aspergillopepsina

Aspergillopepsin: A Comprehensive Reference

1. Identity, Nomenclature, and Natural Source

Chemical and Taxonomic Names

Aspergillopepsin I is an aspartic endopeptidase formally designated by the International Union of Biochemistry and Molecular Biology (IUBMB) under enzyme commission number EC 3.4.23.18, with the CAS registry number 9025-49-4 and EINECS number 232-796-2. Its accepted synonyms include Aspergillus acid protease, carboxyl proteinase, and pepsin-type aspartic proteinase. A closely related but biochemically distinct form, Aspergillopepsin II (also called Aspergilloglutamic Peptidase, or AGP), carries the enzyme commission number EC 3.4.23.19. The Aspergillus niger aspergilloglutamic peptidase (AGP), formerly called aspergillopepsin II and isolated from Aspergillus niger var. macrosporus (EC 3.4.23.19), is a unique protease belonging to the peptidase family A4.

The discovery of the acid proteinase aspergillopepsin I was linked to the crystallization of the serine alkaline proteinase oryzin from Aspergillus oryzae. This protease, formerly known as aspergillopeptidase A, was isolated from Aspergillus saitoi, a microorganism used in the fermentation of the traditional Japanese liquors awamori and shochu.

Natural Source Organisms

Growth of the imperfect fungus Aspergillus depends upon having both cell wall-bound and extracellular proteolytic enzymes to satisfy requirements for nutrition, because the fungi feed entirely by absorption. Aspergillopepsins are extracellular proteinases secreted by fungal mycelia. The enzymes are of practical importance for fungal nutrition in an acidic environment. Commercially relevant species include Aspergillus niger, Aspergillus niger var. macrosporus, Aspergillus oryzae, Aspergillus luchuensis, and Aspergillus saitoi.

In the 1960s, two extracellular acid endopeptidases — Aspergillopepsin I and II — were discovered in the culture filtrate of A. niger var. macrosporus (Koaze, Goi, Ezawa, Yamada, & Hara, 1964). Aspergillopepsin I is a typical pepsin-type aspartic proteinase, active at pH 2–4.

Aspergillopepsin II was discovered in 1964 in the culture filtrate of Aspergillus niger var. macrosporus together with aspergillopepsin I and isolated from the crude powder of the filtrate. It was thus named proctase A and has also been called Aspergillus proteinase A. Assay is routinely performed with the protein substrates cattle hemoglobin at pH 3.5 and 37°C or casein at pH 2.6 or 1.5 and 30°C.

Common Commercial Forms and Preparations

Commercial food-grade preparations contain aspergillopepsin I (EC 3.4.23.18) and aspergillopepsin II (EC 3.4.23.19) activities, produced with non-genetically modified Aspergillus niger var. macrosporus strain PTG8398 by Meiji Seika Pharma Co., Ltd. Such food enzyme preparations are considered free from viable cells of the production organism. N-terminal sequencing of the major 41 kD protein in commercial ASP powder has yielded a sequence consistent with its identity as aspergillopepsin A precursor (aspergillopepsin I) having a molecular weight of 41 kD. In the dietary supplement sector, aspergillopepsin is typically found in capsule or tablet form, frequently as part of multi-enzyme blends. One widely studied commercial supplement formulation (GliadinX; AVI Research, LLC) contains 325 mg per capsule of AN-PEP preparation comprising 70% AN-PEP, 30% maltodextrin, and citric acid. A commercially marketed aspartic protease from Aspergillus saitoi is known as Molsin F (Kikkoman Corp., Japan), and another supplement employs food-grade Aspergillus niger prolyl endopeptidase (AN-PEP, also marketed as Tolerase G, supplied by DSM).

