Discovery and Origin of Nattokinase

Historical Background

Natto originated in China during the Qin and Han dynasties, and was introduced to Japan during the Tang Dynasty where it evolved into its modern form. In 1980, Japanese scientist Dr. Yukimasa Sumi discovered the powerful thrombolytic properties of natto fermentation products at the University of Chicago Medical School. The active substance isolated was named nattokinase.

Production Process

Nattokinase is a serine protease secreted by Bacillus subtilis during natto fermentation. It exists primarily in this traditional fermented  food.

Molecular Structure and Physicochemical Properties

Molecular Structure

Mature nattokinase consists of 275 amino acids as a single-chain polypeptide without disulfide bonds. Its full-length gene sequence is 1473bp, with the N-terminal 29 amino acids forming a signal peptide, residues 30-106 composing a propeptide, the 352-amino acid without signal peptide as the zymogen of nattokinase.

Physicochemical Properties

Nattokinase appears as a white/yellowish solid with no odor, soluble in water. It has an isoelectric point of 8.6±0.3, remaining stable at pH 7-12 (optimal activity at pH 7-9). While degraded in gastric acid, it remains stable in the small intestine. Activity stays stable below 45°C, decreasing above 60°C, and retains 95% activity after 5 freeze-thaw cycles.

Physiological Functions

Thrombolytic Effect

Nattokinase dissolves existing thrombi and prevents new clot formation as an efficient and safe fibrinolytic enzyme. It activates plasminogen through urokinase stimulation, directly hydrolyzes fibrin, improves blood viscosity, and enhances vascular elasticity.

Antihypertensive Properties 

By degrading plasma fibrin and inhibiting angiotensin II elevation, nattokinase helps prevent and treat hypertension.

Gastrointestinal Regulation

Produced by natto bacteria, nattokinase promotes beneficial anaerobic gut bacteria growth while inhibiting harmful aerobic bacteria, maintaining stability in intestinal environments.

Additional Benefits

Nattokinase also aids in treating cardiovascular diseases, anti-atherosclerosis, lipid-lowering, neuroprotection against Alzheimer's,      chronic sinusitis treatment, and regulation of oxidative stress injury and retinal neovascularization.

Preparation and Purification

Production Methods

Solid-state fermentation

Uses soybean as raw material, simple equipment with low cost but difficult for parameter monitoring and scale-up.

Liquid fermentation

Employs submerged culture technology, enabling homogeneous mass transfer, automated processes, and easier scale-up for industrial production.

Purification Techniques

Common methods include column chromatography (high recovery but complex), ultrafiltration (activity-preserving but lower purity), extraction (aqueous two-phase or reverse micelle methods with high selectivity), and expanded bed adsorption (direct recovery from fermentation broth).

Application Fields

Pharmaceutical Industry:  Used as dietary supplements in capsule, tablet, powder, or liquid forms (e.g., Nattokinase Capsules, Natto Extract Tablets) for thrombolysis, lipid-lowering, and cardiovascular disease prevention.

Food Industry:  Serves as a natural food additive. Freeze-dried natto powder recommended by EFSA (2016) as a food supplement with a maximum daily intake of 100 mg (2000-2800 FU/day).