Enzymes are globular proteins that act as catalysts for specific chemical reactions. In the body, this means enzymes help break down compounds, such as nutrients. The catch is each enzyme only acts on a specific compound, called a substrate. This specificity is often explained as a lock-and-key-type action, because the physical shape of the enzyme (folded, long protein chains) and substrate have to match in order for the enzyme to engage and catalyze.

Fittingly, there are thousands of enzymes known to man, sourced from animals, plants, fungus or microbes. In the natural products industry, such enzymes are used to make enzyme supplements, cosmeceuticals, or as processing and delivery components.

Digestive Health

One of the most common health-related uses of enzymes is in digestion products. In this capacity, enzymes are almost always hydrolases, which hydrolyze the substrate to promote its break down. Hydrolase enzymes are categorized as carbohydrases (such as amylases), proteases, lipases, cellulases, pectinases, xylanases, hemicellulases and other subtypes. Among these, proteases target proteins, amylases catalyze carbohydrates, lipases act on fats or lipids and cellulases break down cellulose fibers.

Many enzymes are manufactured in vivo, but a good number come from foods eaten. In an ideal system, these two sources should suffice. However, enzymes are easily denatured (unfolded and deactivated) or degraded by heat, such as in processed foods and by humidity/moisture (as hydrolases). They can also be pre-occupied by non-nutrient compounds (i.e. drugs) that mimic the shape of the enzymes targeted nutrient.

Within the digestion market segment, addressing enzyme deficiencies and nutrient intolerances have become increasingly popular targets. One of the common of these is intolerance to lactose (milk sugar), but a growing category is gluten intolerance. Nena Dockery, technical services manager at National Enzyme Co., said she has seen a growing interest in gluten issues, an area in which her company is active. If you can break down gluten, you will not have the problems of gluten intolerance, she confirmed, noting this is a buzzing area of research in the enzyme industry.

In late 2010, scientists from the University of Salermo and the European Laboratory for the Investigation of Food-Induced Diseases at the University of Naples Frederico II in Salermo, Italy, published a report in Enzymes Research on the various methods being explored to use enzymes in the detoxification of gluten and gliadin. The most natural starting point is to use enzymes to break down the peptides from gluten that are resistant to native protease populations in people with gluten intolerance (aka celiacs). Unfortunately, the acidic stomach environment deactivates these potentially helpful enzymes; with encapsulation, the enzymes failed to efficiently degrade gluten peptides before they reach the small intestines, where they wreak most of their infamous havoc.

Despite these setbacks, the researchers noted a prolyl endoprotease derived from food-grade Aspergillus niger has been found to degrade gluten peptides and intact gluten proteins in the stomach, limiting the peptides success in reaching the small intestine. The endoprotease also has an optimal pH for the stomach environment and is resistant to degradation from pepsin. They added a lyophilized powder combination of a glutamine-specific endoprotease and a propyl-specific endoprotease from Sphingomonas capsulate provides a one-two punch to gluten, surviving the stomach and detoxifying the peptides before they reach the intestines.

Another developing method is to inactivate the peptides in gluten that cause an immune reaction by using an enzyme called transglutaminase to help swap the gluten peptides with an appropriate (i.e. innocuous) amine donor, a process called transamidation.

While this is exciting development on gluten peptides, intolerance to milk and dairy is not yet old news. Dockery noted such intolerance is not just defined by an inability to handle lactose (milk sugar), but also involves digestive problems with milk fat and protein. For this, a blend of enzymes targeting these substrates would be a powerful product, addressing the consumer trend of wanting stronger and better digestive products, according to Dockery. She said there are a couple of reasons why blends have also become popular requests from B2B customers. The ability to protect a proprietary blend appeals to companies, she said. Blends can also be created with multiple purposes, combining a number of enzymes with different capabilities, delivering multiple effects at the same time.

Bret Wyant, sales manager at American Laboratories, reported todays digestive supplement market has embraced the multiple-enzyme blend craze, noting some such products have labels containing seven to 10 different enzymes per dose to claim a marketing advantage over similar formulas in the same market segment. The issue that many contract manufacturers are dealing with in todays cGMP (current good manufacturing practice) marketplace, is the testing and identification of these multiple enzyme blends they are purchasing, he noted.

