Food Research International 134 (2020) 109230

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Food Research International

journal homepage: www.elsevier.com/locate/foodres

Review

A review on mushroom-derived bioactive peptides: Preparation and T

biological activities
Juanjuan Zhoua,1, Mengfei Chena,b,1, Shujian Wua,b, Xiyu Liaoa,b, Juan Wangc, Qingping Wub,
Mingzhu Zhuanga, Yu Dinga,b,⁎
a
Department of Food Science & Technology, Institute of Food Safety and Nutrition, Jinan University, Guangzhou, China
b
Guangdong Institute of Microbiology, State Key Laboratory of Applied Microbiology Southern China and Guangdong Provincial Key Laboratory of Microbial Culture
Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangzhou, China
c
College of Food Science, South China Agricultural University, Guangzhou, China

ARTICLE INFO ABSTRACT

Keywords: Mushroom bioactive peptides (MBAPs) refer to bioactive peptides extracted directly or indirectly from mush-
Mushroom rooms or their mycelia. Owing to the presence of a large quantity of high-quality proteins, many mushrooms are
Bioactive peptides promising sources of bioactive peptides. The beneficial effects, including antihypertensive, antioxidant, and
Preparation antimicrobial activities, of MBAPs are being increasingly recognized with regards to health promotion and
ACE inhibitor
disease prevention. However, this field is relatively undeveloped and relevant reviews are scarce. Hence, the aim
Antioxidant
of this review was to present the current research status of MBAPs, focusing on their preparation and biological
Antimicrobial
functions. An insight regarding the direction of future research has been also discussed.

1. Introduction derived ACE inhibitory tripeptides (VPP and IPP) (Hernández-Ledesma,

Bioactive peptides (BAPs) are defined as isolated small fragments of
proteins that provide some physiological health benefits (Bhandari
et al., 2020). Most BAPs contain 2–20 amino acids (AAs), although
some contain >20 AAs (Ryan, Ross, Bolton, Fitzgerald, & Stanton,
2011). According to the BIOPEP database (http://www.uwm.edu.pl/
biochemia/index.php/pl/biopep), thousands of BAPs with a wide range
of biological activities have been identified. Noteworthy, some of them
display multiple bioactivities which depend on their AA composition
and secondary structure (Bechaux, Gatellier, Le Page, Drillet, & Sante-
Lhoutellier, 2019). Unlike proteins, BAPs could be absorbed completely
by the intestine, therefore they can either directly produce local effects
in the digestive tract, or enter the circulatory system in intact forms
enabling them to exert their physiological effects (Erdmann, Cheung, &
Schröder, 2008). Furthermore, BAPs generally possess a remarkable
potency, high tissue affinity, less toxicity and better stability (Daliri,
Oh, & Lee, 2017; Mishra et al., 2018), therefore BAPs are ideal in-
gredients for functional foods and medicines, especially when con-
sidering the adverse side effects of synthetic compounds (Karami &
Akbari-adergani, 2019). Some commercial products, containing BAPs,
have been released into the market, such as Calpis® and Evolus®, which
are two well-known antihypertensive products that contain the milk-
del Mar Contreras, & Recio, 2011; Korhonen, 2009). To date, numerous
BAPs have been isolated from various foods, especially milk (Capriotti,
Cavaliere, Piovesana, Samperi, & Laganà, 2016). Animal-derived BAPs
are the most commonly studied due to their rich protein content, fol-
lowed by the plant-derived BAPs (Piovesana et al., 2018; Wong, Xiao,
Wang, Ee, & Chai, 2020), while BAPs isolated from mushrooms have
not received much attentions.
Mushrooms are significant sources of natural bioactive proteins and
peptides (Zhou et al., 2019; Erjavec, Kos, Ravnikar, Dreo, & Sabotič,
2012; Xu, Yan, Chen, & Zhang, 2011). According to reviews conducted
by Zhou et al. (2019), Erjavec et al. (2012) and Xu et al. (2011),
mushrooms contain a considerable amount and type of bioactive pro-
teins especially enzymes, which have been extensively investigated;
however, only few mushroom-derived bioactive peptides (MBAPs) have
been reported. Since proteins are the most important source of BAPs,
the great diversity of BAPs can be generated, which is well demon-
strated by the qualitative and quantitative relationships between an-
imal-derived BAPs with their origin of proteins (Bechaux et al., 2019).
In addition, the biological function of most bioactive proteins has been
attributed to the encoded BAPs that can be released without losing the
bioactivities (Daliri et al., 2017; Montesano, Gallo, Blasi, & Cossignani,
2020). Moreover, peptides from protein hydrolysates generally

⁎
Corresponding author at: Department of Food Science & Technology, Institute of Food Safety and Nutrition, Jinan University, Guangzhou 510632 China.
E-mail address: dingyu@jnu.edu.cn (Y. Ding).
1
These authors contributed equally to this paper.