2. Traditional and Historical Use

East Asian Fermentation Traditions

For over a thousand years, Aspergillus strains have been extensively used as starter cultures in the manufacture of Koji in the Japanese traditional fermentation industry, involving the production of rice wine (sake), soy sauce (shoyu), soybean paste (miso), and distilled spirits (shochu). Although the ancient practitioners did not isolate or identify aspergillopepsin as a discrete enzyme, the proteolytic activity of Aspergillus-derived cultures — of which aspergillopepsin is a primary component — was central to the flavor development, protein hydrolysis, and nutritional transformation of these fermented products.

Koji was first mentioned in the 6th-century Chinese text "Qiming Yaoshu," where koji was said to turn starch into sugar and alcohol with steamed grains (a process known as saccharification). By the 7th century, Japan had started to use koji for early sake brewing, starting with moldy rice at home.

Koji elaboration consists of the solid-state culture of molds on seeds to produce hydrolytic enzymes, including amylases and proteases. The koji thus obtained was used as a source of enzymes for the hydrolysis of starchy materials as a previous step in the manufacture of a variety of Oriental fermented foods including sake (the traditional alcoholic beverage of Japan made from rice), soy sauce, and sufu (soybean cheese).

In the Meiji era, the traditional technique to isolate and propagate the mould was perfected, and is still used to this day with modern technology. It was through this progressive refinement that Aspergillus-derived enzyme preparations were eventually isolated and characterized in the 20th century.

Industrial and Food-Processing Historical Applications

Some of the earlier industrial applications of aspartic proteolytic enzymes — encompassing aspergillopepsins — are found in the manufacturing of cheese where they were used as milk-clotting agents. The aspergillopepsin I from Aspergillus saitoi, commercially marketed as Molsin F by Kikkoman Corp., Japan, has been used in the winery as it successfully removes haze-forming proteins, reducing bentonite requirements.

3. Key Constituents, Active Compounds, and Mechanisms of Action

Biochemical Classification

Aspergillopepsins I are aspartic endopeptidases that catalyse the hydrolysis of peptide bonds in proteins with broad specificity, favouring hydrophobic residues at the P1 and P1' positions, but also accepting lysine (Lys) at P1, resulting in the generation of peptides and free amino acids.

Traditionally, acid-acting fungal peptidases were assigned to the aspartic protease family and include aspergillopepsin from various Aspergillus species and penicillopepsin from Penicillium species. These enzymes have two active-site aspartic acid residues and are strongly inhibited by pepstatin.

Structural Features of Aspergillopepsin I

Aspergillopepsin I is characterized as a pepsin-type aspartic protease possessing the conserved active residues D (84, 115), Y (131, 168), and D (281, 326). Characterized variants exhibit maximum proteolytic activity in the pH range of 2.5–3.0 and at temperatures around 50°C.

Site-directed mutagenesis studies have shown that substitution of Asp-76 to serine or threonine, and deletion of Ser-78 in the S1 subsite (corresponding to positions in mammalian aspartic proteinases), caused drastic decreases in activity towards substrates containing a basic amino acid residue at P1. In contrast, substrates with a hydrophobic residue at P1 were effectively hydrolyzed by each mutant enzyme. These results demonstrate that Asp-76 and Ser-78 residues on the active site flap play important roles in the recognition of a basic amino acid residue at the P1 position.

Based on homology modeling and predicted secondary structure, the aspartic protease is rich in β-structures, which was also confirmed by circular dichroism measurements.

Distinctive Substrate Specificity

Aspergillopepsin I from A. saitoi primarily hydrolyzes two bonds in the oxidized B chain of insulin: Leu15–Tyr16 and Phe24–Phe25. Aspergillopepsin I and other fungal aspartic proteinases are distinct from the mammalian aspartic proteases in their ability to cleave substrates with lysine in the P1 position. Thus, aspergillopepsin I is similar to other pepsin-type enzymes in preferring hydrophobic groups at P1 and P1', but can also accommodate Lys at P1 and therefore act as an enteropeptidase in the activation of trypsinogen.

