reference standard"]
        EQ3["Protease azocasein assay — shio-koji marinade pre-digestion readout"]
        EQ4["Amylase DNS reducing-sugar assay — batch QC"]
        EQ5["Tier 3 first-run calibration — anchors home assays to clinical units"]
        EQ6["Quantification Ladder — canonical 4-tier framework definition"]
        EQ7["Smartphone photometry — Tier 2 bridge between kitchen and bench"]
    end

    %% Core relationships
    A1 --> B1
    A4 --> B1
    A2 --> D1
    A2 --> D2
    A3 --> D3
    A3 --> D4

    %% Problem to immune cascade
    B1 --> B2
    B2 --> C1
    C1 --> C2
    C2 --> C3
    C3 --> C4
    C4 --> C5

    %% Platform engineering
    D1 --> F1
    D2 --> F2
    D3 --> F3
    D4 --> F4

    F1 --> E1
    F1 --> E2
    F2 --> E2
    F3 --> E2
    F4 --> E2

    E1 --> E3
    E2 --> E3

    %% Wild-type baseline / home fermentation delivery formats
    %% (source: koji-home-fermentation.md)
    F9 -->|"wild-type koji produces"| F2
    F9 -->|"wild-type koji produces"| F3
    F9 -->|"wild-type koji produces"| F4
    F9 -->|"processed into"| F7
    F9 -->|"processed into"| F8
    F7 -->|"pre-digests protein in marinade"| A3
    F8 -->|"amylase-active digestive aid"| A3
    E2 -->|"engineered strain must outperform"| F9
    %% Koji-kin two-stage process (source: koji-home-fermentation.md)
    F10 -->|"inoculates steamed rice to produce"| F11
    F11 -->|"is the working enzyme substrate"| F9
    %% OTC PERT benchmark and dose-timing framework (source: digestive-enzyme-optimization.md)
    F12 -->|"40k FIP = ~9-10k USP (In Vitro)"| F2
    F12 -->|"n=1 dose-timing informs"| F13
    F13 -->|"2-cap or split-dose required for"| A3
    E2 -->|"1g engineered koji targets"| F12

    %% Mechanism pathway
    E1 --> G1
    E2 --> G1
    F5 --> G1
    G1 --> G2
    G2 --> G3
    G3 --> G4

    %% Barrier repair path
    I1 --> H1
    I1 --> H3
    I2 --> I4
    I4 --> H3
    H1 --> B3
    H3 --> B3

    %% NLRP3 inhibition path
    J1 --> J3
    J1 --> C2
    J2 --> J4
    J2 --> C2
    %% Colchicine: dual-hit CP2 (P2X7 pore block) + CP3 (microtubule-mediated ASC transport block)
    %% (source: colchicine.md; Leung 2015 PMID 26228647; Misawa 2013 PMID 23502856)
    J5 -->|"P2X7 pore block (CP2)"| C2
    J5 -->|"microtubule depolymerization blocks ASC transport (CP3)"| C3
    %% Colchicine cardiovascular repositioning (COLCOT/LoDoCo2 → Lodoco FDA 2023)
    %% and ULT-initiation prophylaxis role (source: colchicine.md)
    J6 -->|"ULT-initiation prophylaxis prevents dissolution flares"| C5
    J6 -->|"CV repositioning — NLRP3 suppression reduces plaque instability"| C2
    %% Anakinra SC for acute gout flare (source: gout-action-guide.md, gout-clinical-pipeline.md)
    J7 -->|"IL-1R1 antagonist (CP5a); off-label gout protocol 100 mg/d × 3d SC"| C4
    J7 -->|"faster onset (hours vs days), cleaner cumulative burden vs prednisone"| C5
    %% Topical CBD+THC for acute flare (source: gout-action-guide.md, cannabinoids-terpenes.md)
    J8 -->|"CB2-mediated NLRP3 suppression (CP2/CP3)"| C2
    J8 -->|"TRPV1 desensitization + cooling → pain reduction"| C5
    %% BHB contraindicated during active flare (source: gout-action-guide.md, bhb-ketones.md)
    J9 -->|"transient UA rise 5-10% via MCT/URAT1 competition → compounds flare"| C5
    J9 -.->|"only prophylactic NLRP3 use during intercritical periods; suspend during flare"| K1