https://doi.org/10.1016/j.foodres.2020.109230
Received 13 January 2020; Received in revised form 20 March 2020; Accepted 9 April 2020
Available online 12 April 2020
0963-9969/ © 2020 Elsevier Ltd. All rights reserved.
J. Zhou, et al.
Fig. 1. Protein content of regular consumed vegetables (diagram based on the
data obtained from U.S. Department of Agriculture, https://fdc.nal.usda.gov/,
updated on 2019-04-01).
Fig. 2. Protein content and counts of different mushrooms (diagram based on
the data obtained from Akata, Ergonul, & Kalyoncu, 2012; Barros et al., 2007;
Barros, Venturini, Baptista, Estevinho, & Ferreira, 2008; Beluhan & Ranogajec,
2011; Bernaś & Jaworska, 2012; Colak, Kolcuoglu, Sesli, & Dalman, 2007;
Dadáková, Pelikánová, & Kalač, 2009; Diez & Álvarez, 2001; Gonçalves et al.,
2012; Heleno et al., 2015; Khatun, Islam, Cakilcioglu, Guler, & Chatterjee,
2015; Kim et al., 2009; Kumar Sharma & Gautam, 2017; Landi et al., 2017; Liu,
Wang, Zhou, Guo, & Hu, 2010; Manzi, Marconi, Aguzzi, & Pizzoferrato, 2004;
Ouzouni, Petridis, Koller, & Riganakos, 2009; Ouzouni & Riganakos, 2007;
Öztürk et al., 2011; Pereira, Barros, Martins, & Ferreira, 2012; Reis et al., 2011;
Reis, Barros, Martins, & Ferreira, 2012; Xu, Yan, Chen, & Zhang, 2011; Yin &
Zhou, 2008; Zhang & Chen, 2011, 2012; Zhou & Yin, 2008; Zhu, Wang, &
Xiong, 2007).
demonstrate improved bioactivities in comparison with their parent
proteins (Udenigwe & Aluko, 2012). Since there are many bioactive
proteins in mushrooms, especially those unique to Basidiomycetes
(Sabotic, Trcek, Popovic, & Brzin, 2007), there may be more, even
novel MBAPs, that remain to be discovered. Basically, protein-rich
foods are potential sources of BAPs (Kehinde & Sharma, 2020). Ac-
cording to the data provided by the U.S. Department of Agriculture
(https://fdc.nal.usda.gov/), mushrooms are rich in protein with a pro-
tein content higher than that of most vegetables (Fig. 1). This suggests
that mushrooms provide an ideal material basis for the discovery of
BAPs. It is worth noting that there are thousands of different mushroom
species, and Fig. 1 only displays the commonly consumed mushroom
species (data type: Food and Nutrient Database for Dietary Studies
(FNDDS) Survey). However, a question remains on the choice of the
mushroom species. Based on data from 130 samples in 28 reports, listed
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Food Research International 134 (2020) 109230
in Fig. 2, the average protein content in mushrooms is
23.80 g ± 9.82 g/100 g dry weight (DW). This indicates that mush-
room species with an extremely high protein contents are available and
should be used to identify MBAPs, especially when considering the
advantages related to cost and yield. For example, the protein content
of Agaricus bisporus, a widely studied mushroom and demonstrated to
be rich in BAPs, is up to about 40% on dry basis (Karnwal, Dohroo, &
Sharma, 2020). Hence, mushrooms are promising sources of BAPs as
they contain a large quantity of high-quality proteins. Moreover,
MBAPs are ideal alternative food supplements for vegetarians who
avoid consuming animal-derived products (Ghorai et al., 2009). Al-
though MBAPs are not as extensively investigated as polysaccharides,
proteins, and phytochemicals (Zhang et al., 2016), all the aforemen-
tioned advantages indicate that mushrooms are a potentially rich
source of BAPs. Therefore, this review summarized the relevant litera-
ture, to date, in order to provide references for more extensive studies
on MBAPs in the future.
Most studies on MBAPs focused on two main aspects: (i) bioactivity-
oriented peptide extraction, purification and characterization; and (ii)
exploring the possible functional/physiological properties and the un-
derlying mechanisms of these actions. Thus, a general overview of these
two aspects have been discussed.
2. Preparation of MBAPs
Considering the relevant literature, the approaches that are com-
monly used in the preparation of MBAPs have been illustrated in Fig. 3.
Basically, there are two approaches that are most popular with regards
to an MBAP preparation. The one approach involves performing the
extraction directly from the mushroom in order to obtain endogenous
MBAPs, and the other uses the proteolytic action of exogenous enzymes
(e.g., hydrolysis by papain) to release of peptide fragments from the
isolated mushroom proteins. Microbial fermentation, another popular
method used to produce BAPs (Piovesana et al., 2018; Saadi, Saari,
Anwar, Abdul Hamid, & Ghazali, 2015), has not been discussed in this
review because it has rarely been used in the preparation of MBAPs, to
date.
2.1. Preparation of endogenous MBAPs
Like other organisms, mushrooms also secrete various BAPs in order
to survive in changing environments. These types of BAPs usually have
an intrinsic origin and are synthesized by specific pathways (Sasaki,
Osaki, & Minamino, 2013). Their structures and biological functions
change according to the mushroom species and growing environments,
and so should the extraction methods. Until now, many endogenous
MBAPs, especially those with antihypertensive and antimicrobial
properties, have been directly extracted from fresh fruiting bodies (Lau,
Abdullah, Shuib, & Aminudin, 2014), dried powders (Mishra et al.,
2018) or fermented powders (He, He, Sui, Zhou, & Wang, 2008) using
distilled water at 4 °C/25 °C (Geng et al., 2016; Girjal, Neelagund, &
Krishnappa, 2012), 30 °C/50 °C (Jang et al., 2011; Kang et al., 2013),
and 95 °C/100 °C (Choi, Cho, Yang, Ra, & Suh, 2001; Wang, Wang, &
Ng, 2007), respectively, Tris-HCl buffer (Mishra et al., 2018), ethanol or
methanol (Jang et al., 2011; Sillapachaiyaporn & Chuchawankul,
2019). A wider range of pretreatments, temperatures, and solvents have
been used in the preparation of endogenous MBAPs in comparison with
those used for proteins, possibly due to the improved stability of pep-
tides. The differences among these pretreatments and solvents have
been discussed in the subsequent sections.
In terms of pretreatment, freezing seems to be the best choice. When
comparing the fresh fruiting bodies of grey oyster mushrooms, freeze-
drying process was found to enhance the amount of proteins extracted,
using distilled water, by at least two-fold. More importantly, the ac-
tivity of ACE inhibitory peptides was not lost or negatively affected by
the freeze-drying process (Lau, Abdullah, Aminudin, & Shuib, 2013).
J. Zhou, et al.
Fig. 3. General flowchart for the preparation and characterization of MBAPs (the dotted lines mean that these processes are not always employed).
Similar results were also obtained from freeze-dried Portuguese wild
edible mushrooms (Barros, Baptista, Correia, Morais, & Ferreira, 2007).
Among the fresh, oven-, microwave-, freeze- and sun-dried Shiitake
(Lentinus edodes), the extraction of MBAPs from freeze-dried Shiitake,
using 80% ethanol, evidenced the highest total antioxidant capability
and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging ability
(Zhang, Lv, Pan, Wu, & Fan, 2009). The solvent used is also crucial for
optimal extraction. Some reports have indicated that the bioactivities of
water or Tris-HCl buffer extracts were stronger than those of ethanol or
methanol extracts (Choi et al., 2001; Jang et al., 2011; Koo et al., 2006;
Lee, Kim, Park, Choi, & Lee, 2004). On the premise of bioactivities,
extraction methods that are simple and environmentally friendly should
be advocated, therefore distilled water is an appropriate first choice.
After extraction and preliminary bioactivity screening, a bioassay-
guided purification is usually conducted using ultrafiltration, gel fil-
tration chromatography (GFC), size exclusion chromatography (SEC),
ion exchange chromatography (IEC), affinity chromatography, fast
protein liquid chromatography (FPLC) (using the gel filtration tech-
nique), or reversed-phase-high-performance liquid chromatography
(RP-HPLC). The proper combinations of the above-mentioned processes
can shorten purification time and increase recovery yield. Thereafter,
identification and characterization of the peptides are often conducted
using a matrix-assisted laser desorption/ ionization time-of-flight mass
spectrometry (MALDI-TOF-MS), a surface-enhanced laser desorption/
ionization time-of-flight mass spectrometry (SELDI-TOF-MS), or liquid
chromatography tandem-mass spectrometry (LC-MS/MS). This process
is similar to the purification and identification of BAPs from other
sources. Capriotti et al. (2016) and Piovesana et al. (2018) have ela-
borated on the recent trends in the identification of milk- and plant-
derived BAPs, respectively, which provides a suitable references point
for the mushroom-derived BAPs. Some technologies, such as the elec-
tron transfer dissociation (ETD) mass spectrometry (MS) (in compara-
tion to a tandem MS), is more suitable for the large-scale identification
of endogenous BAPs due to their size heterogeneity and multiple in-
ternal basic residues (Sasaki et al., 2013).
2.2. Preparation of proteolytic MBAPs
Although some BAPs exist in their natural sources, the over-
whelming majority of known BAPs are encrypted in their parent
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Food Research International 134 (2020) 109230
proteins and could be released by enzymatic processes (Sánchez &
Vázquez, 2017). Currently, the enzymatic hydrolysis of food proteins is
the most utilized and efficient approach in producing BAPs (Saadi et al.,
2015; Sánchez & Vázquez, 2017). It is also a promising way to manu-
facture pharmaceutical-grade BAPs on an industrial-scale (Agyei &
Danquah, 2011). In most cases, the protein hydrolysates, especially
peptides with a low molecular weight (MW), exhibit stronger bioac-
tivity compared to the original proteins. This is because BAPs are
generally inactive when incorporated within their parent proteins and
hydrolysis can liberate potent peptides from intact proteins (Daliri
et al., 2017; Saadi et al., 2015; Shahidi & Li, 2015; Udenigwe & Aluko,
2012). Indeed, MBAPs with diverse biological activities including an-
tioxidative, antimicrobial, antidiabetic, and tyrosinase inhibitory
properties, have reportedly been produced by an enzymatic hydrolysis.