Analysis of the degree of hydrolysis of commercial substrates indicated the order of cleaving ability of one characterized A. niger aspartic protease to be: hemoglobin > defatted soya flour > gluten > gelatin > skim milk powder.

pH Stability and Gastric Relevance

AN-PEP, a distinct prolyl endoprotease from Aspergillus niger that is related to but distinct from aspergillopepsin I, is active between a pH of 2 and 8, with optimal activity between pH 4 and 5. It is not degraded by pepsin, thereby remaining fully functional in the stomach. It specifically degrades gluten epitopes by cleaving behind proline residues.

Aspergillopepsin (ASP) from Aspergillus niger and dipeptidyl peptidase IV (DPPIV) from Aspergillus oryzae are both widely used in foods, feeds, food processing, and the dietary supplement industries. Research data suggest that whereas neither enzyme preparation alone is able to detoxify gluten under simulated gastric conditions, a defined dose ratio of the two enzyme preparations is able to detoxify moderate quantities of dietary gluten.

Pro-aspergillopepsin A is believed to spontaneously self-activate into the mature enzyme under acidic conditions. This property is directly relevant to its utility as an orally administered digestive supplement, as the acidic gastric environment enables enzyme activation in situ.

Aspergillopepsin II: A Structurally Distinct Related Enzyme

Aspergilloglutamic peptidase (formerly aspergillopepsin II) has demonstrated potential to hydrolyze plant allergens such as alpha-amylase/trypsin inhibitors in the gastrointestinal system, as well as in food matrices containing said inhibitors. Unlike aspergillopepsin I, which belongs to the classic pepsin-family (clan AA), aspergillopepsin II belongs to the glutamic peptidase family A4 and uses a different catalytic mechanism.

4. Scientific Evidence by Area of Use

4.1 Gluten Digestion and Celiac Disease / Non-Celiac Gluten Sensitivity

Background: The Challenge of Gluten Digestion

Gluten is characterized by a high abundance of glutamine and proline (approximately 15% of amino acids). Proline residues are not accepted by most proteases' potential cleavage sites, which makes proline-rich gluten proteins resistant to digestion by enzymes of the human gastrointestinal tract.

In Vitro Studies

The 2009 study by Ehren et al. evaluated the gluten detoxification properties of two food-grade enzymes: aspergillopepsin (ASP) from Aspergillus niger and dipeptidyl peptidase IV (DPPIV) from Aspergillus oryzae. The ability of each enzyme to hydrolyze gluten was tested against synthetic gluten peptides, a recombinant gluten protein, and simulated gastric digests of whole gluten and whole-wheat bread. ASP and DPPIV did not efficiently degrade immunotoxic gluten epitopes when administered in isolation. Aspergillopepsin first breaks down larger proteins into short peptides, which can subsequently be cleared by DPP-IV, as it is more specific to these potentially immuno-toxic peptides. The combination resulted in the complete hydrolyzation of approximately one gram of gluten before it reached the small intestine. However, this study also found that in the presence of competing proteins such as casein, aspergillopepsin was less effective than when it was introduced to gluten alone.

Due to its markedly greater hydrolytic activity against gluten than endogenous pepsin, food-grade ASP may also augment the activity of therapeutically relevant doses of glutenases such as EP-B2 and certain prolyl endopeptidases.

Human/Clinical Studies — AN-PEP (Aspergillus niger Prolyl Endoprotease)

Note on nomenclature: AN-PEP is a prolyl endopeptidase produced by Aspergillus niger and is a closely related but biochemically distinct enzyme to aspergillopepsin I; both appear in the same research literature and some commercial products. AN-PEP degrades gluten at gastric pH levels and has been the focus of the most robustly conducted clinical studies in this field.

A study by Salden et al. had 12 healthy volunteers receive either a low or high calorie liquid meal containing 4 g of gluten together with either AN-PEP or placebo in a crossover design. AN-PEP efficiently degraded gluten in the stomach of the healthy subjects, irrespective of the caloric density of the meal and thus the gastric emptying rate.