    %% Metabolic modulation
    K1 --> K2
    K1 --> K3
    K1 --> K4
    K4 --> B4
    K2 --> J2

    %% Clinical precedent links
    L1 -.->|"validated mechanism, program ended"| G1
    L2 --> F1
    L3 --> B4
    L4 -->|"systemic IV, treatment-naive gout"| F1
    L5 -->|"C. utilis uricase, IV"| F1
    L6 -->|"approved IL-1b mAb"| C4
    L7 -->|"flare biomarker, distinct from NLRP3/IL-1b"| C5

    %% Barrier damage prevention
    B3 --> B5
    B4 --> B5
    B5 --> A3

    %% 5-LOX / LTB4 parallel neutrophil chemotaxis path (from nlrp3-inhibitor-screen.md ChEMBL cross-check)
    %% Now formally CP6a in v1.2 exploit map
    C1 -->|"MSU also drives 5-LOX"| N1
    N1 -->|"produces"| N2
    N2 -->|"recruits neutrophils"| N3
    N3 --> C5
    N4 -->|"inhibits at 300 nM"| N1
    N5 -->|"allosteric ~2.7 μM"| N1
    N6 -->|"substrate redirect → RvE1 (→ CP5b)"| N1

    %% CP0 — Complement C5a priming (v1.2 restructure, 2026-04-24)
    %% MSU directly activates complement → C5a → ROS → NLRP3 priming (Cumpelik 2016, Khameneh 2017)
    C1 -->|"MSU activates complement"| O1
    O1 -->|"binds"| O2
    O2 -->|"triggers ROS burst"| O3
    O3 -->|"primes NLRP3 (non-transcriptional)"| C2
    O4 -.->|"inhibits (pharma adjunct)"| O2
    O5 -->|"DAMP amplifies NF-κB priming"| Q2
    %% Two-chassis CP0 architecture (comp-037 + comp-012, 2026-05-17)
    O6 -->|"inhibits C1r/C1s/MASP-2 at classical/lectin entry"| O1
    O7 -->|"accelerates decay of C3/C5 convertases at MSU surface"| O1
    O6 -->|"expressed in EcN LBP (MODERATE, kinetic-competition gated)"| O1
    O7 -->|"expressed in A. oryzae koji (LOW protease risk, wet-lab gated)"| O1
    %% Houttuynia cordata polysaccharides — dietary CP0 (comp-018 Phase 2, 2026-05-17)
    O8 -->|"multi-target C2+C4+C5, CH50 79-318 µg/mL"| O1

    %% CP1a — TNFSF14 (LIGHT) amplifier (Round 1 work)
    Q1 -->|"amplifies via HVEM"| Q2
    Q2 -->|"transcriptional priming"| C2

    %% CP5b — ALX/FPR2 active resolution (v1.2 restructure, 2026-04-24)
    %% RvD1/MaR1 in MSU gout models (Zaninelli 2022 PMID 35716378, Jiang 2023 PMID 37996809)
    P2 -->|"activates"| P1
    P3 -->|"activates (AMPK/Nrf2 arm)"| P1
    P1 -->|"resolves"| P4
    P4 -.->|"resolves"| N3
    C4 -->|"GSDMD pore-driven NET release"| P5
    P5 -->|"sequesters cytokines → resolution"| P4
    P6 -->|"partial resolution overlap"| P1

    %% Multi-chokepoint proteins/compounds (v1.2 synthesis platform endgame)
    R1 -->|"LPS/CD14 + NF-κB suppression"| Q2
    R1 -->|"GSDMD direct suppression via mitophagy (Shan 2026 PMID 41524100)"| C4
    R1 -->|"partial SPM resolution overlap"| P1
    %% Lactoferrin substrate-supply synergy with uricase via TNFα → ABCG2 axis
    %% (Speculative; composed of Animal Model + In Vitro links; source: lactoferrin.md §4.7, koji-endgame-strain.md §2.2)
    R1 -->|"suppresses TNFα (Animal Model)"| AM3
    AM3 -.->|"TNFα suppression relieves ABCG2 block (Speculative)"| S5
    R2 -->|"proteasome block stabilizes IκBα → NF-κB"| Q2
    R2 -->|"suppresses caspase-1"| C4
    R3 -->|"FDA-approved 5-LOX inhibitor, gout-untested"| N1
    R4 -->|"removes upstream MSU crystal trigger"| C1
    R5 -->|"NLRP3-NEK7 disruption (CP2/CP3 assembly)"| C2
    R5 -->|"TF3 suppresses TNFSF14-induced IL-6 (CP1a)"| Q1
    R5 -->|"URAT1/GLUT9 downregulation"| B1

