By Dr. M. Mamadou, 2013
Enzymes are protein molecules found in every biological system. Their role is vital and consists in catalyzing biochemical reactions. This catalysis action allows otherwise extremely slow biochemical reactions to occur with high speed in a manner compatible with life. The actions of the enzymes are varied.
In a very technical sense, enzymes catalyze reactions to:
- build molecules
- break molecules
- change the 3-D spatial positioning of a molecule
- help the inter-conversion of molecules from being free radicals to being antioxidants
- help transfer a molecular group from one molecule to another
- help remove a part of a molecule without breaking the whole molecule in pieces
As can be seen, enzymes help perform the various reactions that help sustain life within the body. Besides, glycation, which is the spontaneous binding of a glucose molecule to a protein, every known reaction in the body requires an enzyme. The concept and effects of glycation on health and wellness will be discussed in future papers.
Supplemental enzymes are defined here as enzymes that are taken orally and through the digestive system in order to impart nutritional, digestive, or other bio- physiological benefits to the body.
Although the use of supplemental enzymes has been scientifically documented at least since the early 1900’s, there continues to be some misgivings about their applications. The last few decades have seen an improvement in the production, presentation, as well as active scientific and clinical studies about their use in health and wellness.
This paper will attempt to address some key characteristics of supplemental enzymes and provide further understanding on their applications and benefits.
Enzymes, as mentioned above, are protein molecules. As such, they subscribe to the various biochemical properties of proteins.
More specifically, enzymes have a specific 3-D spatial organization that must be kept intact in order for them to perform their catalytic functions. Any factor that temporarily or permanently disturbs the 3- D organization of the enzyme will reduce or inhibit (suppress) the action of the enzyme.
Thus, it is important that an enzyme that is to be used as a supplemental enzyme be stable and/or resist conditions from manufacturing, to ingestion, and within the gastrointestinal tract and beyond that could negatively affect its molecular organization, thus its functionality.
The molecular or 3-D organization of an enzyme molecule compatible with its functional and structural stability is called the native state of that enzyme. When an enzyme is subjected to conditions that disrupt its native state, the enzyme is said to be denatured. A denatured enzyme loses its functionality.
The function of an enzyme is referred to as enzyme activity
The activity of an enzyme is the rate (speed) at which a specific enzyme in a set of given conditions of temperature and pH, substrate concentration, and other factors will perform its function, i.e., its action on a given substrate.
Some of the factors that could denature enzymes include:
- physical: subjecting an enzyme in solution to excess physical agitation or shaking could disrupt its structure and negate its function
- temperature: every enzyme has a temperature range within which it is stable. Within that temperature stability range, there is also what is called the optimum temperature. The optimum temperature is the temperature at which the enzyme, under its normal conditions of activity, has the optimum rate of activity.
Thus, an enzyme can be active within certain range of temperature above or below its optimum temperature, albeit at different rate. However, if an enzyme is completely out of its range, it loses its activity. The loss can be reversible or permanent. Reversibility in enzymology refers to the ability of an enzyme to revert back to its native structure and functionality when the conditions become favorable.
It should be noted that enzymes have been shown to work in almost every temperature conditions. It depends on the enzyme and the organism it is derived from. For instance, there are enzymes that are functional and actually work better in boiling water temperature. Similarly, there are enzymes that work in very cold temperatures. The enzymes used as dietary supplement work best at human body temperature and are usually slowed or denatured when temperatures are raised above 60oC.
Fever which is characterized by increased human body temperature is actually part of an inflammation and a defense mechanism process. The goal of the increased body temperature is to increase the rate of the enzyme reactions in the body to help bring quick resolution to the inflammatory process. However, if the fever temperature is not controlled and is allowed to keep mounting, it will denature the enzymes and other molecules, leading to permanent damage or even death.
- pH: The pH of a solution refers to the relative concentration of hydrogen ions it contains. The pH value of any solution is between 0 and 14. A pH value of 7 is called neutral. Any value above 7 is basic or alkaline. Any value below 7 is acidic.
