Research Notes on
Nattokinase
Nattokinase
 |  |  |  |
What Is Nattokinase?
Nattokinase is a potent fibrinolytic enzyme extracted and highly purified
from a traditional Japanese food called Natto. Natto is a fermented
cheese-like food that has been used in Japan for over 1000 years for its
popular taste and as a folk remedy for heart and vascular diseases. Natto
is produced by a fermentation process by adding Bacillus natto, a benefical
bacteria, to boiled soybeans. The resulting nattokinase enzyme, is
produced when Bacillus natto acts on the soybeans. While other soy foods
contain enzymes, it is only the natto preparation that contains the specific
nattokinase enzyme.
The Discovery of Nattokinase and Its Potential Benefits
Many years ago, Sumi H and co-workers noticed a strong fibrinolytic activity
in the vegetable cheese Natto; Natto is a typical Japanese soybean food.
The average activity was at about 40 CU (plasmin units)/g wet weight. They
found that it was easy to extract this novel fibrinolytic enzyme nattokinase
with saline. The mol. wt and pI were about 20,000 and 8.6, respectively.
They found that nattokinase digested fibrin and also the plasmin substrate
H-D-Val-Leu-Lys-pNA (S-2251). Diisopropyl fluorophosphate and
2,2,2-trichloro-1-hydroxyethyl-o,o-dimethylphosphate strongly inhibited this
fibrinolytic enzyme. [1] Sumi H and co-workers further discovered that oral
administration of natto produced a mild and frequent enhancement of the
fibrinolytic activity in the plasma. To demonstrate its health benefits, they
administered natto capsules to dogs, then, they observed induced
thrombosis, and lysis of the thrombi. They concluded that natto might
benefit people who were suffered from embolism and it might have benefits
of preventing the disease. [2]
In 1993, another group of researchers in Japan purified nattokinase from
the vegetable cheese natto. They extracted nattokinase from natto with
saline and then isolated it by sequential use of hydrophobic
chromatography on Butyl-Toyopearl, ion-exchange chromatography on
CM-Toyopearl, and gel-filtration on Sephadex G-50. They found that the
isolated peptide consisted of a total 275 amino acid residues (M.W =
27,728) and exhibited a high homology with the subtilisins. The purified
nattokinase digested not only fibrin but also several synthetic substrates.
Among the synthetic substrates, the most sensitive substrate was
Suc-Ala-Ala-Pro-Phe-pNA for subtilisin. The results indicate that
nattokinase is a subtilisin-like serine protease. [3] Fujita M et al found that
intraduodenal administration of nattokinase at a dose of 80 mg/kg, resulted
in the degradation of fibrinogen in plasma suggesting transport of
nattokinase across the intestinal tract in normal rats. [4]
Fujita M et al also studied the thrombolytic effect of nattokinase on a
thrombus in the common carotid artery of rat in which the endothelial cells
of the vessel wall were injured by acetic acid. When they stained a section
of occluded vessel for CD61 antigen by immunofluorescence utilizing a
monoclonal antibody, they found antigens around the surface of the
occluded blood vessels. This result suggested that platelet aggregation
caused the occlusive thrombosis. However, when urokinase or tissue
plasminogen activator was added to their model, they observed the
restoration of the blood flow. The results indicate that their model is able to
evaluate a thrombolytic agent. Thus, they used this model to evaluate the
thrombolytic activity of nattokinase And, they found that the thrombolytic
activity of nattokinase is even stronger than that of plasmin or elastase
based on this in vitro study. [5]
Suzuki Y et al investigated the effect of natto extracts produced from
fermented soybeans on intimal thickening of arteries after vessel
endothelial denudation. Natto extracts include nattokinase, a potent
fibrinolytic enzyme having four times greater fibrinolytic activity than
plasmin. They induced intimal thickening in the femoral arteries by
intravenous infusion of rose bengal and then by focal irradiation with a
transluminal green light. They started the dietary natto extract
supplementation 3 weeks before endothelial injury and continued the
supplementation for another 3 weeks after. In ex vivo studies, they
measured euglobulin clot lysis times 3 weeks after the initial
supplementation. They successfully initiated neointima formation and
thickening. The intima media ratio 3 wk after endothelial injury was 0.15 +/-
0.03 in the control group. Dietary natto extract supplementation suppressed
intimal thickening compared with the control group. Natto extracts also
shortened euglobulin clot lysis time. These findings showed that natto
extracts suppressed intimal thickening after vascular injury as a result of
the inhibition of mural thrombi formation. [6] Suzuki Y et al further
investigated the effects of dietary supplementation with natto-extracts on
neointima formation and on thrombolysis at the site of endothelial injury.
