The polyamines are organic compounds having two or more primary amino groups - such as putrescine, cadaverine,spermidine, and spermine - that are growth factors in both eucaryotic and procaryotic cells. Though it is seen that polyamines are synthesized in cells via highly-regulated pathways, their actual function is not entirely clear. As cations, they do bind to DNA, and, in structure, they represent compounds with cations that are found at regularly-spaced intervals (unlike, say, Mg++ or Ca++, which are point charges).
If synthesis of polyamines is blocked, then cell growth is stopped or profoundly slowed. The provision of exogenous polyamines restores the growth of these cells.
Polyamines are also important modulators of a variety of ion channels, including NMDA receptors, AMPA receptors, and inwardly-rectifying, leak potassium channels.
The polyamines are part of a class of proteins called 'Biogenic Amines,' and are present in low concentrations in all human, animal and plant cells.
Polyamines are essential for the maintenance of the high metabolic activity of a normal functioning and healthy body. In addition to the intestine, all other organs of the body require polyamines for their growth, renewal and metabolism. So the first thing to realize when we consider the role of polyamines in the body is that the are widespread, ubiquitous, and essential in proper amounts for health and wellness.
All cell growth requires certain amounts of polyamines. They are also critical to the healthy function of the nervous system and the growth of young children, who as no surprise manufacture larger amounts of polyamines than adults.
Many sources refer to the polyamines as 'dead flesh proteins.' This is because when living tissue is shocked or dies, its protein structure 'cracks' open. Bacteria or enzymes contained in the food itself subsequently convert many of the protein fragments into polyamines. This is why polyamines are found in very high amounts in the tissues of severely injured trauma patients and in food which have been morphologically shocked by excessive processing, such as rapid freezing.
The concentration of polyamines inside the cell is tightly regulated. The range of cellular polyamine concentration is determined at the lower limit by their absolute requirement for cell growth, and at the upper limit by their potential toxicity.
Polyamines are both synthesized in the body, and are also derived form the diet, either in the form of foods which are in themselves high in polyamines, or by the action of the bacteria in the gut, synthesizing polyamines from dietary amino acids. These two methods are called 'exogenous' (outside manufacture by gut bacteria) and 'endogenous' (inside manufacture by the liver and other organs.)
Bacteria can produce polyamines by metabolizing amino acids found in the food. Many strains of bacteria are capable of manufacturing polyamines, including Bacillus, Clostridium, Enterobacteriaceae, Enterococcus, Klebsiella, Morganella, Proteus. Often the process of producing polyamines by bacteria begins long before the food is eaten! Frozen, canned and otherwise tainted foods are loaded with polyamines long before they hit the gut.
When manufactured by the body, polyamines are derived from the amino acid ornithene, through the actions of the enzyme ornithine decarboxylase (ODC). Almost all tissues can manufacture polyamines, but the liver makes the vast majority of them. In humans, the starting point of polyamine synthesis is the amino acid ornithine.
Ornithine is a 'non-essential' amino acid in the sense that the body can make ornithine from other amino acids through what is called the 'Ornithine Cycle.' This pathway converts either of two other amino acids, arginine or citrulline into ornithine through conversion into intermediates such as arginosuccinic acid. These highly controlled conversions are the result of a variety of specialized enzymes.
Arginine is one of the most versatile amino acids in animal cells, serving as a precursor for the synthesis not only of polyamines but also of proteins, nitric oxide, urea, proline, glutamate. Arginine critical for the synthesis of creatine, a major source of high energy phosphate for regeneration of energy production in muscle, and a favorite of body builders everywhere.
The Ornithine Cycle. The amino acid ornithene is 'non-essential' in the sense that it can be made from other amino acids, such as arginine or citrulline. Polyamine synthesis begins with the conversion of ornithene into the polyamine putrescine by the action of the enzyme ornithene decarboxylase (ODC)
From either citrulline or arginine we get to ornithene. From here we start making polyamines. The first polyamine to be made has the lovely name 'putrescine.' Putrescine is made from ornithine by the action of a very interesting enzyme called ornithine decarboxylase, or ODC.
Putrescine can then be converted to two other polyamines, spermine and spermidine, each of which has slightly different effects in the body. Because both spermidine and spermine are made from putrescine, and putrescine is made from the amino acid ornithene by the enzyme ornithene decarboxlase (ODC), blocking ODC is usually sufficient to block the synthesis of all three polyamines.