Enzymes as protein molecules are sensitive to pH changes. Every enzyme has a pH range within which it can maintain its structure, thus its functionality. Some enzymes work best in acid condition. A good example of such enzyme is pepsin in the stomach to help digest proteins. There are other acid-loving enzymes in the body but they are mostly restricted to structures called lysosomes. Most of the enzymes in the body work between pH 6.8 to pH 7.4.
The enzymes used as dietary supplements vary in their pH stability. In selecting a dietary supplement enzyme, it is important that the enzyme be stable and/or effective in the gastrointestinal tract. Through various studies, it has been determined that the enzymes used by reputable manufacturers and supplement companies meet the key criteria of stability and/or effectiveness in the gastrointestinal tract.
For instance, it has been established that while some enzymes maintain a good level activity in highly acid conditions (low pH), other enzymes stop their reaction while in the gastric acid environment and regain it when they reach the small intestine where the pH is higher and where most digestion and absorption take place.
This is a very important aspect of dietary supplement enzyme application. The stability of the enzymes in the gastric environment is one of the main arguments often used to criticize the use of enzymes. This argument is simplistic as enzymes vary widely in their biochemical characteristics including susceptibility to pH and temperature.
While some enzymes require alkaline pH, others work best in acidic environments, and still other enzymes perform optimally at neutral pH. It all depends on the enzyme. Recent enzyme production advances have allowed the selection of enzymes for specific substrates under specific pH conditions.
Many of the enzymes used as dietary supplements maintain effective activity in the gastrointestinal tract. This observation has been proven by scientific and clinical studies.
Another aspect to consider in dietary supplement enzyme formulations is the presence of inhibitory molecules. Enzyme- based formulations must be free of molecules that could inhibit the action of the enzymes.
Similar to pH and temperature, there are molecules that could interfere with either the substrate or the enzyme and slow down or stop enzymatic action. This is one of the reasons that enzyme-based formulations have to be made with some scientific scrutiny and knowledge of which ingredients could be mixed into the product to ensure enzyme benefits.
As mentioned above, enzymes are catalysts in biochemical reactions. In an enzyme catalyzed reaction, there is a substrate and a product. The substrate is the molecule the enzyme acts on to deliver the product of the reaction.
In the use of enzymes as dietary supplements, the main substrates are food molecules such as proteins, lipids (fats), starch, cellulose, and lactose. Other substrates of interest in the area of supplemental enzymes include excess fibrin, cellular debris, pro-inflammatory molecules and others.
Proteins: Proteins are digested (hydrolyzed) by enzymes called proteases, proteolytic enzymes, proteinases, and peptidases. Proteins are very complex in their structures. Proteins are made of amino acids linked together in a very specific bond called peptide bond to form a chain, like the beads strung on a necklace. If you are holding that open chain let’s assume there is a right end and a left end.
In protein digestion, there are
- proteases that only break the bonds from the left end inwards.
- proteases that only break the bonds from the right end inwards.
- proteases that only break bonds made between specific amino acids. In this case, if the amino acids are not found in the protein or are very scarce, the digestion of that protein will be limited.
- proteases that act only on one side of a specific amino acid, and
- proteases with various other specificities and requirements in their catalytic function.
The main point is that proteases are very diverse and their modes of action as well as site(s) of action within protein molecules are also very varied.
It is also important to note that the digestion of proteins is a very heavy task on the body. When proteins are not fully digested, there could be partial peptides that could have detrimental actions such as chronic inflammation of the gastrointestinal structures or even neurobiological and behavior disorders. Additionally, undigested proteins pass in the large intestine where they are metabolized by the microorganisms resulting in the formation of gases with particular foul- smell like rotten meat or egg.
The case in point for neurobiological disorders resulting from partial digestion of proteins is the incomplete or partial digestion of proteins like casein and gluten. In fact, the partial hydrolysis of casein and gluten results in the formation of peptides often referred to as opioid-like peptides because they induce biological actions similar to those of morphine. These peptides from casein and gluten are respectively called casomorphins and gliadorphins.
Another important point to make about the action of proteases is that they act on proteins that have lost their native structure. In general, a protein is susceptible to being hydrolyzed (broken down) only when it is denatured.
This makes sense and prevents the proteases that are naturally in the body from breaking down healthy tissues. Under normal conditions, only cellular debris and other “no-longer-needed molecules” are tagged, broken down, and removed from the body.