They induced endothelial damage in the rat femoral artery by intravenous
injection of rose bengal then by focal irradiation and transluminal green
light. They started dietary natto-extracts supplementation containing
nattokinase 3 weeks before endothelial injury and then continued for
another 3 weeks. They found suppression of intimal thickening in animals
given supplementation compared to the controls. Although femoral arteries
were reopened both in control animals and those treated with nattokinase
within 8 hours after endothelial injury, they observed mural thrombi at the
site of endothelial injury. In the control group, the center of vessel lumen
was reopened and mural thrombi were attached on the surface of vessel
walls. In contrast, in nattokinase -treated groups, thrombi near the vessel
wall showed lysis and most of them detached from the surface of vessel
walls. In conclusion, dietary natto-extracts supplementation suppressed
intimal thickening produced by endothelial injury in rat femoral artery.
These effects may partially be attributable to nattokinase, which showed
enhanced thrombolysis near the vessel wall. [7]
WHAT DOES A TYPICAL COMMERCIAL PRODUCT CONTAIN?
In most brands of Nottokinase supplements, a serving of Nattokinase
provides 2000 FU (Fibrinolytic Units).
DOES OTHER FERMENTED SOYBEAN PRODUCT ALSO CONTAIN A
FIBRINOLYTIC ENZYME?
KOREAN FERMENTED-SOYBEAN SAUCE Bacillus sp. strain CK 11-4,
which produces a strongly fibrinolytic enzyme, was screened from
Chungkook-Jang, a traditional Korean fermented-soybean sauce. The
fibrinolytic enzyme (CK) was purified from supernatant of Bacillus sp. strain
CK 11-4 culture broth and showed thermophilic, hydrophilic, and strong
fibrinolytic activity. [8]
TAIWAN SOY PRODUCT A mutant of Bacillus subtilis IMR-NK1, which is
used for the production of fermented soy food in Taiwan, produced high
fibrinolytic enzyme activity by solid-state fermentation using wheat bran as
medium in a study. [9]
CHINESE FERMENTED SOYBEAN FOOD Bacillus amyloliquefaciens DC-4,
which produces a strongly fibrinolytic enzyme, was isolated from douchi, a
traditional Chinese soybean-fermented food. A fibrinolytic enzyme (subtilisin
DFE) was purified from the supernatant of B. amyloliquefaciens DC-4
culture broth and displayed thermophilic, hydrophilic and strong fibrinolytic
activity. Subtilisin DFE has molecular mass of 28000 Da and a pI of 8.0.
The optimal pH value and temperature for activities were 9.0 and 48
degrees C, respectively. Subtilisin DFE not only hydrolyzed fibrin but also
several synthetic substrates, particularly Suc-Ala-Ala-Pro-Phe-pNA, and
phenylmethylsulfony fluoride can completely inhibit its fibrinolytic activity.
These results indicated that subtilisin DFE is a subtilisin-family serine
protease, similar to nattokinase from Bacillus natto. The first 24 amino acid
residues of the N-terminal sequence of subtilisin DFE were
AQSVPYGVSQIKAPALHSQGFTGS, which is identical to that of subtilisin
K-54, and different from that of NK and CK. [10]
ARE THERE OTHER SOURCES OF NATTOKINASE-LIKE FIBRINOLYTIC
ENZYMES?