Polyamine synthesis. The amino acid ornithine (1) serves as the starting point for polyamine synthesis. It is converted to putrescine (2) by the actions of the enzyme ornithene de-carboxylase (3). From putrescine, the other polyamines spermidine (4) and spermine (5) can also be synthesized.
Interestingly, the production of arginosuccinic acid, a key intermediate in the production of ornithene (and thus a major factor in the synthesis of polyamines) is genetically linked to ABO blood type. The gene for the enzyme that manufactures arginosuccinic acid, called argininosuccinate synthase (ASS), lies adjacent to the ABO gene on 9q34 and studies have shown their linkage to strongly correlate.
Effects on cell growth
Basically, polyamines make things grow; hence they are essential to cellular proliferation and differentiation. Kids have high polyamines; bodybuilders think they need high levels as well. It was believed that most of the polyamines needed for growth were synthesized in the gut. However, recent work has shown that polyamines accumulated in the small bowel are largely obtained from the food consumed in our diet.
Just exactly how polyamines stimulate growth is far from clear. What we do know is that they have a profound stabilizing effect on a cell's genetic material (DNA). One mechanism for their involvement in growth processes may be via their influence on the activity of growth promoting genes. The size and electrical charge of the polyamines permit them to interact with huge molecules such as DNA and RNA, and pass through phospholipid membranes and compartments with ease.
There appears to be an intimate relationship between polyamines RNA and the hormone insulin. Insulin, whose primary effect once inside the cell is to activate growth, does this by providing stimulation to the protein synthesizing factory of the cell, the ribosomes. Ribosomes act on instructions from 'messenger RNA' which carries the blueprint for which particular type of protein coded in the DNA. Polyamines seem to stabilize and amplify the 'message' contained in messenger RNA, which serves to increase the protein produced from it.
Effects on polyamines on cell growth. Inside the cell, polyamines work to increase growth by two separate mechanisms. The first (1) involves having a direct influence on specific growth promoting genes. The second mechanism involves the enhancement of the production of the various cell proteins needed for growth. By this mechanism polyamines amplify the effects of DNA (2) and insulin (2) by acting to stabilize messenger RNA (4). This results in more the synthesis of larger amounts of protein (5).
Human milk is very high in polyamines; particularly spermine, where they are suspected to account for the possible protective effect of human milk against allergies. The data indicates that human milk provides substantial amounts of spermine and spermidine to newborns and infants that could potentially modulate the maturation of the infant's intestines. In one study, the polyamine concentration of human milk was measured from 60 women during a period extending from the 1st week to the 6th month of lactation and compared with the polyamine content of 18 infant formulas. The spermine and spermidine content of these powdered milks was lower that that of the human milk.
During the first week after birth, putrescine levels in human milk remain very low and vary little, while spermidine and spermine concentrations rose markedly during the first 3 days, reaching levels that were twelve times higher, respectively, than the values measured on the first day. In artificial powdered formulas, the polyamine concentration was approximately 10 times lower than in human milk, with no difference in putrescine and spermine contents between 'first-age' and 'second-age' formulas.
Low maternal protein intake decreases the activity of ornithine decarboxylase and consequently the levels of polyamines in the placenta. This has been shown to result in reduced fetal growth. And perhaps is part of the reason that offspring of [vegan? vegetarian] parents are typically smaller than average.
Polyamines, particularly putrescine, in sufficient amounts are important in maintaining the healthy structure and function of the intestinal mucosa, a function which seems to also require vitamin D as well as putrescine. Long term feeding of polyamine deficient diets in animals results in shrinking of the intestinal lining in both the small intestine and the colon.
In infants, polyamines are very important growth facts. Their high concentration in human milk probably helps explain why breast-fed babies are on average a bit larger than formulas fed, and have a lower incidence of food allergy later on in life.
Polyamines and cancer
Since polyamines make cells grow, it should seem logical that cells that grow a lot require more polyamines than ones that do not. This is certainly the case with cancer cells, which are voracious consumers of polyamines, and in fact, the strategy of 'polyamine deprivation' shows promise as a new horizon in cancer treatment, especially cancers which are in themselves hormonally sensitive, such as prostate and breast cancer.