In the digestive system, the initial steps in the stomach such as production of hydrochloric acid, adequate mixing and churning are very important in ensuring effective and complete digestion of the proteins. The acid helps denature the food proteins and thus enhancing their digestibility by the various proteases (endogenous and supplemental).
Thus, it is important to blend various proteolytic enzymes in supplemental digestive enzyme formulations. Sometimes, people focus much on the high activity of an enzyme. High activity is important and so is resiliency of the enzymes to be used in formulations. The rule of thumb is to combine various enzymes that
- have high and low activity
- are stable in the gastrointestinal tract, and
- act on various peptide bonds
Another major substrate in human foods is starch. Starch is digested by amylase to ultimately yield glucose. In most cultures, starchy foods constitute a major portion of the diets. Often, people refer to amylase as the enzyme to digest carbohydrates. Although amylase breaks down starch which is the main carbohydrate in most human diets, it cannot break down other carbohydrates.
As with proteins, undigested starch will pass in the large intestine and serve as a fermentation food for the microorganisms. The results are bloating, excess gas, flatulence, and other metabolic complications overtime.
Other carbohydrates are also commonly found in human diets and need to be addressed in supplemental enzyme formulations. Examples of such carbohydrates are lactose and cellulose.
Lactase is the enzyme responsible for breaking down the milk sugar lactose into glucose and galactose. Even when milk is not directly consumed, there still is a lot of lactose consumed, specially, when one consumes processed foods. Many processed foods use lactose as an ingredient/additive.
Whether lactose-intolerant or not, it is a good idea to have supplemental enzymes with the enzyme lactase present. One of the characteristic symptoms of inadequate lactase to digest lactose is the occurrence of diarrhea and excess gas.
The undigested lactose pulls more water from the body into the gut which results in increased peristaltic movement, and thus diarrhea. Additionally, the undigested lactose moves into the large intestine where it will serve as food for the bacteria. This results in excess gas formation bloating, and flatulence.
Cellulase is the enzyme that breaks down cellulose. Cellulose is the main structural and cementing molecule in plant-derived foods. Although vegetables are very good because of the health-promoting molecules they provide, the human body does not produce any cellulase, the enzyme needed to digest cellulose.
In fact, there are no known animals that naturally produce cellulase. Even grazing animals do not produce celluase on their own! The enzyme cellulase has only been found in microorganisms inside or outside of the body.
The main reason humans and animals can consume and benefit from cellulose- contained foods is because of the presence of the probiotics in the gut.
The ultimate or complete digestion of cellulose yields glucose. However, partial digestion of cellulose could lead to formation of molecules that could help detoxify the gut and promote regular bowel movement.
Thus, adding cellulase in supplemental digestive enzyme products helps in the digestion of cellulose and in maintaining probiotics ecological balance, especially for people who consume mostly vegetables and other plant-derived foods.
Other common human food ingredients are lipids or fats. The fats in human diets are mostly triglycerides. Triglycerides are digested in the small intestine in the presence of lipase and bile to release fatty acids. The digestion of fats helps also release the fat soluble vitamins such as vitamins A, D, E, and K that are in the foods. When fats are not properly digested, there is oily diarrhea called steatorrhea. This increased diarrhea may impair the absorption of many other nutrients leading to malnutrition.
There are various lipases that have been shown to be highly effective in supplementing the digestive process and ensuring the hydrolysis of triglycerides. One characteristic of some of these lipases is that they appear to have the ability to hydrolyze lipids in absence of an emulsifying agent such as bile salts. The exact mechanism is not understood.
So, it is important to always have a supplemental digestive enzyme product that contains various enzymes every time one eats.
There is hardly any food that is made up of only protein, lipids, or carbohydrates. All these molecules are found mixed in a given food, unless if that food is fully processed. However, some foods may have a higher content of one type of molecules than others.
For instance, meat will have mostly proteins. But there are also lipids and some carbohydrates in the form of glycoproteins, or lipoproteins, or glycogen, etc… Grains may contain mostly starch but they have lipids as well as proteins that need to be effectively digested to avoid gluten-related issues.