    %% Style the v1.2 additions distinctly
    linkStyle default stroke-width:1px
    classDef cp0Style fill:#ffccee,stroke:#cc0066,stroke-width:2px
    classDef cp5bStyle fill:#cce6ff,stroke:#0066cc,stroke-width:2px
    classDef multiCPStyle fill:#e6ffcc,stroke:#66aa00,stroke-width:2px
    class O1,O2,O3,O4,O5 cp0Style
    class P1,P2,P3,P4,P5,P6 cp5bStyle
    class R1,R2,R3,R4 multiCPStyle

    %% Androgen-urate axis (2026-04-24)
    %% Sex hormones gate the transporter biology that sits upstream of hyperuricemia
    S1 -->|"upregulates"| S4
    S1 -->|"suppresses"| S5
    S2 -->|"downregulates"| S4
    S2 -->|"boosts secretion via OAT1/3"| S5
    S4 -->|"↑reabsorption → hyperuricemia"| B1
    S5 -.->|"↓secretion → hyperuricemia (including gut-lumen sink ceiling)"| G1
    S3 -->|"binds T → lowers Free T for given Total T"| S1
    S6 -->|"suppresses SHBG synthesis; high sensitivity = ↑SHBG"| S3
    S7 -->|"↑endogenous T, modestly ↑SHBG, ↑E2"| S1
    S7 -->|"peripheral ER agonism"| S2
    S9["Tongkat Ali (Eurycoma longifolia) — dual T-up + UA-down"]
    S9 -->|"SHBG displacement → ↑free-T"| S3
    S9 -->|"multi-target transporter modulation (URAT1↓, GLUT9↓, ABCG2↑)"| S4
    S9 -->|"multi-target transporter modulation"| S5

    %% PRPS / purine biosynthesis chokepoint (source: prps-purine-biosynthesis-chokepoint.md)
    PR1 -->|"catalyzes rate-limiting step →"| PR2
    PR2 -->|"substrate for"| PR3
    PR3 -->|"produces purines → catabolized to"| B1
    PR4 -->|"suppresses PRPS (In Vitro)"| PR1
    PR4 -->|"component of"| S9
    PR5 -->|"fructose-driven ATP depletion relieves PRPS inhibition"| PR1
    PR5 -->|"canonical fructose-gout link"| B1
    PR6 -->|"human RCT evidence for"| S9
    PR6 -->|"SUA reduction via multi-target mechanism"| B1

    %% ABCG2 modulators (2026-04-26)
    %% Pharmacological levers on the gut urate sink — separate from sex-hormone axis
    AM1 -->|"PPARγ activation → induction"| S5
    AM1 -->|"HDAC inhibition → trafficking rescue"| AM4
    AM2 -->|"Nrf2 activation → induction"| S5
    AM3 -->|"NF-κB → suppression"| S5
    AM4 -->|"folding/trafficking defect → reduced apical expression"| S5
    AM5 -->|"functional inhibition (acute, dose-dependent)"| S5
    S8 -->|"blocks T→E2 aromatization (↑T, ↓E2)"| S1
    S8 -.->|"loss of estrogen's urate-excretion boost"| S2

