Nattokinase

Overview

• Nattokinase is a serine‑protease enzyme produced during the fermentation of soybeans with Bacillus natto, the bacterium that creates the traditional Japanese food “natto.”
• In nutraceutical form, it is marketed primarily for its fibrinolytic (blood‑clot‑dissolving) activity.
• It may help maintain normal vascular function and support cardiovascular health.

Benefits

• Cardiovascular Health: Reduces plasma fibrinogen levels and enhances clot lysis, supporting cardiovascular health and reducing the risk of thrombosis.
• Blood Pressure Support: Modestly improves blood pressure, likely through enhanced endothelial nitric oxide production and reduced arterial stiffness.
• Cerebrovascular Circulation: Supports cerebrovascular circulation, which may aid cognitive function in older adults by preserving microvascular flow.
• Anti-inflammatory Effects: Exhibits anti-inflammatory effects by down-regulating NF-κB and cytokine release, potentially benefiting metabolic syndrome.
• Fibrinolytic Capacity: Enhances fibrinolytic capacity without affecting platelet count, offering a safer alternative to traditional anticoagulants for low-to-moderate risk individuals.
• Evidence: The bulk of evidence comes from randomized controlled trials (RCTs) of 2–6 months duration and meta-analyses of ≥10 studies.
• Effect Sizes: Effect sizes range from small (BP – 4–6 mm Hg systolic reduction) to moderate (fibrinogen reduction 15–20 %).

How It Works

• Fibrinolysis: Nattokinase (NK) is a 28 kDa serine protease that preferentially cleaves fibrin at the α- and β-chains, directly degrading fibrin clots (fibrinolysis) and accelerating endogenous plasminogen activation.
• Additional Actions: Hydrolyzes fibrinogen, reduces plasma viscosity, and modestly activates tissue-type plasminogen activator (t-PA) while inhibiting plasminogen activator inhibitor-1 (PAI-1).
• Thrombus Reduction: By lowering circulating fibrinogen and enhancing plasmin activity, NK reduces thrombus formation.
• Other Pathways:
  • Up-regulation of endothelial nitric-oxide synthase (eNOS) → increased NO → vasodilation.
  • Suppression of the NF-κB pathway → lower pro-inflammatory cytokines (IL-6, TNF-α).
• Overall Effects: These combined actions improve vascular compliance, reduce platelet aggregation, and may protect microcirculation.

Dosage

• Typical Dosage: Most human trials have used 2,000–4,000 FU (fibrinolytic units) per day.
• Dosage Regimen: Typically divided into two doses (e.g., 2,000 FU in the morning and 2,000 FU in the evening).
• Blood Pressure Support: Lower doses (500–1,000 FU) are often used for blood pressure support.
• Acute Thrombotic Risk: Higher doses (up to 10,000 FU) have been examined for acute thrombotic risk under medical supervision.
• Administration: The enzyme is acid-stable; capsules are usually taken with food to minimize gastric irritation, though some formulations advise empty-stomach intake for optimal absorption.
• Special Populations: For individuals on anticoagulants or with bleeding disorders, a reduced dose (1,000–1,500 FU) is recommended, with physician oversight.
• Study Duration: Duration in studies ranges from 4 weeks (short-term safety) to 12 months (long-term efficacy).

Safety & Side Effects

• General Tolerance: Nattokinase is generally well-tolerated at ≤10,000 FU/day.
• Adverse Events: Mild adverse events (gastro-intestinal discomfort, mild headache) reported in <5 % of participants.
• Contraindications:
  • Active bleeding.
  • Recent surgery (<2 weeks).
  • Severe thrombocytopenia.
  • Known coagulation disorders.
• Drug Interactions: Major drug interactions involve anticoagulants (warfarin, direct oral anticoagulants, heparin) and antiplatelet agents (aspirin, clopidogrel), where additive anticoagulation can increase bleeding risk.
• Special Populations: Caution is advised for pregnant or lactating women due to insufficient safety data.
• Allergies: Individuals with soy allergy should avoid nattokinase derived from soy-based fermentation.
• Monitoring: Routine monitoring of PT/INR is recommended when combined with anticoagulants.

Chemistry

• Enzyme Type: Nattokinase (EC 3.4.21.107) is a single-chain serine protease belonging to the subtilisin family.
• Structure: Its mature form consists of 275 amino acids (≈27 kDa) with a catalytic triad of Asp-32, His-64, and Ser-221 (chymotrypsin-like).
• Primary Structure: MDSLGKYY... (full sequence available in UniProt P19121).
• IUPAC Name: The enzyme’s IUPAC name is not assigned (as it is a protein).
• Key Structural Features:
  • β-sheet core.
  • A calcium-binding site that stabilizes the active conformation.
  • An N-terminal leader peptide removed during maturation.
• Optimal Activity: The enzyme exhibits optimal activity at pH 7–9 and 37 °C, retaining >70 % activity after 2 h at 60 °C, which underlies its stability in supplement formulations.

Sources & Quality

• Source: Commercial nattokinase is extracted from Bacillus natto cultured in soy-bean fermentations.
• Production:
  • The fermentation broth is harvested.
  • The enzyme is purified by ammonium-sulphate precipitation, ion-exchange chromatography, and spray-drying.
  • Produces a powder with ≥2,000 FU/g.
• Recombinant Nattokinase: Some manufacturers produce recombinant nattokinase (rNK) using E. coli or Pichia pastoris expression systems to increase purity and reduce batch-to-batch variability.
• Quality Standards: Quality-grade supplements are required to meet GMP standards and contain <5 % heavy-metal contamination (per USP <231>) and no detectable soy protein allergens (if purified).
• Third-Party Testing: Third-party testing (e.g., NSF, USP) ensures activity claims (FU) match label, and ensures absence of microbial endotoxins.
• Recommendations: Selecting products with transparent certificates of analysis (COA) and a stable, acid-resistant capsule is recommended for optimal bioavailability.