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nattokinase, enzimes, fibrinolytic activity
The enzyme of enzymes -
Nattokinase
Townsend Letter for Doctors and Patients, Nov, 2002 by Nicholas Dr. Calvino
Recently a new metabolic, "biological" enzyme with potent fibrinolytic
activity, that rivals pharmaceutical agents, has been discovered and shows great
potential in providing support for hypercoagulative states and in supporting the
activation of many of the body's 3,000 endogenous enzymes. This all-natural
enzyme, Nattokinase (NK), is derived from a fermentation process of soy and the
bacteria Bacillus natto. Already, backed by convincing and novel research,
Nattokinase shows promise in supporting areas such as cardiovascular disease,
stroke, angina, venous stasis, thrombosis, emboli, atherosclerosis, fibromyalgia/chronic
fatigue, claudication, retinal pathology, hemorrhoid, varicose veins, soft
tissue rheumatisms, muscle spasm, poor healing, chronic inflammation and pain,
peripheral vascular disease, hypertension, tissue oxygen deprivation,
infertility, and other gynecology conditions (e.g. endometriosis, uterine
fibroids). To comprehend the magnitude of this new finding, a review of
biological enzymes is n ecessary.
Enzymes, the Fountain of Life
Biological enzymes are enzymes which regulate endogenous chemical processes and
have been called "the fountain of life" -- because without them, life
could not exist. These enzymes speed and regulate all chemical reactions in the
body in an orchestration of intelligence and control. Enzymes are made in the
body from proteins and are provided by the ingestion of enzyme rich foods.
During times of stress, sickness or reduced nutrient intake, the body can fall
behind in the demand for the constant upkeep and creation of enzymes. Luckily
the body has evolved to derive many of its enzymes from food, which helps to
reduce the burden of the high enzyme production needs. Unfortunately, however,
the enzyme content of foods has significantly decreased over the years due to
processing, soil depletion, refining and preservation techniques of the food
industry and a decreased consumption of fermented foods and fresh foods, which
are high in enzyme content. Enzymes are an essential component of the diet --
like vitamins, m inerals, phytonutrients, fat, protein, carbohydrates, etc. --
and without them, a deficiency state does occur. This deficiency state has been
linked by various researchers, such as Dr. Edward Howell, Dr. M. Wolf, Dr.
Francis Pottenger, Dr. Royal Lee, and Dr. Weston Price, to chronic disease,
accelerated aging and premature death. Enzymes function by activating vitamins
and minerals to forms usable by the body, by assisting in the liberation of
nutrients from food, by helping to destroy harmful microbial agents, by
signaling and regulating chemical processes (such as detoxification), and by
activating other enzymes and hormones (cleaving zymogens [right arrow] enzymes
and pro-hormones [right arrow] hormones).
There are three major groups of biological enzymes: (1) Food Enzymes, (2)
Digestive Enzymes and (3) Metabolic Enzymes. In the past, the therapeutic use of
enzymes has largely focused on the use of digestive enzymes. Digestive enzymes
can be directly beneficial because they assist in digestion, help regulate
immune responses in the intestinal tract, and relieve the body of its relative
requirement of digestive enzyme production, allowing for biological energy and
resources to be further allocated to the production of metabolic enzymes,
indirectly.
Until now, the nutritional use of enzyme supplements has been almost exclusively
in the form of Digestive Enzymes. Recently, however, a new Metabolic Enzyme has
been isolated from a traditional fermented Japanese food (although it is
consumed by other cultures in the same or similar forms), Natto, that appears to
have metabolic effects and to work directly in concert with the metabolic
enzymes. The name of this new enzyme is Nattokinase (meaning the enzyme from
Natto) and has been called, "The Enzyme of Enzymes" by its discoverer,
Dr. Hiroyuki Sumi. Natto has been used in Japanese culture 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
beneficial bacterium, to boiled soybeans. The resulting nattokinase enzyme, is
produced when Bacillus natto acts on the soybeans. Nattokinase has been the
subject of 17 studies, including two small human trials. Nattokinase's most
intriguing role promises to b e its involvement in coagulation homeostasis.