Among these MBAPs, more antioxidant peptides are produced through
this way as plenty of reports have evidenced that peptides exhibit su-
perior antioxidant potentials than their parent proteins (Mishra et al.,
2018).
In order to take full advantage of the mushroom-derived proteins,
before performing hydrolysis, they should be extracted from fresh,
freeze-dried, or air-dried mushroom fruiting bodies or mycelia using
Tris-HCl buffer (pH 7.3 or 8.0) (Farzaneh, Khanahamadi, Ehsani, &
Sharifan, 2018; Li, Wen, Zhang, An, & Liu, 2011), 5% (v/v) chilled
acetic acid with 0.1% (v/v) β-mercaptoethanol (Kimatu et al., 2017;
Yuan et al., 2017), distilled water (Lau, Abdullah, Shuib, & Aminudin,
2012; Qian, Zhang, & Liu, 2016), 0.15 M NaCl solution (Zheng, Wang,
& Zhang, 2011), 0.1 M HEPES-KOH buffer (pH 7.5) (Takakura, Sofuku,
Tsunashima, & Kuwata, 2016), acetone (Chen, Ma, Tsai, Wang, & Wu,
2010), or NaOH solution (pH 12.0) (Zhang, Wu, Fan, Li, & Sun, 2018).
Thereafter, proteins should either be precipitated out in a stepwise
process using (NH4)2SO4 with 10% to 100%, 30% to 70% or 60% to
80% salt saturation, or by means of one-step precipitation using a
certain concentration of (NH4)2SO4 or HCl solution. Although the
stepwise precipitation method may prolong the extraction time, it will
considerably simplify and shorten the subsequent purification pro-
cesses, especially in discovering endogenous MBAPs. For example, after
performing a stepwise precipitation, eight antihypertensive peptides
were successfully isolated and identified from the mushroom A. bisporus
using only three steps including RP-HPLC, SEC, and LC-MS/MS (Lau
et al., 2014).
J. Zhou, et al.
In order to improve the efficiency of hydrolysis, proper pre-pro-
cessing, such as ultra-high-pressure treatment, can improve the soluble
protein content thereby enhancing the degree of hydrolysis (Zhao, Huo,
Qian, Ren, & Lu, 2017). It is also important to consider the choice of the
most appropriate enzyme. The characteristic AA sequences of the re-
leased peptides depend on the parent protein as well as the protease
specificity. The number or type of BAPs obtainable from food proteins is
limitless due to the fact that the number of BAPs produced from a single
food protein can be increased by the type of enzymes used or serially
combining them (Agyei & Danquah, 2011). Thus, selecting suitable
proteases is very important. Gastrointestinal (GI) enzymes, such as
trypsin, pepsin, α-chymotrypsin and pancreatin, are commonly utilized
to generate MBAPs, possibly because the resultant peptides are more
stable when digested in the human GI tract and have higher bioavail-
ability when reaching the absorption sites (Xu, Hong, Wu, & Yan,
2019). Other enzymes, such as papain, neutrase, flavourzyme, and al-
calase, and their combinations with GI enzymes at their respective
optimum reaction conditions, have been successfully utilized in pro-
ducing MBAPs. However, no consensus has been reached regarding
which enzyme or enzyme combination works best. Therefore, in some
situations, screening for suitable enzymes continues to be a part of the
process, especially when the mushroom species has not previously been
studied.
At present, most reports regarding the MBAPs produced by the en-
zymatic hydrolysis of mushroom-derived proteins have not character-
ized the AA sequence, but have only conducted a preliminary pur-
ification using ultrafiltration and/or GFC to obtain different peptide
fractions, or obtained a peptide mixture without implementing pur-
ification. In contrast, endogenous MBAPs are usually purified, identi-
fied, or even synthesized. According to their different preparation
methods and properties, produced and endogenous MBAPs are distin-
guishable for a number of reasons. Endogenous BPAs are usually se-
creted via regular pathways, in other words, they are relatively limited
and stable. Endogenous BAPs are either unique to just one species of
mushroom, such as Cordymin which is currently only found in the
medicinal mushroom Cordyceps sinensis, or ubiquitous, such as glu-
tathione (GSH). Moreover, breaking down the cell wall and then ex-
tracting the internal substances using certain solutions is the standard
method for preparing endogenous MBAPs. Without purification, sub-
stances cannot be verified as peptides, and in the absence of AA iden-
tification, it cannot be established whether the peptide is unique. In
contrast, the enzymatic hydrolysis of mushroom-derived proteins to
obtain BAPs involves quite a different process. Usually, a protein is first
extracted and then hydrolyzed by enzymes to produce a hydrolysate
consisting of a mixture of peptides; therefore purification is unnecessary
in this case. Furthermore, as previously mentioned, numerous peptides
can be produced from one single mushroom species by optimizing
factors, such as the type of enzymes used, the degree of hydrolysis, and
the modification methods performed (e.g., glycosylation reactions and
selenization), which presents a great challenge to the purification and
identification. Besides, the identification of peptides, especially small
peptides (<5 AAs), is not easy when using tandem-MS because of the
low number of MS fragments obtained (Lahrichi, Affolter, Zolezzi, &
Panchaud, 2013). Mushrooms are a relatively untapped source of BAPs,
therefore information regarding mushroom species, biological func-
tions, and preparation methods are scarce and sometimes only one of
these is discussed in a report. However, without structural information,
peptide bioactivities or mechanisms of action cannot be understood
(Arroume et al., 2016). This is one of the major hindrances regarding
the application of MBAPs as therapeutic aids. The good news is that
studies investigating purification and identification, including in vivo
activity testing, have been claimed to be in progress (Kimatu et al.,
2017).
In addition to the above-mentioned classical or empirical ap-
proaches for the preparation of MBAPs, which remains as the most
popular approaches used, bioinformatics-driven (in silico) approaches
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Food Research International 134 (2020) 109230
with unique advantages, such as a high efficiency and accuracy, have
successfully been introduced to some fields, especially in preparing
milk-derived BAPs (Capriotti et al., 2016; Tu, Cheng, Lu, & Du, 2018).
One interesting example which demonstrated the power of bioinfor-
matics-driven approaches was reported by Guerrero et al. (2014), who
mechanistically analyzed and identified 700 endogenous BAPs in
human milk. The specific site where proteolysis occurred was also de-
tected using a computational program called Peptide Extractor (PepEx)
which was developed by the same research group (Guerrero et al.,
2014). The introduction of such labor- and time-saving approaches to
the identification of MBAPs will considerably accelerate the develop-
ment of this field.
3. Bioactivities of MBAPs
To date, MBAPs have been reported to render various biological
activities, including antihypertensive, antioxidant, antimicrobial and
other functions, which have been discussed in the following four sec-
tions.
3.1. Antihypertensive activity of MBAPs
Hypertension (or high blood pressure) has a range of negative ef-
fects on health and is known as the “silent killer” because it leads to
multi organ dysfunctions, including cardiovascular diseases, strokes,
and renal complications (Yahaya, Rahman, & Abdullah, 2014). There-
fore, preventing or managing hypertension is key in preventing the
development of multiple diseases, especially cardiovascular disease
which has been recognized as the leading cause of death worldwide
(Singh, Vij, & Hati, 2014). Blood pressure is regulated by a variety of
biochemical systems, including (i) the renin-angiotensin system (RAS);
(ii) the kinin-nitric oxide system (KNOS); (iii) the neutral endopeptidase
system (NEPS); and (iv) the renin-chymase system (RCS) (Shahidi & Li,
2015). Among these, RAS is considered as the major control system
regarding blood pressure regulation, with renin and ACE as key reg-
ulators. ACE has a dual effect on increasing blood pressure and is
therefore the main target in an antihypertensive therapy (Bechaux
et al., 2019; Shahidi & Li, 2015).
In contrast to the synthetic ACE inhibitors, such as captopril which
has various side-effects (e.g., coughing and skin rashes), the ACE in-
hibitory peptides are promising alternatives probably due to their high
bioavailability and lack of side-effects. Therefore, they are the most
extensively researched BAPs (Bechaux et al., 2019; Ryan et al., 2011). It
is important to note that a discrepancy has been observed between ACE
inhibitory peptide in vitro and in vivo test findings, possibly due to in-
testinal modifications experienced in vivo (Ryan et al., 2011). On a more
positive note, most mushroom-derived ACE inhibitory peptides have
demonstrated remarkable efficacies in vivo. To date, many ACE in-
hibitory peptides have been isolated from mushrooms, some of which
have been summarized in Table 1.
One ACE inhibitory peptide, isolated from the water extract of
Tricholoma giganteum fruiting bodies, was identified as a novel tripep-
tide with an AA sequence of GEP. Once purified, this ACE inhibitor
exhibited a significant (p < 0.05) antihypertensive effect in sponta-
neously hypertensive rats (SHRs) at a dosage as low as 1 mg/kg of the
body weight (BW). Two hours after administrating this ACE inhibitor,
the systolic blood pressure (SBP) dropped by 36 mmHg, which was
greater than that of the positive control captopril (SBP dropped by
27 mmHg), a commercial antihypertensive drug. Moreover, no toxicity
or side effects, such as allergic reactions and coughing, were noted (Lee
et al., 2004). Another ACE inhibitory peptide, isolated from a water
extract of Pholiota adiposa fruiting bodies, was identified as a penta-
peptide with the AA sequence of GEGGP, and also demonstrated a clear
antihypertensive effect in SHRs at the same dosage (1 mg/kg of BW).
The maximum decrease in SBP was a drop of 22 mmHg at 2 h post-
administration, therefore it was slightly less efficient than captopril
J. Zhou, et al. Food Research International 134 (2020) 109230