Many new anti-cancer drugs are being prepared which block the ability of cancer cells to benefit from polyamines. By and large, these drugs work by inhibiting ODC. One in particular, alpha-difluoromethylornithine (DFMO), shows promise in prostate cancer.
In addition to stimulating cell growth, high polyamine levels inhibit the anti-cancer response of the body through specialized anti-tumor cells called NK or [Natural Killer cells]?. Deprivation and lowering of polyamines, through blocking their manufacture or uptake from the intestines, on the other hand, increases NK cell activity. In one study, the authors concluded that "polyamines, secreted by the tumor itself as well as absorbed through the gastrointestinal tract, could now be considered not only as growth factors for the cancer, but also as natural immunosuppressive factors as well."
Certain vitamins have been thought to be contraindicated in cancer patients, such as folic acid in patients receiving certain forms of chemotherapy. There is ample evidence that vitamin B6 has a profoundly stimulating effect on ODC and consequently on polyamine synthesis.
Changes in ODC activity and polyamine synthesis and changes in the expression of the blood group antigens are considered two of the most important biological markers of colonic precancer. This has led researchers to hypothesize that the monitoring of both blood type alterations and polyamine levels may eventually become an important screening tool in early detection and prevention of colon cancer.
Polyamines made by gut bacteria or present in food itself are an important stimulus to tumor growth. When polyamines are 'systematically blockaded' by the use of drugs which inhibit ODC and the elimination of all external sources by use of a polyamine-free diet and decontamination of their gastrointestinal tracts, the number of metastases (tumor spread) was significantly reduced.
Perhaps the higher levels of polyamines typical in growing children may help explain why certain types of cancers, particularly leukemias and lymphomas tend to be so more aggressive in that stage of life.
The concentration of polyamines in spoiled food can be toxic. Fish tissue, which is more perishable than animal tissue, is very susceptible to microorganism invasion. This is why freshly caught fish stored at moderate temperature (60F) will remain unspoiled for 1 day or less. A condition called 'Scombroid Poisoning' is associated with polyamine toxicity. The poisoning got its name because of the widespread consumption of Scombroidea species, mackerel, tuna, bluefish, and skipjack, and the association with a seafood poisoning. These fish, an other rapidly moving fish, like mahi-mahi (yellow-fin dolphin), sardines, anchovies, and herring are subject to a rather rapid microbial decomposition.
All of these fish have a relatively high content of the amino acid histidine in their tissues. Bacterial decomposition of the fish converts the histidine to histamine. Histamine can reach concentrations of up to fairly high concentrations without the development of off-flavors that would cause it to be rejected. Some individuals claim to have detected a sharp, peppery taste with this poisoning.
In most cases the histamine will not produce the observed toxicity - histamine has a relatively low oral toxicity. However, putrescine is also encountered in fish, Putrescine actually enhances the effects of histamine and causes a violent allergic reaction. These chemically are stable and will not be reduced by cooking, freezing, or other processing.
The symptoms of Scombroid poisoning can begin in less than 10 minutes or up to 2 hours after consumption of the tainted fish. Most of the acute symptoms are gone within 16 - 24 hr. The symptoms resemble a severe allergic reaction and may include a facial flush, tightness of chest, sweating, nausea, vomiting, tingling, body rash (hives or urticaria), severe headache, shortness of breath, dizziness, throbbing, thirst, and diarrhea. Not unlike 'Chinese Restaurant Syndrome' with which it is often confused.
Hunters experience a similar event. The "wild" or "gamey" flavor associated with harvested wildlife is due to bacterial decomposition of the tissue. When game is shot, unless it is rapidly cooled down, this breakdown occurs. Fortunately, game tissue is not high in histidine and no similar poisoning is associated with this game.
Paraquat, the herbicide sprayed by the government on marijuana plants in the 1970's is a substantial lung carcinogen. Its cancer causing abilities have in part been shown to be the result of huge increases of polyamines in the lungs.
Polyamines and lectins
Dietary lectins have been shown to be potent inducers of polyamine production in the gut. Lectins typically damage the delicate finger link projections of the mucosa called microvilli.
Many lectins cause growth increases in several organs including the liver, pancreas and spleen. These organ enlargements are the result of a huge influx of polyamines into the organs.