While other soy foods contain beneficial enzymes, it is only the natto
preparation that contains the specific nattokinase enzyme.
Coagulation Homeostasis Overview
To understand the impact of Nattokinase on coagulation, a review of coagulation
homeostasis and therapy is warranted. Some of the endogenous and exogenous
agents involved in coagulation homeostasis are Plasmin, Heparin, Coumarin/Warfarin,
and TPA. However, most of these agents either have limitations, and/or serious
side effects. A brief discussion on each:
* Plasmin is an endogenous protease that resembles trypsin (a digestive
protease), and is the activated form of plasminogen. It is able to digest fibrin
fibers, however, its limitation is that it is slowly activated, and therefore,
slow acting, and works better to dissolve small clots, rather than larger ones.
* Heparin is a drug given IV that acts as an anticoagulant by inhibiting
thrombin. Heparin is often associated with side effects, such as increased
bleeding and hemorrhage.
* Coumarin/Warfarin is a drug that works by competing with vitamin K for
reactive sites in the enzymatic process for the formation of prothrombin and
clotting factors, thereby blocking the clotting action of vitamin K.
* t-PA (Tissue Plasminogen Activator) is a "clot buster" that is
effective in activating plasminogen to plasmin. Although given as an IV drug,
this is also a naturally occurring substance produced endogenously, albeit in
much smaller amounts.
* Streptokinase is another enzyme, derived from beta-hemolytic streptococci,
which is used as a "clot buster." Its limitation is that its effect is
rather short lived and eventually its therapeutic efficiency declines.
In addition to serious side effects and limitations, the "clot
busters" lack true broad utility in that to be therapeutic, they must be
injected. Therefore, there has been a renewed interest in discovering and using
oral anti-clotting enzymes.
Fibrinolytic therapy by oral administration of enzymes was investigated by Sumi
and coworkers over 10 years ago in an animal model where enteric-coated
urokinase (UK) capsules were given to normal and experimental dogs with
saphenous vein thrombosis. Previous findings indicated that intravenous (IV)
administration did not show any clear thrombolytic effect, but that oral
administration enhanced the fibrinolytic activity, serving as a treatment to
lyse the thrombi in a mild but maintained way. The underlying mechanism of such
fibrinolytic therapy by oral administration was then confirmed by basic research
to involve absorption of the administered UK across the intestinal tract, and
release into the blood of endogenous plasminogen activator which originated from
the liver and/or endothelial cells. The enteric-coated UK capsules (60,000 U/day
for 7 days) also exhibited a clinical efficacy against cerebral thrombi.
Moreover, more effective results were obtained in double-blind tests at
multicenter trials employin g a dose of 120,000 U/day for 7 days. This supported
the idea that oral enzyme agents can and do have systemic fibrinolytic
properties, however, an oral fibrinolytic agent that had sustained activity and
minimal side-effects was further pursued.
Nattokinase was later discovered by Dr. Sumi and research has found it to be a
most promising agent as an ideal oral fibrinolytic agent -- not only reversing
clots but in preventing them and modulating the clotting process in ways that
help re-establish coagulation homeostasis. Nattokinase is a serine endopeptidase
with a molecular weight of 20,000 Daltons and a point of ionization (pI) of 8.6.
This isolated fibrinolytic enzyme, derived from a traditional Japanese food,
Natto, was discovered by Dr. Hiroyuki Sumi and resembles plasmin. Nattokinase is
derived from the vegetable cheese, Natto, a typical and popular fermented
soybean food in Japan. It shows potent fibrinolytic activity and was named
Nattokinase (NK) -- literally meaning, an enzyme derived from Natto. Dr.