    %% Koji endgame strain architecture (source: koji-endgame-strain.md, engineered-koji-protocol.md §15-16)
    KE1 -->|"gates single-strain feasibility"| KE2
    KE1 -->|"gates single-strain feasibility"| KE3
    KE2 -->|"CP0-upstream trigger elimination"| C1
    KE3 -->|"CP1a + CP4 + CP6b coverage"| C2
    KE3 -->|"suppresses TNFα → relieves ABCG2 block (Speculative)"| AM3
    KE4 -->|"URAT1/GLUT9 downregulation (Animal Model)"| B1
    KE5 -->|"NF-κB suppression (In Vitro)"| Q2
    KE6 -->|"ROS scavenging → CP1b (In Vitro)"| O3
    KE7 -->|"protease hydrolysis rules out"| KE4
    KE8 -->|"preserves peptide payloads"| KE4
    %% Androgen-axis precision countermeasure (source: koji-endgame-strain.md §2.5)
    %% Note: S1 --> S4 edge already exists in Androgens subgraph above
    KE4 -->|"carnosine counters androgen-driven URAT1 upregulation (Animal Model)"| S4
    %% H01 Killshot #1 result (2026-05-05): architecture validated submerged; solid-state open
    %% (source: H01-ward-dual-cassette.md)
    KE9 -->|"architecture validated In Vitro submerged"| KE1
    KE9 -->|"solid-state format remains Mechanistic Extrapolation"| KE3
    KE10 -->|"required for Lf titer threshold (In Vitro)"| KE3
    KE11 -->|"provides 5 integration slots"| KE2
    KE11 -->|"provides 5 integration slots"| KE3
    %% comp-010 cassette compatibility (2026-05-05): LOW overall risk; two design notes
    %% (source: cassette-compatibility-computational.md)
    KE12 -->|"confirms LOW cassette-design risk"| KE1
    KE12 -->|"KEX2 pos 579 moderate risk — monitor SDS-PAGE"| KE3
    KE12 -->|"uricase SKL PTS1 — verify secretion in 1.9"| KE2
    %% comp-022 uricase cassette ranking (2026-05-14): ClockBase-style exhaustive enumeration
    %% (source: uricase-cassette-ranking-computational.md)
    KE13 -->|"confirms PamyB + amyB SP + direct-secretion architecture"| KE2
    KE13 -->|"three gene-synthesis-time refinements: 5p-softened codon, PTS1-blocking tag, N191Q ablation"| KE1
    KE13 -->|"v2 retrofit: ESM2 pseudo-pLDDT + ViennaRNA MFE; 71 pass N-of-5 ≥ 4; v1 top cluster survives 100%"| KE1
    %% comp-023 cordycepin cassette burden (2026-05-14): FBA on iWV1314
    %% (source: cordycepin-cassette-burden-computational.md)
    KE14 -->|"GREEN FBA burden verdict at Jeennor 2023 titer"| KE1
    KE14 -->|"cytosolic; PDI load 0; bypasses secretion entirely"| CH5
    KE14 -->|"cns1+cns2 cordycepin arm metabolic-burden-feasible"| MT2
    KE14 -->|"carnS+panD also GREEN; two mutually exclusive cytosolic third-cassette options"| KE4

    %% Chaperone-orthogonal stacking framework (2026-05-05)
    %% (source: chaperone-orthogonal-stacking.md)
    %% Cassette → chaperone load mapping
    KE2 -->|"BiP-transit only (0 disulfides, 0 N-glycans)"| CH1
    KE3 -->|"PDI-heavy (16 disulfides per Notari 2023 PMC10465537; arch-adjusted effective load 24-40)"| CH2
    KE3 -->|"calnexin-moderate (3 N-glycans)"| CH3
    KE3 -->|"BiP-heavy (691 aa single chain)"| CH1
    KE4 -->|"bypasses secretion entirely (cytosolic)"| CH5
    %% Framework retroactively explains endgame strain design
    CH5 -->|"predicts ≥0.85 synergy for 4-molecule endgame strain"| KE1
    CH5 -->|"informs which 5th cassette to add (fill underused load classes)"| KE2
    CH5 -.->|"falsifiable test"| CH6
    %% Supporting evidence
    CH7 -.->|"validates light-substrate super-additivity"| CH5
    CH8 -.->|"validates PDI-heavy ceiling"| CH5
    %% Capacity expansion levers
    KE10 -->|"raises secretion floor for PDI-heavy substrates"| CH2
    CH4 -->|"upregulates BiP, PDI, ERAD"| CH1
    CH4 -->|"upregulates BiP, PDI, ERAD"| CH2
    CH4 -->|"upregulates BiP, PDI, ERAD"| CH3
    CH9 -->|"rules out naive HacA-CA in koji (RESS feedback suppresses native amylase)"| CH4
    CH10 -->|"highest-leverage untested lever in koji (Pichia precedent)"| CH5
    CH11 -->|"refines bulk disulfide count for PDI load prediction"| CH5
    CH12 -->|"DAF SCR1-4 routed to separate strain per framework prediction"| CH5
    CH12 -->|"wet-lab gate formalized as validation-experiments 1.25"| KE1