[Wheat germ lectin]? induces significant polyamine production. Incorporating wheat germ lectin into the diet of lab reduced the digestibility and utilization of dietary proteins and slowed down significantly the growth of the test animals. As a result of its binding and uptake by the cells of the small intestine, wheat germ lectin induced extensive polyamine-dependent growth of the small bowel tissue by increasing its content of proteins, RNA and DNA.
Furthermore, an appreciable portion of the absorbed wheat germ lectin was transported across the gut wall into the systemic circulation, where it was deposited in the walls of the blood and lymphatic vessels. Wheat germ lectins also induces growth of the pancreas. These same effects have been shown to occur with several bean and legume lectins as well.
Polyamines are typically found in fermented foods like cheese beer, sauerkraut and yeast extracts. The polyamines are thought to be produced from amino acids by fermentation by enzymes formed by the micro-organisms.
Polyamines are also found in foods which through processing have had the structural integrity of their tissues 'shocked' or damaged through food preparation such as quick freezing or canning.
- Putrescine: Most 'aged' or 'sharp' cheeses are very high in putrescine. Vegetables such as potatoes, canned/frozen vegetables (other than green vegetables) or certain fruit products, such as oranges and tangerines, can have very high concentrations of putrescine. Fermented soy sauce (containing wheat) is also a rich source of polyamines, particularly putrescine. Shrimp, especially the packaged and frozen types have also been shown to have high levels of putrescine.
- Spermidine: Mature cheeses, fermented soybeans, fermented tea, Japanese Sake, domestic mushrooms, potatoes and fresh bread are high sources of spermidine.
- Spermine: Cereals (other than bread), canned or frozen vegetables, meat products, red meat and poultry are high sources of spermine.
The polyamines putrescine, spermidine and spermine are essential for cell renewal and, therefore, are needed to keep the body healthy. Studies show the amounts of polyamines supplied by the average daily diet in Britain probably satisfies the basic metabolic requirements. The major sources of putrescine were fruit, cheese and non-green vegetables. All foods contributed similar amounts of spermidine to the diet, although levels were generally higher in green vegetables. Meat was the richest source of spermine.
Although polyamines temporarily rise in the first stages of fasting, which is probably a response on the part of the liver to the lack of dietary sources. In human subjects after a text meal of yogurt, putrescine levels in the small intestine were observed to rise about 25%.
Effect of phytohaemagglutinin on intestinal cell proliferation. Role of polyamines
Arch Latinoam Nutr 1996 Dec;44(4 Suppl 1):16S-20S Bardocz S, Rowett Research Institute, Aberdeen, Scotland, UK.
- The polyamines, putrescine, spermidine and spermine, mediate the effects of hormones and growth factors as second messengers. They are necessary for every step of protein, RNA and DNA synthesis and are therefore essential for cell growth and proliferation. As with hormones and peptide growth factors, plant lectins which bind to cell surface receptors of the brush border membrane are powerful extraneous growth factors for the gut and as a result, by interacting with brush border epithelial receptors, induce extensive proliferation and changes in the metabolism of epithelial cells via activation of second messenger pathways.These metabolic changes require vast amounts of polyamines, mostly spermidine. Thus, one of the first effects of the PHA signal is to stimulate the basolateral polyamine uptake system for the sequestration of polyamines from blood circulation in sufficient amounts to sustain the growth of the tissue.
The polyamines spermine and spermidine protect proteins from structural and functional damage by AGE precursors: a new role for old molecules?
Life Sci. 2003 Apr 25;72(23):2603-16. Gugliucci A, Menini T.
- Due to the importance of glycation in the genesis of diabetic complications, an intense search for synthetic new antiglycation agents is ongoing. However, a somewhat neglected avenue is the search for endogenous compounds that may inhibit the process and be a source of protodrugs. Based on their ubiquity, their polycationic nature, their essential role in growth, their relatively high concentrations in tissues, and their high concentrations in sperm, we hypothesized that polyamines inhibit glycation and that might be one of their so far elusive functions. In this study we demonstrate a potent antiglycation effect of physiological concentrations of the polyamines spermine and spermidine. We employed two approaches: in the first, we monitored structural changes on histones and ubiquitin in which polyamines inhibit glycation-induced dimer and polymer formation. In the second we monitored functional impairment of catalytic activity of antithrombin III and plasminogen. Protection is afforded against glycation by hexoses, trioses and dicarbonyls AGE precursors and is comparable to those of aminoguanidine and carnosine.