Two fibrinolytic enzymes (QK-1 and QK-2) purified from the supernatant of
Bacillus subtilis QK02 culture broth had molecular masses of 42,000 Da
and 28,000 Da, respectively. The first 20 amino acids of the N-terminal
sequence are AQSVPYGISQ IKAPALHSQG. The deduced protein
sequence and its restriction enzyme map of the enzyme QK-2 are different
from those of other proteases. The enzyme QK-2 digested not only fibrin
but also a subtilisin substrate, and PMSF inhibited its fibrinolytic and
amidolytic activities completely; while QK-1 hydrolyzed fibrin and a plasmin
substrate, and PMSF as well as aprotinin inhibited its fibrinolytic activity.
Researchers also found that Asp32, His64 and Ser221 in the amino acid
sequence deduced from the QK gene are identical to the active site of
nattokinase (NK) produced by B. subtilis natto. [11]
WHAT ARE THE SIDE EFFECTS OF NATTOKINASE?
Most traditional Asian fermented soy food e.g. natto has been used safely
for over 1000 years. Nattokinase appears to be safe without serious side
effects based upon the long-term traditional use of this food.
However, those with blood coagulation disorders or those currently taking
any anti-coagulant (blood-thinning) medications, please consult a health
practitioner prior to use.
REFERENCE
[1] Sumi H et al, A novel fibrinolytic enzyme (nattokinase) in the vegetable cheese Natto;
a typical and popular soybean food in the Japanese diet. Experientia. 1987 Oct
15;43(10):1110-1. [2] Enhancement of the fibrinolytic activity in plasma by oral
administration of nattokinase. Acta Haematol. 1990;84(3):139-43. [3] Fujita M et al,
Purification and characterization of a strong fibrinolytic enzyme (nattokinase) in the
vegetable cheese natto, a popular soybean fermented food in Japan. Biochem Biophys
Res Commun. 1993 Dec 30;197(3):1340-7. [4] Transport of nattokinase across the rat
intestinal tract. Biol Pharm Bull. 1995 Sep;18(9):1194-6. [5] Thrombolytic effect of
nattokinase on a chemically induced thrombosis model in rat. Biol Pharm Bull. 1995
Oct;18(10):1387-91. [6] Suzuki Y et al, Dietary supplementation with fermented
soybeans suppresses intimal thickening. Nutrition. 2003 Mar;19(3):261-4. [7] Dietary
supplementation of fermented soybean, natto, suppresses intimal thickening and
modulates the lysis of mural thrombi after endothelial injury in rat femoral artery. Life
Sci. 2003 Jul 25;73(10):1289-98. [8] Kim W, Choi K, Kim Y, Park H, Choi J, Lee Y, Oh H,
Kwon I, Lee S. Purification and characterization of a fibrinolytic enzyme produced from
Bacillus sp. strain CK 11-4 screened from Chungkook-Jang. Appl Environ Microbiol
1996 Jul;62(7):2482-8. [9] Chang CT, Fan MH, Kuo FC, Sung HY. Potent fibrinolytic
enzyme from a mutant of Bacillus subtilis IMR-NK1. J Agric Food Chem 2000
Aug;48(8):3210-6. 10. Peng Y et al, Purification and characterization of a fibrinolytic
enzyme produced by Bacillus amyloliquefaciens DC-4 screened from douchi, a
traditional Chinese soybean food. Comp Biochem Physiol B Biochem Mol Biol. 2003
Jan;134(1):45-52. [11] Ko JH et al, Identification of two novel fibrinolytic enzymes from
Bacillus subtilis QK02. Comp Biochem Physiol C Toxicol Pharmacol. 2004
Jan;137(1):65-74.
Nattokinase is a potent fibrinolytic enzyme extracted and highly purified
from a traditional Japanese food called Natto. Natto is a fermented
cheese-like food that has been used in Japan for over 1000 years for its
popular taste and as a folk remedy for heart and vascular diseases. Natto
is produced by a fermentation process by adding Bacillus natto, a benefical
bacteria, to boiled soybeans. The resulting nattokinase enzyme, is
produced when Bacillus natto acts on the soybeans. While other soy foods
contain enzymes, it is only the natto preparation that contains the specific
nattokinase enzyme.