Hiroyuki Sumi, while doing research work at the University of Chicago's Medical
School, conducted research on about 200 kinds of food, including several types
of liquors, from all over the world in search of natural substance that could
dissolve and even prevent blood clots. He found that Natto had the highest
fibrinolytic activity among all those foods tested. In 1986, Dr. Sumi presented
the results of his research in Japan for the first time.
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 (ISSN: 0024-3205)
Suzuki Y; Kondo K; Matsumoto Y; Zhao BQ; Otsuguro K; Maeda T; Tsukamoto Y; Urano
T; Umemura K
Department of Pharmacology, Hamamatsu University School of Medicine, 1-20-1
Handayama, Hamamatsu City, Shizuoka 431-3192, Japan. yapplel@hama-med.ac.jp.
We have previously demonstrated that natto-extracts containing nattokinase (NK)
inactivates plasminogen activator inhibitor type 1 and then potentiates
fibrinolytic activity. In the present study, we investigated the effects of
dietary supplementation with natto-extracts on neointima formation and on
thrombolysis at the site of endothelial injury. Endothelial damage in the rat
femoral artery was induced by intravenous injection of rose bengal followed by
focal irradiation by transluminal green light. Dietary natto-extracts
supplementation containing NK of 50 or 100 CU/body was started 3 weeks before
endothelial injury and then continued for another 3 weeks. Intimal thickening in
animals given supplementation was significantly (P<0.01) suppressed compared
with controls and the intima/media ratio in animals with 50 and 100 CU/body NK
and control group was 0.09 +/- 0.03, 0.09 +/- 0.06 and 0.16 +/- 0.12,
respectively. Although femoral arteries were reopened both in control animals
and those treated with NK within 8 hours after endothelial injury, mural thrombi
were histologically observed 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 NK-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 NK, which showed enhanced thrombolysis
near the vessel wall.
The profibrinolytic enzyme subtilisin NAT purified from Bacillus subtilis
Cleaves and inactivates plasminogen activator inhibitor type 1.
J Biol Chem 2001 Jul 6;276(27):24690-6 (ISSN: 0021-9258)
Urano T; Ihara H; Umemura K; Suzuki Y; Oike M; Akita S; Tsukamoto Y; Suzuki I;
Takada A
Department of Physiology, Hamamatsu University School of Medicine, 3600,
Handa-cho, Hamamatsu, 431-3192, Japan. uranot@hama-med.ac.jp.
In this report, we demonstrate an interaction between subtilisin NAT (formerly
designated BSP, or nattokinase), a profibrinolytic serine proteinase from
Bacillus subtilis, and plasminogen activator inhibitor 1 (PAI-1). Subtilisin NAT
was purified to homogeneity (molecular mass, 27.7 kDa) from a saline extract of
B. subtilis (natto). Subtilisin NAT appeared to cleave active recombinant
prokaryotic PAI-1 (rpPAI-1) into low molecular weight fragments. Matrix-assisted
laser desorption/ionization in combination with time-of-flight mass spectroscopy
and peptide sequence analysis revealed that rpPAI-1 was cleaved at its reactive
site (P1-P1': Arg(346)-Met(347)). rpPAI-1 lost its specific activity after
subtilisin NAT treatment in a dose-dependent manner (0.02-1.0 nm; half-maximal
effect at approximately 0.1 nm). Subtilisin NAT dose dependently (0.06-1 nm)
enhanced tissue-type plasminogen activator-induced fibrin clot lysis both in the
absence of rpPAI-1 (48 +/- 1.4% at 1 nm) and especially in the presence of
rpPAI-1 (78 +/- 2.0% at 1 nm). The enhancement observed in the absence of PAI-1
seems to be induced through direct fibrin dissolution by subtilisin NAT. The
stronger enhancement by subtilisin NAT of rpPAI-1-enriched fibrin clot lysis
seems to involve the cleavage and inactivation of active rpPAI-1. This mechanism
is suggested to be important for subtilisin NAT to potentiate fibrinolysis.
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