Although plant-derived foods contain many health-promoting molecules (antioxidants, vitamins, minerals…) their cementing structures are cellulose, other complex carbohydrates, proteins, and even lipids that must be broken down to release the nutrients.
Besides their function in ensuring digestion of foods, supplemental enzymes have also been shown to provide health and wellness benefits in controlling
- blood clot formations, thus minimizing the risks of ischemia, hypoxia, or stroke
- inflammation to reduce the damaging effects of chronic inflammation;
- bacterial infections by hydrolyzing toxins and/or preventing bacterial adhesions to biological tissues
- excess production of pro- inflammatory cytokines
The use of supplemental enzymes for systemic benefits in the blood circulation and at inflammation sites has been one of the major areas on contention for critics of enzyme application.
Two main arguments against the benefits of enzymes are often cited. One argument deals with the action of the gastric acid, and the other refers to the inability of enzyme molecules to be absorbed intact in the blood circulation and still maintaining their effectiveness. This set of arguments was best addressed in a review by Seifert et al., and many other studies.
Naturally, not all enzymes can survive the gastric acid and/or be absorbed in the blood circulation intact and remain active.
Absorption and effectiveness would be much more challenging for enzymes that are made up of two or more chains. It is very difficult and nearly impossible for such 2 or more chain enzymes to dissociate and regain their native configuration and functionality once absorbed. It is important to note that the enzymes used as supplements are single chain polypeptides.
The various enzyme absorption studies have shown that enzymes and other proteins could use various transport mechanisms across the intestinal mucosa lining to find their way in the blood circulation. Furthermore, the studies have indicated that once absorbed, the enzymes bind to alpha 2-macroglobulin and yet maintain their catalytic function until cleared from the body.
The goal in the science of enzymology dealing with supplemental enzymes is to identify, produce, and make available products that are safe and effective in providing health benefits. Many enzymes are already in use and meet the safe and effective application criteria. There is more and more active research being conducted around the world for new enzymes to be used as dietary supplements.
The enzymes used as dietary supplements come from various sources. Initially, most of the enzymes used were from the animal pancreas (trypsin, chymotrypsin, pancreatin) or from plants such as papaya (papain) and pineapple bromelain).
Recently that trend has shifted to focus mostly on fermentation processes using fungi and bacteria. One advantage in the fermentation approach is that it allows controlled and cost effective production system that address safety and effectiveness considerations.
The productions are done in very controlled conditions that monitor and prevent any potential contamination and can be geared to high standard GMP (good manufacturing practices). Furthermore, the biotechnological advances made help select specific organisms for specific type of enzymes that could function in various pH conditions found in the gastrointestinal tract.
Additionally, specific substrates could be used to induce production of specific enzymes that could hydrolyze various food molecule bonds more effectively. An interesting point in these advances is the availability of naturally producing lipases that do not require bile salts during hydrolysis of triglycerides.
These various innovations could be done with natural selection and without genetic engineering manipulation of the organisms.
After collection of the enzymes from the production bulk, all other molecules that are not the enzyme(s) of interest are completely and effectively removed. These steps multiple in the production steps ensure that the enzymes presently on the market and from reputable producers manufacturers are free from any allergenic or toxigenic molecules. Just the active molecules!
Enzymes are complex molecules and specific in their biochemical characteristics. Although not all enzymes can be used as dietary supplements, many scientific and clinical studies have proven that some enzymes could in fact be used to help in digestion as well as in controlling inflammation and blood clots.
The key is to find and use enzymes that are produced under good manufacturing practices and that could be safely effective in the gastrointestinal tract. Such enzymes are already available, and more are being discovered, isolated, and characterized.
Barrett A.J., et al., 1973: The interaction of alpha 2-macroglobulin with proteinases. Biochem J. 133:709
Barillas, C., et al., 1987: Effective reduction of lactose maldigestion in preschool children by direct addition of beta- galactosidase (lactase) to milk at mealtime. Pediatrics 79:766.
Gardner MLG and Steffens KJ, 1995: Absorption of orally administered enzymes. Springer-Verlag. Stuttgart, Germany.
Miller, J et al., 1964. The increased proteolytic activity of human blood serum after the oral administration of bromelain. Exp. Med. Surf. 11:277
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