The Discovery of Nattokinase and Its Potential Benefits
Many years ago, Sumi H and co-workers noticed a strong fibrinolytic activity
in the vegetable cheese Natto; Natto is a typical Japanese soybean food.
The average activity was at about 40 CU (plasmin units)/g wet weight. They
found that it was easy to extract this novel fibrinolytic enzyme nattokinase
with saline. The mol. wt and pI were about 20,000 and 8.6, respectively.
They found that nattokinase digested fibrin and also the plasmin substrate
H-D-Val-Leu-Lys-pNA (S-2251). Diisopropyl fluorophosphate and
2,2,2-trichloro-1-hydroxyethyl-o,o-dimethylphosphate strongly inhibited this
fibrinolytic enzyme. [1] Sumi H and co-workers further discovered that oral
administration of natto produced a mild and frequent enhancement of the
fibrinolytic activity in the plasma. To demonstrate its health benefits, they
administered natto capsules to dogs, then, they observed induced
thrombosis, and lysis of the thrombi. They concluded that natto might
benefit people who were suffered from embolism and it might have benefits
of preventing the disease. [2]
In 1993, another group of researchers in Japan purified nattokinase from
the vegetable cheese natto. They extracted nattokinase from natto with
saline and then isolated it by sequential use of hydrophobic
chromatography on Butyl-Toyopearl, ion-exchange chromatography on
CM-Toyopearl, and gel-filtration on Sephadex G-50. They found that the
isolated peptide consisted of a total 275 amino acid residues (M.W =
27,728) and exhibited a high homology with the subtilisins. The purified
nattokinase digested not only fibrin but also several synthetic substrates.
Among the synthetic substrates, the most sensitive substrate was
Suc-Ala-Ala-Pro-Phe-pNA for subtilisin. The results indicate that
nattokinase is a subtilisin-like serine protease. [3] Fujita M et al found that
intraduodenal administration of nattokinase at a dose of 80 mg/kg, resulted
in the degradation of fibrinogen in plasma suggesting transport of
nattokinase across the intestinal tract in normal rats. [4]
Fujita M et al also studied the thrombolytic effect of nattokinase on a
thrombus in the common carotid artery of rat in which the endothelial cells
of the vessel wall were injured by acetic acid. When they stained a section
of occluded vessel for CD61 antigen by immunofluorescence utilizing a
monoclonal antibody, they found antigens around the surface of the
occluded blood vessels. This result suggested that platelet aggregation
caused the occlusive thrombosis. However, when urokinase or tissue
plasminogen activator was added to their model, they observed the
restoration of the blood flow. The results indicate that their model is able to
evaluate a thrombolytic agent. Thus, they used this model to evaluate the
thrombolytic activity of nattokinase And, they found that the thrombolytic
activity of nattokinase is even stronger than that of plasmin or elastase
based on this in vitro study. [5]
Suzuki Y et al investigated the effect of natto extracts produced from
fermented soybeans on intimal thickening of arteries after vessel
endothelial denudation. Natto extracts include nattokinase, a potent
fibrinolytic enzyme having four times greater fibrinolytic activity than
plasmin. They induced intimal thickening in the femoral arteries by
intravenous infusion of rose bengal and then by focal irradiation with a
transluminal green light. They started the dietary natto extract
supplementation 3 weeks before endothelial injury and continued the
supplementation for another 3 weeks after. In ex vivo studies, they
measured euglobulin clot lysis times 3 weeks after the initial
supplementation. They successfully initiated neointima formation and
thickening. The intima media ratio 3 wk after endothelial injury was 0.15 +/-
0.03 in the control group. Dietary natto extract supplementation suppressed
intimal thickening compared with the control group. Natto extracts also
shortened euglobulin clot lysis time. These findings showed that natto
extracts suppressed intimal thickening after vascular injury as a result of
the inhibition of mural thrombi formation. [6] Suzuki Y et al further
investigated the effects of dietary supplementation with natto-extracts on
neointima formation and on thrombolysis at the site of endothelial injury.