A subsequent randomized placebo-controlled crossover study investigated the efficacy of AN-PEP in a physiological meal setting. In this study, 18 gluten-sensitive subjects consumed a porridge containing 0.5 g gluten together with two tablets containing either a high or low dose of AN-PEP, or placebo. The success rate of high-dose AN-PEP, defined as at least 50% gluten degradation compared to placebo in the duodenum, was achieved in 10 of 13 comparisons. In the stomach, gluten levels were reduced from a median of 176.9 to 22.0 µg × min/ml (p = 0.001) in the high dose and to 25.4 µg × min/ml (p = 0.001) in the low dose. In the duodenum, gluten levels were reduced from 14.1 in the placebo to 6.3 µg × min/ml (p = 0.019) in the high dose and to 7.4 µg × min/ml (p = 0.015) in the low dose.

The study concluded that the AN-PEP enzyme is effective in degrading small amounts of gluten as part of a complex meal in the stomach. Even though the use of AN-PEP is not intended to replace a gluten-free diet in gluten-related disorders, it appears to be effective as a digestive aid protecting against the unintentional intake of gluten.

Clinical Trial in Celiac Disease Patients (2024)

A trial published in 2024 examined the effects of orally administered AN-PEP on inadvertent gluten exposure and symptom prevention in adult celiac disease patients following their usual gluten-free diet. This was an exploratory, double-blind, randomized, placebo-controlled trial. After a 4-week run-in period, patients were randomized to 4 weeks of two AN-PEP capsules (GliadinX; AVI Research, LLC) at each of three meals per day, or placebo. Outcome endpoints included average weekly stool gluten immunogenic peptides (GIP), celiac symptom index (CSI), celiac disease-specific serology, and quality of life.

The AN-PEP treatment did not significantly reduce the overall GIP stool concentration. However, given the observation of a significantly lower prevalence of patients with severe symptoms in the AN-PEP arm, further clinical research is warranted.

The potential of oral administration of AN-PEP in preventing the effects of inadvertent gluten exposure, as confirmed by gluten immunogenic peptide stool excretion, and in reducing celiac disease-specific symptoms in adults remains uncertain.

Evidence Strength Assessment: Gluten Digestion

The evidence for aspergillopepsin/AN-PEP in gluten digestion consists of: multiple in vitro hydrolysis experiments demonstrating activity against immunogenic gluten peptides; a small number of controlled human pharmacokinetic/pharmacodynamic studies in healthy and gluten-sensitive subjects demonstrating gastric gluten reduction; and one exploratory randomized controlled trial in celiac disease patients that failed to show a significant reduction in objective gluten exposure biomarkers, though secondary symptom endpoints were suggestive. Overall, the clinical evidence base is preliminary and limited in both scale and scope. Clinical studies are warranted to evaluate the activity of this food-grade enzyme preparation in celiac sprue patients with an inadequate response to a gluten-free diet. No regulatory body has approved aspergillopepsin or AN-PEP as a treatment for celiac disease.

4.2 General Protein Digestion Support

Scientific investigations into aspergillopepsin's efficacy have primarily focused on its biochemical properties, demonstrating robust protease activity under acidic conditions similar to those found in the stomach. Some in vitro and animal studies suggest that aspergillopepsin can effectively hydrolyze dietary proteins, potentially aiding individuals with compromised digestive function. However, clinical research in humans remains limited.

Aspergillopepsin I is an aspartic endopeptidase that catalyses the hydrolysis of peptide bonds in proteins with broad specificity. This non-specificity, combined with its acid pH optimum, makes it a candidate for broad dietary protein hydrolysis in the stomach. No large-scale human clinical trials have been published specifically assessing aspergillopepsin as a standalone digestive enzyme supplement for general protein digestion.