    %% Discovery engine → repurposing surface (source: open-enzyme-vision.md §2)
    DE1 -->|"produces"| DE2
    DE2 -->|"surfaces"| DE3
    DE2 -->|"surfaces"| DE4
    DE2 -->|"surfaces"| DE5
    DE1 -->|"synthesizes"| DE6
    DE3 -->|"CP6a 5-LOX inhibitor"| N1
    DE4 -->|"CP6b GSDMD inhibitor"| C4
    DE5 -.->|"CP0 C5aR1 antagonist (pharma adjunct)"| O2
    %% Modality × Target Matrix (source: modality-chokepoint-matrix.md)
    DE7 -->|"orthogonal exploration of"| DE1
    DE7 -->|"surfaces novel modalities for"| DE2
    %% Paperclip literature MCP (source: paperclip-deep-dive.md)
    DE8 -->|"full-text search augments"| DE1
    DE8 -->|"literature delta surfaces"| DE2
    %% TCM × Modern Rigor lens (source: tcm-modern-rigor-intersection.md)
    DE9 -->|"applies chokepoint mapping to"| DE1
    DE9 -->|"ChEMBL cross-checks"| DE2
    DE9 -->|"surfaces formula-decomposed"| DE10
    DE9 -->|"surfaces single-compound"| DE11
    DE10 -->|"XO inhibition + NLRP3 (Animal Model)"| C2
    DE11 -->|"XO inhibition + URAT1 modulation"| B1
    %% comp-013 TCM compound triage (source: tcm-gout-compound-triage-computational.md)
    DE13 -->|"4 GUT-LUMINAL VIABLE: luteolin, astilbin, emodin, berberine"| DE9
    DE13 -->|"ChEMBL coverage gap is load-bearing for TCM compounds"| DE2
    %% comp-014 medicinal mushroom compound mapping (source: medicinal-mushroom-compound-mapping-computational.md)
    DE14 -->|"Phase 2 ChEMBL+LOTUS+PubMed complete; 6,798 compounds, 55 species"| DE1
    DE14 -->|"C5aR1 platform gap confirmed empirically — zero direct fungal antagonists"| O2
    DE14 -->|"spawned Phase 7 medicinal mushroom complement track"| MT1
    DE14 -->|"surfaced ADA + PINK1/mitophagy chokepoint candidates"| DE1
    DE15 -->|"purine catabolism upstream of XO; GLPP + cordycepin/pentostatin coverage"| B1
    DE16 -->|"mitochondrial quality control upstream of NLRP3 mtROS (CP2)"| C2
    %% comp-019 gut-lumen uricase × ABCG2 genotype flux model (source: uricase-abcg2-genotype-stratification-computational.md)
    DE17 -->|"genotype-robust; WT/WT LARGEST ΔSUA (−0.83 mg/dL); substrate-limited regime"| G1
    DE17 -->|"Q141K genotype stratification → allopurinol response gap mapped"| AM4
    DE17 -->|"Phase 2b RCT design: typical-gout, Q141K+Q126* as stratification"| L1
    %% comp-018/comp-020 upstream complement modulator sweep (source: upstream-complement-modulator-sweep-computational.md, upstream-complement-verification-rerun-computational.md)
    DE18 -->|"dietary upstream-CP0 axis: rosmarinic acid + luteolin + Helicteres lignans"| O1
    DE18 -->|"engineered C1-INH parallel thread to H05 DAF SCR1-4"| DE1
    %% Compounding pharmacy track (source: compounding-pharmacy-track.md)
    DE19 -->|"delivery route for"| DE2
    DE19 -->|"highest-priority candidate"| DE4
    DE19 -->|"candidate"| DE3
    DE19 -->|"candidate (custom-dose colchicine)"| J5
    %% Ginkgo Cloud Lab evaluation (source: ginkgo-cloud-lab-evaluation.md)
    DE20 -->|"cell-free pre-gate validates uricase sequences"| KE1
    DE20 -->|"cell-free weak for DAF/CD55 SCR1-4 (glycoprotein, disulfide-rich)"| CH12
    DE20 -->|"complements (different gate)"| DE12
    %% Global lab access (source: ward-1995-lab-access-global.md)
    DE12 -->|"provides NSlD-dP10 chassis for"| KE10
    DE12 -->|"parallel path via C19 chassis"| KE1
    %% Delivery Route × Compound Class Matrix (source: delivery-route-matrix.md)
    DE21 -->|"orthogonal route axis to"| DE7
    DE21 -->|"surfaces non-oral cells for"| DE2
    DE21 -->|"chassis-as-formulation: H2O2 housekeeping advantage"| KE1
    DE21 -->|"intra-articular uricase + catalase as #1 open vector"| B1
    DE21 -->|"open-source SEL-212-equivalent extends engineering layer"| DE19
    %% Gout kill-chain delivery route analysis (source: gout-kill-chain-delivery-routes.md)
    DE22 -->|"chokepoint × route per-node companion to"| DE21
    DE22 -->|"compounding pharmacy candidates: zileuton + disulfiram + VX-765"| DE19
    DE22 -->|"comp-019 SUA reduction band cited at Uricase node"| DE17
    DE22 -->|"IA delivery as systematic gap across CP2-CP6b"| DE25
    %% GSDMD pore self-delivery paradox (source: gsdmd-pore-delivery-paradox.md)
    DE23 -->|"size-selective delivery window for OE biologics in 10-20 nm range"| DE22
    DE23 -->|"KPV / nanobody / single-SCR / lactoferrin / IL-1RA pass through pore"| DE21
    %% Purine-degrading bacteria (source: purine-degrading-bacteria.md)
    DE24 -->|"gut PDB as independent CP6 urate disposal — needs non-koji chassis"| DE25
    DE24 -->|"butyrate -> ABCG2 PPARγ + Q141K HDAC rescue compounds the mechanism"| AM4
    DE24 -->|"natural genotype-targeted therapy for Q141K (#1 GWAS variant)"| AM4
    %% comp-030 DAF SCR1-4 cassette ranking (source: daf-cd55-scr14-cassette-ranking-computational.md)
    DE26 -->|"confirms §1.25 PamyB+amyB SP+direct-secretion+max-CAI architecture"| CH12
    DE26 -->|"α-coefficient CORRORORATED: ESM2 pLDDT 100% above 80, range [87.6,89.8]"| CH11
    DE26 -->|"§1.25 baseline 60-candidate shortlist; N-of-5=5 strict tier 40 cassettes"| KE1
    %% comp-023 cordycepin cassette burden (source: cordycepin-cassette-burden-computational.md)
    DE27 -->|"GREEN FBA verdict; <1% carbon, breakpoint ~1,000× Jeennor titer"| KE1
    DE27 -->|"cordycepin arm metabolic-burden-feasible; informs §1.9 extended design"| KE14
    DE27 -->|"cns1+cns2 cytosolic; PDI load 0; bypasses secretion entirely"| CH5
    DE27 -->|"native C. militaris pentostatin co-formulation alternative to ADA engineering"| MT2
    %% comp-032 ABCG2 Q141K chaperone screen (source: abcg2-q141k-chaperone-screen-computational.md)
    DE28 -->|"GREEN: 5 FDA-approved candidates; diflunisal Tier-1 lowest-friction first call"| AM4
    DE28 -->|"CFTR-corrector positive controls rank top 11%; FDA surface NOT empty"| DE25
    DE28 -->|"next: per-hit Caco-2 Q141K trafficking-rescue assay"| KE1
    %% comp-035 IA uricase H₂O₂ reaction-diffusion (source: intra-articular-uricase-h2o2-reaction-diffusion-computational.md)
    DE29 -->|"GREEN: all 3 architectures clear <10 µM safe threshold by 5-50×"| DE25
    DE29 -->|"catalase kcat/Km is dominant safety driver; proximity claims NOT mechanism"| DE21
    DE29 -->|"next: Amplex Red microelectrode in synovial-fluid mimic"| DE22
    %% comp-029 combined CP0 systems model (source: combined-cp0-systems-model-computational.md)
    DE30 -->|"YELLOW: RA gut-luminal-transient, not systemic; combined 1.08-1.10× singleton"| DE18
    DE30 -->|"gated on §1.25 DAF SCR1-4 α ≥ 0.5 for GREEN re-run"| CH12
    %% comp-033/036 inhaled mRNA-IL-1RA (source: inhaled-mrna-il1ra-pulse-computational.md, repeat-dose-inhaled-mrna-il1ra-pkpd-computational.md)
    DE31 -->|"RED single-dose; YELLOW repeat-dose at corrected Kd 0.1-10 nM"| DE25
    DE31 -->|"prednisone-displacement reframe: partial occupancy × cleaner side-effect profile"| DE22
    %% comp-037 C1-INH protease stability + glycosylation feasibility (2026-05-17)
    DE32 -->|"MODERATE — LOW strictly-degradative, GREEN glycosylation, RCL kinetic-competition gated"| O6
    DE32 -->|"substantiates two-chassis CP0 architecture (C1-INH EcN + DAF SCR1-4 koji)"| O7
    %% Chassis-pending interventions (source: chassis-pending-interventions.md)
    DE25 -->|"operationalizes chokepoint-first chassis-second discipline"| DE2
    DE25 -->|"PDB / siRNA-URAT1 / engineered-LBP / mRNA-IL-1RA / IA-uricase entries"| DE7