Table 1
ACE inhibitory peptides derived from mushrooms.
Mushroom species Amino acid sequence IC50 Mode of inhibition Reference

Grifola frondosa VIQKYP 97 μg/mL Competitive Choi et al. (2001)

Tricholoma giganteum GEP 40 μg/mL Competitive Lee et al. (2004)
Pholiota adiposa GEGGP 44 μg/mL Competitive Koo et al. (2006)
Pleurotus cornucopiae RLPSEFDLSAFLRA 0.46 mg/mL Non-competitive Jang et al. (2011)
RLSGQTIEVTSEYLFRH 1.14 mg/mL Non-competitive
Hypsizygus marmoreus LSMGSASLSP 190 μg/mL Non-competitive Kang et al. (2013)
Pleurotus cystidiosus AHEPVK 62.8 μM Competitive Lau et al. (2013)
GPSMR 277.5 μM ND
Agaricus bisporus AHEPVK 63 μM Competitive Lau et al. (2014)
RIGLF 116 μM Competitive
PSSNK 129 μM Non-competitive
Tricholoma matsutake WALKGYK 0.40 μM Non-competitive Geng et al. (2016)
LLVTLKK 0.95 μM ND
IISKIK 1.19 μM ND
ILSKLK 4.02 μM ND
LIDKVVK 0.62 μM ND
Ganoderma Lucidum QLVP 127.9 μM mixed-type Wu et al. (2019)
QLDL 151.5 μM Non-competitive
QDVL 155.8 μM Competitive

ND, not detected.