They induced endothelial damage in the rat femoral artery by intravenous
injection of rose bengal then by focal irradiation and transluminal green
light. They started dietary natto-extracts supplementation containing
nattokinase 3 weeks before endothelial injury and then continued for
another 3 weeks. They found suppression of intimal thickening in animals
given supplementation compared to the controls. Although femoral arteries
were reopened both in control animals and those treated with nattokinase
within 8 hours after endothelial injury, they observed mural thrombi at the
site of endothelial injury. In the control group, the center of vessel lumen
was reopened and mural thrombi were attached on the surface of vessel
walls. In contrast, in nattokinase -treated groups, thrombi near the vessel
wall showed lysis and most of them detached from the surface of vessel
walls. In conclusion, dietary natto-extracts supplementation suppressed
intimal thickening produced by endothelial injury in rat femoral artery.
These effects may partially be attributable to nattokinase, which showed
enhanced thrombolysis near the vessel wall. [7]
WHAT DOES A TYPICAL COMMERCIAL PRODUCT CONTAIN?
In most brands of Nottokinase supplements, a serving of Nattokinase
provides 2000 FU (Fibrinolytic Units).
DOES OTHER FERMENTED SOYBEAN PRODUCT ALSO CONTAIN A
FIBRINOLYTIC ENZYME?
KOREAN FERMENTED-SOYBEAN SAUCE Bacillus sp. strain CK 11-4,
which produces a strongly fibrinolytic enzyme, was screened from
Chungkook-Jang, a traditional Korean fermented-soybean sauce. The
fibrinolytic enzyme (CK) was purified from supernatant of Bacillus sp. strain
CK 11-4 culture broth and showed thermophilic, hydrophilic, and strong
fibrinolytic activity. [8]
TAIWAN SOY PRODUCT A mutant of Bacillus subtilis IMR-NK1, which is
used for the production of fermented soy food in Taiwan, produced high
fibrinolytic enzyme activity by solid-state fermentation using wheat bran as
medium in a study. [9]
CHINESE FERMENTED SOYBEAN FOOD Bacillus amyloliquefaciens DC-4,
which produces a strongly fibrinolytic enzyme, was isolated from douchi, a
traditional Chinese soybean-fermented food. A fibrinolytic enzyme (subtilisin
DFE) was purified from the supernatant of B. amyloliquefaciens DC-4
culture broth and displayed thermophilic, hydrophilic and strong fibrinolytic
activity. Subtilisin DFE has molecular mass of 28000 Da and a pI of 8.0.
The optimal pH value and temperature for activities were 9.0 and 48
degrees C, respectively. Subtilisin DFE not only hydrolyzed fibrin but also
several synthetic substrates, particularly Suc-Ala-Ala-Pro-Phe-pNA, and
phenylmethylsulfony fluoride can completely inhibit its fibrinolytic activity.
These results indicated that subtilisin DFE is a subtilisin-family serine
protease, similar to nattokinase from Bacillus natto. The first 24 amino acid
residues of the N-terminal sequence of subtilisin DFE were
AQSVPYGVSQIKAPALHSQGFTGS, which is identical to that of subtilisin
K-54, and different from that of NK and CK. [10]
ARE THERE OTHER SOURCES OF NATTOKINASE-LIKE FIBRINOLYTIC
ENZYMES?
Two fibrinolytic enzymes (QK-1 and QK-2) purified from the supernatant of
Bacillus subtilis QK02 culture broth had molecular masses of 42,000 Da
and 28,000 Da, respectively. The first 20 amino acids of the N-terminal
sequence are AQSVPYGISQ IKAPALHSQG. The deduced protein
sequence and its restriction enzyme map of the enzyme QK-2 are different
from those of other proteases. The enzyme QK-2 digested not only fibrin
but also a subtilisin substrate, and PMSF inhibited its fibrinolytic and
amidolytic activities completely; while QK-1 hydrolyzed fibrin and a plasmin
substrate, and PMSF as well as aprotinin inhibited its fibrinolytic activity.
Researchers also found that Asp32, His64 and Ser221 in the amino acid
sequence deduced from the QK gene are identical to the active site of
nattokinase (NK) produced by B. subtilis natto. [11]
WHAT ARE THE SIDE EFFECTS OF NATTOKINASE?