    %% Medicinal mushroom complement track (source: medicinal-mushroom-complement-track.md)
    MT1 -->|"ADA + GLUT9 + OAT1 — 40.6% UA reduction HUA mice"| B1
    MT2 -->|"URAT1 modulation — SUA 337→203 µmol/L (Animal Model)"| B1
    MT2 -->|"native pentostatin ADA-inhibitor pairing protects cordycepin"| MT2
    MT3 -->|"Keap1/Nrf2/HO-1 redox modulator — NLRP3 priming layer"| C2
    MT3 -->|"dietary 50-100g fresh oyster delivers 12-24 mg EGT"| MT3
    MT4 -->|"cardiovascular cholesterol-lowering — vessel-wall NLRP3-adjacent"| C2
    MT5 -->|"NGF-inducing CNS-relevant"| MT5
    MT6 -->|"β-glucan immunomodulator — FDA-approved adjuvant in Japan"| C2
    MT7 -->|"triterpenoid chemistry overlapping reishi"| MT1
    MT8 -->|"falsification card for track viability — 3 dimensions"| MT1
    MT9 -->|"SOP-1 GLPP fractionation gated on Phase 5b CNKI dive"| MT1
    MT9 -->|"SOP-3 EGT HILIC-HPLC lowest-friction entry point"| MT3