4.3 Food and Beverage Industrial Applications (Relevant to Dietary Exposure)

In the production of wine and wine vinegars, aspergillopepsin I increases the yield of fermentation and hydrolyses haze-forming proteins, such as chitinases and thaumatin-like proteins, into peptides, thus reducing the formation of haze during wine storage.

The combination of a mixture of Aspergillopepsin I and II and flash pasteurization has been shown to successfully heat-stabilize white wine without adverse effects on sensory characteristics.

EFSA-evaluated food enzyme preparations containing aspergillopepsin I are intended for use across a range of food manufacturing processes, including: (1) processing of dairy products for the production of modified milk proteins; (2) processing of meat and fish products for the production of protein hydrolysates; (3) processing of cereals and other grains for brewed products and distilled alcohol; (4) processing of fruits and vegetables for the production of juices, wine and wine vinegar, and other alcoholic beverages; and (5) processing of plant- and fungal-derived products for protein hydrolysates.

Aspergillopepsin I from Aspergillus spp. is used by the International Organisation of Vine and Wine (OIV) to prevent protein haze in still white and rosé wines and sparkling wines. After addition of the aspergillopepsin I preparation, one short-term wine heating must be applied, which contributes to the unfolding of haze-forming proteins and facilitates their enzymatic degradation by proteases, as well as leads to denaturation of the protease itself.

4.4 Potential Effects on Alpha-Amylase/Trypsin Inhibitors

Research has demonstrated that aspergilloglutamic peptidase (formerly aspergillopepsin II) has the potential to hydrolyze plant allergens such as alpha-amylase/trypsin inhibitors in the gastrointestinal system, as well as in food matrices containing said inhibitors, and it has therefore been explored as a component of dietary supplements or pharmaceutical compositions. Alpha-amylase/trypsin inhibitors are wheat proteins distinct from gluten that have been implicated in non-celiac wheat sensitivity and inflammatory responses. The clinical evidence for this application is, however, limited to patent-level and preclinical research at this time.

5. Body Systems and Health Areas

• Gastrointestinal system: Historically, enzymes from Aspergillus species have played an important role in food processing and dietary supplementation, with aspergillopepsin specifically recognized for its proteolytic activity — its ability to break down proteins into peptides and amino acids. This characteristic has led to its inclusion in various nutritional products, such as digestive enzyme blends, where it is intended to support protein digestion and overall gastrointestinal health.
• Immune/inflammatory response (in gluten-related conditions): The primary research focus has been on its capacity to degrade immunogenic gluten peptides, particularly the proline-rich sequences (such as the 33-mer α2-gliadin peptide) that trigger inflammatory responses in the intestinal mucosa of individuals with celiac disease or non-celiac gluten sensitivity.
• Wine and food processing: The addition of aspergillopepsins secreted by A. niger to grape juice enables winemakers to reduce the amount of bentonite needed to stabilize white wines.

6. Dosage Forms and Reported Dosages

Aspergillopepsin appears in commerce in the following forms, with the following dosages reported specifically in published research:

• Oral capsules (dietary supplement): In a double-blind, randomized, placebo-controlled trial in celiac disease patients, the dosage used was two AN-PEP capsules (GliadinX; AVI Research, LLC) at each of three meals per day for 4 weeks. Each capsule contained 325 mg of the AN-PEP preparation (70% AN-PEP, 30% maltodextrin, and citric acid).
• Oral tablets (clinical pharmacokinetic study): In the 2017 randomized placebo-controlled crossover study, 18 gluten-sensitive subjects consumed two tablets containing either a high or low dose of AN-PEP together with a meal containing 0.5 g gluten.
• Dietary supplement (patent dosage range): One patent specification for a dietary supplement containing aspergilloglutamic peptidase (aspergillopepsin II) describes a dosage range of 1 to 100 HPU units of enzyme per serving, preferably from 10 to 50 HPU per serving.
• Food enzyme (EFSA evaluation, wine processing): Based on maximum use levels in wine production, dietary exposure to the food enzyme — expressed as total organic solids (TOS) — was estimated to be up to 0.14 mg TOS/kg body weight per day in European populations.