Most traditional Asian fermented soy food e.g. natto has been used safely
for over 1000 years. Nattokinase appears to be safe without serious side
effects based upon the long-term traditional use of this food.
However, those with blood coagulation disorders or those currently taking
any anti-coagulant (blood-thinning) medications, please consult a health
practitioner prior to use.
REFERENCE
[1] Sumi H et al, A novel fibrinolytic enzyme (nattokinase) in the vegetable cheese Natto;
a typical and popular soybean food in the Japanese diet. Experientia. 1987 Oct
15;43(10):1110-1. [2] Enhancement of the fibrinolytic activity in plasma by oral
administration of nattokinase. Acta Haematol. 1990;84(3):139-43. [3] Fujita M et al,
Purification and characterization of a strong fibrinolytic enzyme (nattokinase) in the
vegetable cheese natto, a popular soybean fermented food in Japan. Biochem Biophys
Res Commun. 1993 Dec 30;197(3):1340-7. [4] Transport of nattokinase across the rat
intestinal tract. Biol Pharm Bull. 1995 Sep;18(9):1194-6. [5] Thrombolytic effect of
nattokinase on a chemically induced thrombosis model in rat. Biol Pharm Bull. 1995
Oct;18(10):1387-91. [6] Suzuki Y et al, Dietary supplementation with fermented
soybeans suppresses intimal thickening. Nutrition. 2003 Mar;19(3):261-4. [7] Dietary
supplementation of fermented soybean, natto, suppresses intimal thickening and
modulates the lysis of mural thrombi after endothelial injury in rat femoral artery. Life
Sci. 2003 Jul 25;73(10):1289-98. [8] Kim W, Choi K, Kim Y, Park H, Choi J, Lee Y, Oh H,
Kwon I, Lee S. Purification and characterization of a fibrinolytic enzyme produced from
Bacillus sp. strain CK 11-4 screened from Chungkook-Jang. Appl Environ Microbiol
1996 Jul;62(7):2482-8. [9] Chang CT, Fan MH, Kuo FC, Sung HY. Potent fibrinolytic
enzyme from a mutant of Bacillus subtilis IMR-NK1. J Agric Food Chem 2000
Aug;48(8):3210-6. 10. Peng Y et al, Purification and characterization of a fibrinolytic
enzyme produced by Bacillus amyloliquefaciens DC-4 screened from douchi, a
traditional Chinese soybean food. Comp Biochem Physiol B Biochem Mol Biol. 2003
Jan;134(1):45-52. [11] Ko JH et al, Identification of two novel fibrinolytic enzymes from
Bacillus subtilis QK02. Comp Biochem Physiol C Toxicol Pharmacol. 2004
Jan;137(1):65-74.
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Eleuthero
Ellagic Acid
Eve. Primrose Oil
Fish Oil
Flaxseed
Garlic
Ginger
Ginseng
Ginkgo Biloba
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Polycosanol
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THIS WEBSITE TALKS ABOUT THE SIDE EFFECTS AND THE POTENTIAL HEALTH BENEFITS OF HERBS, SUPPLEMENTS,
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DOCTOR IMMEDIATELY. ALL RIGHTS RESERVED 2008. DO NOT COPY NOR TRANSFER ARTICLES TO OTHER WEBSITES NOR OTHER
FORMS OF PUBLICATIONS. Privacy Policy. ARTICLE INDEX
PHYTONUTRIENTS AND DRUG PRODUCTS. THIS WEBSITE ALSO TALKS ABOUT SOME POPULAR HEALTH ISSUES AND DISEASES.
ARTICLES IN THIS WEB SITE IS FOR YOUR REFERENCE ONLY. IF YOU HAVE ANY QUESTION, YOU SHOULD CONSULT WITH YOUR
DOCTOR IMMEDIATELY. ALL RIGHTS RESERVED 2008. DO NOT COPY NOR TRANSFER ARTICLES TO OTHER WEBSITES NOR OTHER
FORMS OF PUBLICATIONS. Privacy Policy. ARTICLE INDEX
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