    %% Enzyme quantification protocol (source: enzyme-quantification-protocol.md)
    EQ1 -->|"provides assay methodology for"| F9
    EQ1 -->|"Tier 3 first-run anchors home assays to clinical units"| F12
    EQ2 -->|"p-NPP lipase assay vs Creon-cap-equivalent"| F2
    EQ3 -->|"azocasein protease assay for marinade pre-digestion"| F7
    EQ4 -->|"DNS amylase assay for batch QC"| F4
    EQ5 -->|"calibration bridge: Tier 1 home → Tier 3 bench → clinical U/g"| EQ1
    %% Quantification ladder (source: quantification-ladder.md)
    EQ6 -->|"canonical 4-tier framework instantiated by"| EQ1
    EQ6 -->|"canonical 4-tier framework instantiated by"| MT9
    EQ7 -->|"smartphone photometry bridges kitchen to bench for"| EQ1

    %% Platform architecture — route-agnostic principles (source: delivery-route-matrix.md, open-source-platform.md)
    PA1 -->|"catalase kcat/Km is dominant safety driver for ALL uricase delivery formats"| DE29
    PA1 -->|"generalizes chassis-as-formulation advantage across all routes"| KE1
    PA2 -->|"universal across mushroom + koji + LBP tracks; 1.2x-100x yield effects"| MT1
    PA2 -->|"substrate is most-accessible optimization axis for distributed production"| MT3
    PA2 -->|"substrate engineering track overlaps with"| KE5
    PA3 -->|"genotype -> compound selection -> home/community-biolab production -> Tier 2 QC -> dose -> track"| AM4
    PA3 -->|"operational instantiation of rigorous-but-accessible principle"| DE17
    PA4 -->|"comp-005->comp-034->section1.10 pattern for structured-mandatory linkers"| KE3
    PA4 -->|"classify vulnerability as structural-mandatory vs structural-removable"| CH12