No authoritative pharmacopeial monograph specifying a standardized therapeutic dosage for aspergillopepsin as a dietary supplement has been identified in the published literature reviewed.

7. Safety Considerations

Toxicological Assessment (EFSA)

Genotoxicity tests conducted by EFSA's Panel on Food Contact Materials, Enzymes and Processing Aids did not indicate a safety concern. Systemic toxicity was assessed by means of a repeated-dose 90-day oral toxicity study in rats. The Panel identified a no observed adverse effect level (NOAEL) of 919 mg TOS/kg body weight per day — the highest dose tested — which, when compared with the estimated dietary exposure, results in a margin of exposure above 6,700.

The EFSA Panel considered that, under the intended conditions of use, the risk of allergic sensitisation and elicitation reactions by dietary exposure cannot be excluded, but the likelihood for this to occur is considered low. Based on the data provided, the Panel concluded that this food enzyme does not give rise to safety concerns under the intended conditions of use.

In a separate EFSA evaluation for aspergillopepsin I from Aspergillus luchuensis, the Panel used a NOAEL of 1,600 mg TOS/kg body weight per day (the highest dose tested), which when compared with the estimated dietary exposure, results in a margin of exposure of at least 942.

Allergenicity

No reports on oral or respiratory sensitisation or elicitation reactions of the aspergillopepsin I under assessment have been published. In addition, no allergic reactions upon dietary exposure to any aspergillopepsin have been reported in the literature.

Sequence homology analysis has identified matches with two respiratory allergens using the criterion of greater than 35% identity in a sliding window of 80 amino acids. The matching allergens were Asp f 10 (63.8% sequence identity), an aspergillopepsin from Aspergillus fumigatus, and pepsin A (42.5% sequence identity) from pig (Sus scrofa).

Asp f 10 is an inhalant allergen from A. fumigatus associated with allergic aspergillosis. Pepsin A from S. scrofa is associated with occupational asthma and rhinitis. However, several studies have shown that individuals respiratorily sensitised to an enzyme are usually able to ingest the corresponding allergen without acquiring clinical symptoms of food allergy.

An EFSA panel concluded that the results of the sequence homology search and the available literature do not indicate a risk of allergic reactions upon dietary exposure to the aspergillopepsin I under assessment.

Occupational Exposure Risk

The production strain belongs to the Aspergillus genus, which is known to cause respiratory allergy. Allergic reactions upon dietary exposure have been observed, but are rare. The primary allergenicity concern for workers is through inhalation rather than oral ingestion.

Inhibition by Pepstatin

The aspartic protease activity of aspergillopepsin is reversibly inhibited by pepstatin A, with a Ki value of 0.045 µM reported in one characterized preparation. Pepstatin A is a specific inhibitor of aspartic proteases; this interaction is of scientific but not practical dietary relevance for most users.

Limitations in Efficacy under Mixed-Meal Conditions

Research has found that in the presence of competing proteins such as casein, aspergillopepsin was less effective than when it was introduced to gluten alone. This represents an inherent practical limitation when aspergillopepsin is used as an oral supplement intended to degrade dietary gluten during consumption of mixed meals.

Regulatory Context

All food enzymes currently on the EU market and intended to remain on that market, as well as all new food enzymes, shall be subjected to a safety evaluation by the European Food Safety Authority (EFSA) and approved via an EU Community list. Multiple EFSA safety opinions on aspergillopepsin I preparations from various Aspergillus strains have been issued between 2022 and 2026, reflecting ongoing regulatory oversight. As a dietary supplement in many markets, aspergillopepsin-containing products are not subject to the same pre-market approval requirements as food enzymes or pharmaceuticals.

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