(Koo et al., 2006).
A study conducted by Geng et al. (2016) highlighted an ACE in-
hibitory peptide, purified from a water extract of Tricholoma matsutakei
(a highly prized mushroom) fruiting bodies, with an IC50 value of
0.40 μM, which was lower than the IC50 values of all whey- and casein-
derived ACE inhibitory peptides and most meat- and byproducts-de-
rived ACE inhibitory peptides listed in two reviews conducted by
Hernandez-Ledesma et al. (2011) and Bechaux et al. (2019), respec-
tively. Its AA sequence was identified as WALKGYK. Thereafter, it was
chemically synthesized and designated as TMP. To confirm its in vivo
ACE inhibitory activity, TMP was orally administered to SHRs and re-
sults evidenced that TMP could significantly (p < 0.05) lower the SBP
of SHRs at the dosages of 25 mg/kg and 50 mg/kg of BW with a
maximum decrease of 18 mmHg and 36 mmHg, respectively, 2 h post-
administration. No side-effects, such as allergic reactions or coughing,
were noted during or following the experiment. Additionally, TMP was
identified as a non-competitive ACE inhibitor, displayed a remarkable
thermostability (40–90 °C) and pH stability (2–11), and exhibited an
antioxidant activity (discussed in Section 3.2). It has therefore been
suggested that T. matsutake may be used as a functional food to help
prevent hypertension-related diseases (Geng et al., 2016). Furthermore,
this highlighting MBAP present a higher ACE inhibitory activity than
another difunctional (antihypertensive and antioxidant) peptide de-
rived from the edible marine animal Styela clava, with an IC50 value of
16.42 μM and the decrease in SBP of ca. 22 mmHg at a dosage of
40 mg/kg of BW (Kang et al., 2020).
A water extract of Pleurotus cornucopiaethe fruiting bodies demon-
strated a clear antihypertensive action in SHRs at a dosage of 600 mg/
kg of BW, with the maximum decrease in SBP of 50 mmHg at 2 h post-
administration. This result was similar to that of the positive control,
captopril, at a dosage of 100 mg/kg of BW. After purification, two ACE
inhibitory peptides, with AA sequences of RLPSEFDLSAFLRA and
RLSGQTIEVTSEYLFRH, were obtained and their IC50 values were de-
termined as 0.46 mg/mL and 1.14 mg/mL, respectively. Moreover,
their ACE inhibitory activities both increased after GI digestion;
therefore, it was postulated that these two oligopeptides were con-
verted into “true ACE inhibitors” by the digestive tract (Jang et al.,
2011).
Another water extract of the fruiting bodies of the edible mushroom
Hypsizygus marmoreus, also exerted clear antihypertensive action in
SHRs at a dosage of 800 mg/kg of BW. Two hours after administration,
the SBP decreased from 180 mmHg to 154 mmHg and then increased
slightly to 166 mmHg 6 h post-administration. It exhibited
antihypertensive effects similar to that of the positive control, captopril,
at a dose of 100 mg/kg of BW. Three peptides displaying an ACE in-
hibitory activity were identified from this water extract and their AA
sequences, along with their individual IC50 values, were as follows:
TTENVLFG (IC50: 3.03 mg/mL), LSMGSASLSP (IC50: 0.19 mg/mL), and
LVNDLVTPVFDNL (IC50: 4.00 mg/mL). The ACE inhibitory peptide
with the AA sequence LSMGSASLSP was recognized as the one with the
most potential with regards to an antihypertensive ability (Kang et al.,
2013).
Mushrooms are rich in protein, which makes them a potentially
good source of antihypertensive peptides (Lau et al., 2012). Lau et al.
(2012) found that all water extracts of fruiting bodies from nine edible
mushroom species inhibited more than 70% of the ACE in vitro at
10 mg/mL. Thereafter, two potential ACE inhibitory peptides, from the
mushroom Pleurotus cystidiosus, were identified and their AA sequences,
along with their IC50 values, were as follows: AHEPVK (IC50: 62.8 μM)
and GPSMR (IC50: 277.5 μM). Their ACE inhibitory activities, after in
vitro GI digestion, were retained or even enhanced. After GI digestion,
the peptide with the AA sequence of GPSMR was hydrolyzed and pre-
dicted to release a real ACE inhibitor, GP, from its precursor (Lau,
Abdullah, & Shuib, 2013). The fruiting bodies or even the by-products
of another highly prized mushroom A. bisporus are rich in bioactive
compounds (Ramos et al., 2019). Eight novel ACE inhibitory peptides
were identified from the fruiting bodies of A. bisporus. Among them, the
most potent ones had an AA sequence of AHEPVK, RIGLF, and PSSNK,
and their individual IC50 values were 63 μM, 116 μM and 129 μM, re-
spectively. These peptides also exhibited a higher ACE inhibitory ac-
tivity after an in vitro GI digestion, increasing from 63.3 to 80.3% to
more than 90%. The peptides with the AA sequence of RIGLF and
PSSNK were predicted to release a tripeptide (IGL) and a tetrapeptide
(SSNK), respectively. It is therefore suggested that mushrooms are a
potential source of ACE inhibitory peptides and it has been postulated
that these peptides are effective hypotensors in vivo (Lau et al., 2014).
Three novel ACE inhibitory peptides, isolated from the water extracts of
Ganoderma lucidum mycelia, were identified and their AA sequences,
along with their IC50 values, were as follows: QLVP (IC50: 127.9 μM),
QLDL (IC50: 151.5 μM), and QDVL (IC50: 155.8 μM). QLVP with the
lowest IC50 value worked in a mixed-type manner (competitive and
noncompetitive inhibition) against ACE via a hydrogen bond and a salt
bridge bonding to the active and nonactive sites of ACE. Moreover, in
human umbilical vein endothelial cells, the angiotensin I-mediated
phosphorylation of endothelial nitric oxide synthase was activated by
QLVP; the decrease of mRNA and protein expression of the

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Table 2
Antioxidant peptides derived from mushrooms.
Mushroom species Molecular characteristics Evaluating methods and values Reference

Ganoderma lucidum Peptide mixtures Superoxide anion radical scavenging activity, ~45% at 1 mg/mL Sun et al. (2004)
Hydroxyl radical scavenging activity, IC50 = 25 μg/mL
Ferric reducing power
Soybean lipoxygenase activity inhibition, IC50 = 27.1 µg/mL
Ganoderma lucidum Peptide mixtures Hepatoprotective effects on D-galactosamine induced liver injury in mice, at a Shi et al. (2008)
dosage of 180 mg/kg BW (p < 0.01)
Ganoderma lucidum Peptide mixtures Hepatoprotective effects on CCl4 induced liver injury in mice, at a dosage of He et al. (2008)
260 mg/kg BW (p < 0.05)
Ganoderma lucidum 3.35 kDa DPPH radical scavenging activity, 74.21% Girjal et al. (2012)
Rich in Phe, Asp, Pro, His and Ile Superoxide anion radical scavenging activity, 72.16%
Hydroxyl radical scavenging activity, 72.87%
Lipid peroxidation inhibition
(at a dosage of 0.2 mg)
Cordyceps sinensis 10,906 D Prevention effect on focal cerebral ischemic/reperfusion injury in rat, at a dosage Wang et al. (2012)
N-terminal: of 2 mg/kg/day (p < 0.05)
AMAPPYGYRTPDAAQ
Grifola frondosa <3 kDa fraction (2385 and 1138 Da) DPPH radical scavenging activity, 89.6% at 2.5 mg/mL Dong et al. (2015)
Ferric reducing power, 2.71 at 2.5 mg/mL
Ferrous ion chelating activity
Lipid peroxidation inhibition
Tricholoma matsutake WALKGYK DPPH radical scavenging activity, 50% at 10 mg/mL Geng et al. (2016)
Agaricus bisporus 1–3 kDa DPPH radical scavenging activity, IC50 = 0.13 mg/mL Kimatu et al. (2017)
Rich in hydrophobic and negatively charged Ferrous ion chelating activity
AAs Ferric reducing power
Lipid peroxidation inhibition
Pleurotus eryngii Polypeptide DPPH radical scavenging activity Sun et al. (2017)
Hydroxy radical scavenging activity, 41.88% at 1 mg/mL
Superoxide ion radical scavenging activity
Ferric reducing power
Agaricus bisporus Peptide mixtures DPPH radical scavenging activity, 73.68% Farzaneh et al.
Ferrous ion chelating activity, 11.75% (2018)
Ferric reducing power, 0.282
Lipid peroxidation inhibition, 79.71%
(hydrolysate at 0.25 mg/mL)
Terfezia claveryi Peptide mixtures DPPH radical scavenging activity, 51.50% Farzaneh et al.
Ferrous ion chelating activity, 21.36% (2018)
Ferric reducing power, 0.271
Lipid peroxidation inhibition, 85.85%
(hydrolysate at 0.25 mg/mL)
Morchella esculenta Peptide mixtures DPPH radical scavenging activity, IC50 = 6.03 mg/mL Zhang et al. (2018)
ABTS radical scavenging activity, IC50 = 0.071 mg/mL
H2O2 scavenging activity, IC50 = 5.28 mg/mL
Ferric reducing power, 4.76 μg Vc/mg sample
Nitrite and superoxide anion radical scavenging activity
Total antioxidant activity
Ganoderma lucidum Peptide mixtures DPPH radical scavenging activity, IC50 = 22.26 mg/mL Mishra et al. (2018)
ABTS radical scavenging activity, IC50 = 7.09 mg/mL
Heavy metal ions chelating effect
Cordyceps sinensis Peptide mixtures DPPH radical scavenging activity, IC50 = 4.79–18.7 mg/mL Mishra et al. (2019)
ABTS radical scavenging activity, IC50 = 4.51–14.05 mg/mL
Heavy metal ions chelating effect