    %% Cannabinoid/terpene relationships
    M1 -->|"P2X7/NF-kB"| C2
    M2 -->|"CB2/TLR4/NLRP3 — MSU gout model"| C2
    M2 -->|"CB2 agonism — neutrophil block"| C1
    M3 -->|"NF-kB/MAPK — CIA arthritis"| C2
    M3 -->|"CBG colitis data"| B3
    M4 -->|"CB2 agonism (Ki 7.5 nM)"| C2
    M1 -->|"barrier support"| H1
    M5 -->|"Nrf2 + TLR4 suppression — MSU rat 50 mg/kg"| C2
    M5 -->|"NF-kB priming block"| C1

    %% Styling
    style Core fill:#ffe6e6
    style Problem fill:#fff0e6
    style Immune fill:#ffe6cc
    style Host_Enzyme fill:#e6f3ff
    style Platform fill:#e6ffe6
    style Delivery fill:#f0e6ff
    style Mechanism fill:#ffe6f0
    style Barrier fill:#f0f0f0
    style Peptides fill:#e6f9ff
    style Inhibitors fill:#fff9e6
    style Metabolic fill:#e6ffe6
    style Cannabinoids fill:#e6f0e6
    style Clinical fill:#f0e6ff
    style Parallel_Path fill:#fff0f5
    style Complement fill:#ffe0ee
    style Resolution fill:#e0efff
    style TNFSF14_arm fill:#fff5cc
    style MultiCP fill:#f0ffe0
    style Androgens fill:#e8d8f0
    style PRPS_arm fill:#fff0e0
    style DiscoveryEngine fill:#fff8e6
    style KojiEndgame fill:#e6fff0
    style Chaperones fill:#e6f0ff
    style MushroomTrack fill:#f5e6ff
    style EnzymeQC fill:#e6fff5

Key Pathway Descriptions

1. Pathology → Immune Activation Loop

  • Hyperuricemia → MSU crystal formation → NLRP3 activation → IL-1β cascade → acute gout flare
  • Enzyme deficits → poor luminal digestion → dysbiosis + barrier erosion → SIBO

2. Uricase Platform Loop

  • Host loses uricase ~15M years ago → hyperuricemia endemic
  • Engineer S. cerevisiae or A. oryzae with uricase gene
  • Ferment at home → colonize gut lumen
  • Degradation in situ → uric acid ↓ → MSU crystals prevented

3. Barrier Repair + Immunomodulation

  • BPC-157 + KPV → tight-junction integrity
  • Integrity → reduced inflammatory translocation
  • Reduced NLRP3 priming + oridonin/disulfiram for inflammasome block = dual suppression

4. Metabolic Synergy

  • BHB (ketones) → NLRP3 inhibition + probiotic fitness
  • Engineered strains (engineered S. cerevisiae/A. oryzae) outcompete pathogens
  • Prevents SIBO; supports barrier homeostasis

5. Combinatorial Stack (Full Gout Resolution)

Engineered Uricase (S. cerevisiae)
    ↓
Gut-Lumen Sink (enzymatic uric acid ↓)
    ↓
BPC-157 (barrier repair)
    ↓
Oridonin (NLRP3 direct inhibition)
    ↓
BHB (metabolic support + probiotic advantage)
    ↓
**Complete flare prevention + remission**

Reading the Graph

  • Boxes = Concepts (conditions, molecules, mechanisms, platforms)
  • Arrows = Causal or mechanistic relationships
  • Colors = Domains (pathology=red, immune=orange, platform=green, etc.)
  • Subgraphs = Grouped by functional domain for easier navigation

High-Level Dependencies

Must-Have (Gout): - Uricase platform (S. cerevisiae or A. oryzae) - Gut-lumen sink mechanism - NLRP3 inhibition (any of: oridonin, disulfiram, or dietary BHB)

Enhanced (Barrier + Metabolic): - BPC-157 or KPV (barrier repair) - BHB (ketogenic state or supplementation) - Probiotic advantage via metabolic modulation

For EPI: - Engineered A. oryzae with multi-enzyme expression (lipase, protease, amylase) - Same barrier repair stack (BPC-157 + BHB) - SIBO prevention via microbiome management

See wiki/INDEX.md for detailed concept pages.
See docs/ folder for full research citations and methodology.