The digestive health segment has long been the primary territory for enzymes, and it probably will not change for some time to come, if ever. Dockery pointed out digestion is the easiest of possible applications because the methods of action are more known and the benefits message to consumers is easier to convey. Once you get into other areas, such as systemic enzyme supplementation, the actions become more therapeutic, and it becomes more difficult to formulate products with allowable maintenance and supports health-benefits messages, she explained.

System of the Break Down

An ability to affect proteins places protease enzymes in a position to impact other body systems, including the immune and cardiovascular systems. The immune system is comprised of and battles against various types of protein-based compoundsantibodies, antigens (substance that triggers immune reaction) and fibrin are all protein-based. In fact, when antibodies attach to antigens, forming an immune complex, one of the many possible outcomes is autoimmune disease, including rheumatoid arthritis (RA), AIDS and lupus. Proteases can cleave the immune complex, halting the potential for such autoimmune development. Bromelain, trypsin, papain and serrapeptadase are among the hydrolytic enzymes generating positive research results on immune endpoints.

Inflammation is involved in many areas of immune function and autoimmune disease. Enzymes appear to help manage inflammation, as scientists have noticed proteolytic enzymes gather at inflammation sites and might act on inflammatory peptide compounds such as cytokines and TNFalpha. This action can limit the development and progression of the inflammatory process and spare potential damage from chronic inflammation. This is not only a benefit to overall immune function, but can also be an aid in fighting arthritis, asthma and cardiovascular disease (CVD).

The danger zone in CVD, especially atherosclerosis, involves both inflammation and a build up of fibrin and other substances that contribute to arterial plaques. Enzymes such as bromelain, serrapeptidase and nattokinase are known to help breakdown fibrin and help avoid clogging of the arteries.

This fibrin-catalysis is also helpful in tumor-fighting, as these enzymes can help break down the fibrin coatings that envelope and hide cancer cells from the immune system. Exposing these cells can boost the apoptosis that controls tumor development and progression.

Superoxide dismutase (SOD), derived from cantaloupe, can be another powerful enzymatic tool against systemic disease, but it typically fails to survive the early GI tract. An example of technological development in the enzyme market, combining SOD with wheat gliadin biopolymer provides protection in the GI necessary to allow SOD to initiate its beneficial effects, which include antioxidant actions. In fact, SOD can limit oxidative stress-related DNA damage, decrease skin reactions to UV radiation, and reduce arterial wall thickening (oxidized LDL cholesterol trapped in the arterial wall, also called the intima, is one of the major factors in atherosclerosis).

The biggest market [for enzymes] is still digestion, but the fastest-growing market for enzymes is for systemic applications, said Scott Ravech, CEO of Deerland Enzymes, who said people are increasingly accepting such products. Within this category, inflammation is growing fastest, as it crosses a number of boundaries relative to health.

Enzyme Delivery

Technology is helping address the challenges in enzyme delivery, which include the environment of the stomach, as well as heat and moisture from processing, storage and formulation. Enzymes are traditionally delivered as supplements, including tablets and capsules. Ravech noted a supplement, as the dominant delivery form for enzymes, is the easiest entry point for most developers and formulators new to this segment, but there are many possible alternatives such as medical foods, chewables and liquids.

Wyant reported single-use packets are gaining interest, especially in sports nutrition applications. He explained one of the issues with incorporating enzymes into the ever-popular sports product media such as sports beverages is that enzymes activate once they are introduced to moisture. Single-use packets allow the user to add enzymes to a sports nutrition drink prior to consumption, thereby limiting the amount of time the enzyme has to digest the proteins and carbohydrates within the drink mix, he said.

Dockery confirmed the problem with formulating enzymes into functional foods is the enzymes will want to start working on the food ingredients. She added combining enzymes with certain nutraceutical and food ingredients (the matching substrate or a liquid ingredient, for example) can present potential unwanted activation, diminishing the benefits of enzyme intake. On the other hand, combining hydrolase enzymes with other ingredients that are dry and not overly processed with heat will result in little-to-no activation.