BW, body weight; DPPH, 1,1-diphenyl-2-picrylhydrazyl; ABTS, 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid.

vasoconstrictor factor endothelin-1 was also caused by QLVP (Wu et al.,
2019).
It is well known that the AA composition, AAs at N- and C-terminus,
and the size of peptides are closely related to their activities. High
composition of hydrophobic AAs, aliphatic AAs with branched-chain at
the N-terminal, aromatic, proline, branched, or basic AAs at the C-
terminal, and smaller size are important as hydrophilic peptides and
bigger size are incompatible with the active sites of ACE (Bechaux et al.,
2019; Hernandez-Ledesma et al., 2011; Ryan et al., 2011). The struc-
ture-activity relationship of the mushroom-derived ACE inhibitory
peptides has been listed in Table 1 and is generally consistent with the
above-mentioned characteristics, but they continue to possess their own
characteristics. First, Pro and Lys are the main AAs at the C-terminal.
Second, regarding the inhibition pattern, the majority of ACE inhibitory
peptides are recognized as competitive inhibitors (Ryan et al., 2011),
but competitive and non-competitive inhibitors have been divided al-
most equally in Table 1. Third, regarding the preparation method, the
majority of ACE inhibitory peptides derived from other sources (milk,
egg, animal, and plant) were released from food proteins (Martinez-
Maqueda, Miralles, Recio, & Hernández-Ledesma, 2012), while mush-
room-derived ACE inhibitory peptides were mainly purified directly
from the water extracts. Lastly, regarding the decrease of SBP in vivo,
although there is no uniform conclusion due to vast discrepancies in
each source, the potency of the mushroom-derived tripeptide, GEP,
with a SBP decrease of 36 mmHg at a dosage of 1 mg/kg of BW, is
higher in comparison with those provided in a review conducted by
Martinez-Maqueda et al. (2012), with the exception of two milk-derived
tripeptides, IPP (SBP decrease of 28.3 mmHg at a dosage of 0.3 mg/kg
of BW) and VPP (SBP decrease of 32.1 mmHg at a dosage of 0.6 mg/kg
of BW). All these characteristics indicate that mushrooms are a poten-
tially special source of antihypertensive peptides which may be sy-
nergistic with other antihypertensive peptides due to their different
structural characteristics.