Given all the attention being paid to digestive ingredients such as probiotics and prebiotics, combinations of these with enzymes would seem a great fit, though it took research to find the real scoop on compatibility. There was a concern for a long time that probiotics would destroy enzymes if they were paired in a formula, but weve done a lot of work in this area and found this is simply not the case, Dockery said.

She also reported there is a great deal of work being conducted on microencapsulation, enteric coating and other protections for enzyme ingredients, but the biggest challenge in applying these technologies is matching the right coating to the appropriate application. What is good for a food might not work for a beverage, she noted. The technology in the enzyme industry is growing, including recent developments in nanotechnology. All this technology just hasnt really hit the market yet, but I expect it to in the very near future, she said. It is a tremendous opportunity to grow the enzyme market.

One way to ensure an enzyme isnt affected by the stomach is to make the enzyme after the supplement reaches the small intestines. Certain probiotics, such as Bacillus coagulans, can produce beta galactosidases, a class of hydrolytic enzymes which catalyze several substrates including lactose and various glycoproteins.

In the area of delivery, formulators might use the nutrient breakdown abilities of enzymes to improve delivery and absorption of other nutrients. According to Brian ONeill, business development manager for Nutrition Formulators Inc., combining cellulase, hemicellulase and other enzymes can potentially help release nutrients, break down ingredients and improve bioavailability in whole food-based finished products. He further noted proteases can combined with common ingredients to make effective physical recovery ingredients.

The air in the enzyme market is one of potential. With thousands of enzymes either made in the body, taken in from the diet or supplemented by any number of delivery methods, the number of different possible bodily substrates is large enough to include many compounds that figure prominently in digestive, immune and cardiovascular health, as well as other systemic areas. Finding the right combination requires education on the various enzymes types, the research on known methods of actions and benefits, and technologies that can help improve delivery and stability of the enzyme products.

Ravech said customization is one of the biggest trends in the marketplace, and educating customers is a big part of Deerland's services in this area. He advised it is important for customers to know exactly what they area getting and what they are not getting. If a particular proprietary enzyme was involved in key studies, then another company's enzyme of the same generic name may or may not offer the same efficacy. The generic brand might be just as good, but it is important for customers to know which they are getting, and they can make their choices based on price, marketing, etc.

Ravech further noted along with offering expertise and customization of the many enzymes available, being certified GMP (good manufacturing practice) should be paramount. "We test our enzymes multiple times, including potency, microbiology, contaminants, etc.," he said. "We have rejected incoming product at the door." While enzymes present no particular challenges in testing, he said botanicals alongside enzymes in formulation often present the biggest challenges. "Enzymes are the least of our concerns," he assured.

The growing opportunity in the enzyme marketplace is drawing plenty of big companies. Thomas OShaughnessy, vice president of sales and marketing at Dyadic International Inc., said his company has long supplied enzyme solutions to the industrial and feed markets, while only dabbling in the food and nutraceutical markets. However, in 2010, it started to really look into these markets, seeing an opportunity to combine its extensive roster of enzymes (72 proteases) with its strong technical and research backgrounds to offer customized solutions for food and nutraceutical formulators. He noted the company will concentrate less on single, commoditized enzymes and more on special enzymes with very good main and secondary activities. We will work with formulators on what they need in a specialized enzyme product for these markets, he said.

Activity in the enzyme market has often come from outside the natural products industry, especially in the area of research. Enzyme supplement ingredient suppliers reported randomized, controlled trials on enzymes and digestion are very challenging, as many of the endpoints are subjective, which makes getting statistical results challenging. There is a lot of research with enzymes in the pharmaceutical and biopharma markets, Wyant said. He added while it might seem there is a lack of continuous enzyme supplementation research compared to the recent deluge of probiotic publications, enzyme applications are backed by centuries of data and research, with known applications and benefits in various industries. In fact, he said probiotics research is merely catching up with enzyme research, and both product categories have their essential roles in healthy digestion.

In the end, formulators vying for a specialized enzyme product are likely to find a marketplace of suppliers offering numerous options for customized blends, as well as a growing number of delivery options, as long as the right technology is paired with the desired benefit and end user. Whether for digestive of systemic health, an efficacious formulation will, at its most basic, ensure stability and viability of the enzyme payload, and be based on the most current health research available.