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J. Zhou, et al.
3.2. Antioxidant activity of MBAPs
In the human body, free radicals and reactive species, such as re-
active oxygen species (ROS), are continually produced during normal
cellular metabolism. The timely removal of free radicals and reactive
species occurs via endogenous enzymatic and nonenzymatic defense
systems; however, in some cases, including inflammation, smoking, air
pollution, drug use, and irradiation, endogenous antioxidant systems
can become overwhelmed and the resulting oxidative stress can lead to
various conditions, such as cancer, ageing, and atherosclerosis
(Bechaux et al., 2019; Liu, Xing, Fu, Zhou, & Zhang, 2016; Singh et al.,
2014). Antioxidants can remove free radicals directly by providing
protons and/or electrons, or indirectly by inhibiting the activity of
endogenous oxidases, enhancing the activity of antioxidant enzymes
(e.g., via the activation of the Keap1-Nrf2 signaling pathway), and
chelating metal ions involved in the production of radicals (Jin et al.,
2013; Perron & Brumaghim, 2009; Szeto, 2006; Tonolo et al., 2020;
Yang et al., 2018). An inverse relationship exists between the dietary
antioxidant intake and the risk of developing diseases linked to oxida-
tive stress (Hu, Ting, Zeng, & Huang, 2013). Food-derived antioxidants
have little or no side effects, which has led to an increased interest,
worldwide, in discovering antioxidants from various food sources
(Samaranayaka & Li-Chan, 2011).
Numerous studies have confirmed that mushrooms are rich in var-
ious antioxidants, including polysaccharides, phenols, proteins, pep-
tides, carotenoids, ergosterol, vitamins C and E, and so on (Islam,
Ganesan, & Xu, 2019; Kozarski et al., 2015; Reis, Martins, Vasconcelos,
Morales, & Ferreira, 2017; Sánchez, 2017). Moreover, mushrooms can
be grown at a faster rate compared to plants, which makes them a re-
latively abundant source of natural bioactive compounds for commer-
cial applications (Chandra, Sharma, & Arora, 2020). Over the years,
considerable research has focused on antioxidant polysaccharides and
phenols, while antioxidant peptides derived from mushrooms have not
been intensively studied. A summary of some mushroom-derived anti-
oxidant peptides has been provided in Table 2.
As previously mentioned, BAPs, especially antioxidant peptides, can
be released from the digestion of food proteins by various proteases.
Several antioxidant peptide fractions were obtained by hydrolyzing
proteins extracted from Grifola frondosa using six different proteases,
namely papain, neutrase, alcalase, trypsin, pepsin, and protamex, with
the trypsin hydrolysate displaying the highest level of antioxidant ac-
tivity. Thereafter, four fractions with a MW > 10 kDa, 5–10 kDa,
3–5 kDa, and <3 kDa, were separated from the trypsin hydrolysate by
ultrafiltration. Among them, the smallest MW fraction (<3 kDa),
named GFHT-4, showed the strongest antioxidant activity. The removal
of 89.6% of the DPPH radicals was achieved using 2.5 mg/mL of GFHT-
4, which was similar to that by the positive control butylated hydro-
xyanisole (BHA) (88.6% removed using 1.5 mg/mL of BHA) and higher
than that of the broccoli peptides (72.8% removed using 5.0 mg/mL of
peptides) (Chen, Xia, & Zhang, 2020). Using 2.5 mg/mL of GFHT-4 also
(i) reduced Fe3+ to Fe2+ with an absorbance of 2.71, which was similar
to that by 1.5 mg/mL ascorbic acid (absorbance of 2.72); and (ii) in-
hibited the autoxidation of linoleic acid for six days, equivalent to that
by 0.5 mg/mL of BHA (p > 0.05). After further purification of GFHT-4,
two fractions with a MW of 2385 Da and 1138 Da were identified (Dong
et al., 2015). In another study, proteins isolated from A. bisporus were
hydrolyzed using alcalase, pancreatin, flavourzyme, and their combi-
nations, respectively. The resultant hydrolysates were separated into
four fractions (<1 kDa, 1–3 kDa, 3–5 kDa, and 5–10 kDa) by ultra-
filtration. All hydrolysate fractions exhibited antioxidant activities.
Overall, the fraction with a MW of 1–3 kDa from the pancreatin hy-
drolysate evidenced superior antioxidant activity. It displayed the
highest DPPH radical scavenging activity with an IC50 values of
0.13 mg/mL. Although further purification and identification were not
performed, the principal AA composition of the active fraction con-
sisted of hydrophobic AAs (Ala, Leu and Val) which allow easier entry
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Food Research International 134 (2020) 109230
into target organs and interaction with free radicals and negatively-
charged AAs (Asx and Glx) that donate excess electrons to quench the
free radicals (Kimatu et al., 2017). The relationship between AA com-
position and function is consistent with previous reports of other anti-
oxidant peptides summarized in a review conducted by Zou, He, Li,
Tang, and Xia (2016). The GI enzymatic hydrolysates of proteins ex-
tracted from Terfezia claveryi and A. bisporus also exhibited an anti-
oxidant activity. The hydrolysate of A. bisporus protein demonstrated a
superior DPPH radicals scavenging activity (73.68%), while the hy-
drolysate of T. claveryi was more effective in inhibiting linoleic acid
oxidation (85.85%) and Fe2+-chelating activity (21.36%) (Farzaneh
et al., 2018). The papain hydrolysate of proteins extracted from
Morchella esculenta also exhibited potent antioxidant activities that
were verified by various in vitro assays, including DPPH
(IC50 = 6.03 mg/mL), 2,2′-azinobis-3-ethylbenzothiazoline-6-sulfonic
acid (ABTS) (IC50 = 0.071 mg/mL), H2O2 (IC50 = 5.28 mg/mL), and
ferric reducing antioxidant power (4.76 μg Vc/mg sample) (Zhang
et al., 2018). Moreover, the antioxidant activity of the mushroom-de-
rived peptides could be dramatically enhanced (p < 0.01) after gly-
cosylation with xylose or selenization using microwave irradiation
(Zhang et al., 2018, 2019). However, these studies did not consider
whether harmful substances were also produced during peptide mod-
ification.
G. lucidum is a medicinal mushroom that has been used for centuries
(Cao, Xu, Liu, Huang, & Gu, 2018). It is also an important source of
natural bioactive compounds, especially antioxidant compounds (Gill,
Sharma, Kumar, & Kumar, 2016). An antioxidant peptide fraction was
purified from a water extract of fermented G. lucidum powder (Sun, He,
& Xie, 2004). The G. lucidum peptides (GLP) blocked the soybean li-
poxygenase activity with an IC50 value of 27.1 µg/mL. Hydroxyl radi-
cals produced in a deoxyribose assay were quenched by GLP with an
IC50 value of 25 µg/mL. GLP also exhibited a significant (p < 0.05)
antioxidant activity in vitro, which was established by investigating
peroxidation in the mitochondrial membrane and rat liver tissue
homogenates. It was therefore indicated that GLP was the major anti-
oxidant agent in G. lucidum, particularly in inhibiting lipid peroxidation
of biological systems, which was later verified by in vivo assay. A dose of
180 mg/kg of BW of GLP, exerted significant (p < 0.01) hepatopro-
tective effects in a D-galactosamine-induced liver injury in mice by
means of its antioxidant activity, manifested by a significant (p < 0.01)
decrease in the activities of serum aspartate transaminase (AST) and
alanine transaminase (ALT), and malondialdehyde (MDA) levels in the
liver, as well as a significant (p < 0.01) increase in the activity of su-
peroxide dismutase (SOD) and GSH levels in the liver (Shi, Sun, He,
Guo, & Zhang, 2008). Administering GLP, at a dose of 260 mg/kg of
BW, also displayed significant (p < 0.05) hepatoprotective effects in a
carbon tetrachloride (CCl4)-induced liver injury in mice due to its an-
tioxidant activity, which was confirmed by various histopathological
examinations. Serum ALT and AST activities, MDA level, and the
number of necrotic and pathological hepatocytes were significantly
(p < 0.05) reduced in GLP-treated groups compared to those in the
CCl4-treated groups (He et al., 2008). In another study, Girjal et al.
(2012) isolated a peptide with a MW 3.35 kDa from a water extract of
G. lucidum fruiting bodies. This peptide (0.2 mg) was responsible for
scavenging 74.21% of the DPPH radicals, 72.16% of the superoxide
anion radicals, and 72.87% of the hydroxyl radicals which was similar
to that exhibited by ascorbic acid (5 mg). AA analysis evidenced that
this peptide was rich in Phe, Asp, Pro, His, and Ile. Compared to other
reports, the authors proposed that a low MW and specific AA compo-
sition were responsible for a high antioxidant activity (Girjal et al.,
2012), which is also consistent with the report of Zou et al. (2016). In
addition to the G. lucidum fruiting body (GLF), the G. lucidum mycelium
(GLM) also contains antioxidant peptides. Two antioxidant peptide
fractions were isolated from 0.1 M Tris-HCl buffer (pH 7.2) extracts of
GLF and GLM, named GLF1 and GLM1, respectively. Both showed
significant ability in scavenging DPPH and ABTS radicals. However,
J. Zhou, et al. Food Research International 134 (2020) 109230

Table 3
Antimicrobial peptides derived from mushrooms.
Mushroom species Bioactivities Molecular characteristics Targets and inhibitory values Reference

Pseudoplectania nigrella Antibacterial 4398.80 Da Streptococcus pneumoniae (in mice), Mygind et al. (2005)
EIC = 10 mg/kg BW
Agaricus bisporus Antibacterial Peptide mixtures Pseudomonas aeruginosa, Farzaneh et al. (2018)
26.64% at 0.25 mg/mL
Terfezia claveryi Antibacterial Peptide mixtures Bacillus cereus, 27.44% at 0.25 mg/mL Farzaneh et al. (2018)
Ganoderma lucidum Antibacterial Peptide mixtures Salmonella typhi, MIC = 52 μg Mishra et al. (2018)
Escherichia coli, MIC = 60 μg
Pleurotus eryngii Antifungal 10 kDa Fusarium oxysporum, IC50 = 1.35 μM Wang and Ng (2004)
Mycosphaerella arachidicola, IC50 = 3.5 μM
Polyporus alveolaris Antifungal 28 kDa Botrytis cinereal Wang, Ng, and Liu (2004)
F. oxysporum
M. arachidicola
Physalospora piricola
EIC = 8 mg/mL for all
Pleurotus ostreatus Antifungal 7 kDa F. oxysporum, 20% Chu, Xia, and Ng (2005)
N-terminal: VRPYLVAF M. arachidicola, 45%
P. piricola, 63%
(dosage: 15.6 μM)
Agrocybe cylindracea Antifungal 9 kDa F. oxysporum, IC50 = 125 μM Ngai et al. (2005)
Anti-HIV-1 N-terminal: ANDPQCLYGNVAAKF M. arachidicola, IC50 = 60 μM
HIV-1 RT, IC50 = 60 μM
Cordyceps militaris Antifungal 10,906 D Mycosphaerella arachidicola, IC50 = 10 μM Wong et al. (2011)
Anti-HIV-1 N-terminal: AMAPPYGYRTPDAAQ Bipolaris maydis, IC50 = 50 μM
Rhizoctonia solani, IC50 = 80 μM
Candida albicans, IC50 = 0.75 mM
HIV-1 RT, IC50 = 55 μM
Lentinus squarrosulus Antifungal 17 kDa Trichophyton mentagrophytes, IZD = 25.7 mm Poompouang and Suksomtip (2016)
T. rubrum, IZD = 22.8 mm
Aspergillus niger, IZD = 12.64 mm
Candida tropicalis, IZD = 20.54 mm
C. albicans, IZD = 20.62 mm
(dosage: 30 µg/disc)
Russula paludosa Anti-HIV-1 4.5 kDa HIV-1 RT, IC50 = 11 μM Wang et al. (2007)
N-terminal: KREHGQHCEF

EIC, effective inhibitory concentration; BW, body weight; MIC, minimal inhibitory concentration; HIV-1, human immunodeficiency virus type 1; RT, reverse
transcriptase; IZD, inhibition zone diameter.

GLM1, with IC50 values of 43.26 mg/mL and 8.20 mg/mL for DPPH and
ABTS radicals, respectively, displayed a lower antioxidant activity than
GLF1, with IC50 values of 22.26 mg/mL and 7.09 mg/mL for DPPH and
ABTS radicals, respectively (Mishra et al., 2018). Moreover, these
peptides also demonstrated an antibacterial activity (discussed in
Section 3.3).
In addition to G. lucidum, another medicinal mushroom, namely
Ophiocordyceps sinensis (Cordyceps sinensis), is rich in antioxidant pep-
tides. Cordymin, one of the most investigated MBAPs, is unique to the
mushroom C. sinensis and possesses multiple bioactivities. It was in-
itially identified as a novel antifungal peptide with a MW of 10,906 Da
and an N-terminal AA sequence of AMAPPYGYRTPDAAQ (Wong et al.,
2011). Later, more of its biological functions, including anti-in-
flammatory, antinociceptive, antioxidant, and neuroprotective activity
as well as a protective effect on diabetic osteopenia, were discovered
and verified in vivo (Qi et al., 2013; Qian, Pan, & Guo, 2012; Wang
et al., 2012). In terms of an antioxidant activity, Wang et al. (2012)
found that Cordymin provided a protective effect on the focal cerebral
ischemic/reperfusion injury in rats. Further biochemical estimations in
rat tissues demonstrated that orally-adminstered Cordymin (2 mg/kg/
day) significantly (p < 0.05) boosted the defense system against cere-
bral ischemia by enhancing the activity of antioxidants associated with
lesion pathogenesis. Moreover, Cordymin assisted in the restoration of
antioxidant homeostasis in the brain after reperfusion which helped the
brain recover from an ischemic/reperfusion injury. In additon to Cor-
dymin, there are other antioxidant peptides present in C. sinensis. Three
antioxidant peptide fractions were extracted from C. sinensis. They
showed substantial antioxidant potential by scavenging DPPH and
ABTS radicals with IC50 values of 4.79–18.7 mg/mL and
4.51–14.05 mg/mL, respectively (Mishra, Rajput, Singh, Bansal, &
Misra, 2019). They also displayed antibacterial activity (discussed in
Section 3.3).
Apart from the above-mentioned novel antioxidant peptides,
mushrooms are also rich in GSH, a well-known tripeptide and a key
player in the antioxidant systems (Giustarini, Rossi, Milzani, Colombo,
& Dalle-Donne, 2004; Kalaras, Richie, Calcagnotto, & Beelman, 2017).
The first comprehensive analysis of GSH levels in different edible
mushrooms was conducted by Kalaras et al. (2017). They found that all
the selected edible mushrooms contained GSH and its levels varied by
more than 20-fold (0.11–2.41 mg/g DW). Some mushrooms have a
higher GSH content than any other vegetables or fruits reported to date.
Nevertheless, another antioxidant, ergothioneine that has anti-
mutagenic, chemo- and radio-protective activities (Muszyńska, Kała,
Rojowski, Grzywacz, & Opoka, 2017), was also found in all the selected
edible mushrooms, and its level was highly correlated with the GSH
level (Kalaras et al., 2017). Some studies have suggested that GSH is
essential for ergothioneine synthesis, which in turn, may induce GSH
synthesis by inducing the Nrf2/ARE-mediated signaling pathway (Hseu
et al., 2015; Narainsamy et al., 2016). Furthermore, some studies evi-
denced that dietary intake of GSH and ergothioneine were bioavailable,
as an increase in the GSH and ergothioneine levels was observed in
various tissues (Jayakumar, Thomas, Ramesh, & Geraldine, 2010;
Kariya et al., 2007; Richie et al., 2015; Weigand-Heller, Kris-Etherton,
& Beelman, 2012).
As demonstrated in the above-mentioned studies, mushrooms are an
excellent source of antioxidant peptides, and that current research
continues to be in the preliminary stages. Although some antioxidant
peptides have been tested in vivo, such as Cordymin and G. lucidum
peptides, the in vivo biostability, bioavailability, and antioxidant effi-
cacy of most mushroom-derived antioxidant peptides remain unknown

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J. Zhou, et al.
because many MBAPs have not been purified and analyzed. Moreover,
many available peptides with in vitro antioxidant activity have not been
verified as effective against disorders induced by an oxidative injury.
Hence, whether the mushroom-derived antioxidant peptides demon-
strate excellent antioxidant activities against different diseases in vivo
requires further verification.
3.3. Antimicrobial activity of MBAPs
Like other organisms, mushrooms also produce low MW anti-
microbial compounds, such as terpenes and steroids, and high MW
molecules like polysaccharides, proteins and peptides, to protect
themselves from environmental infections (Alves et al., 2012; Bala,
Aitken, Fechner, Cusack, & Steadman, 2011; Stajic, Cilerdzic, &
Vukojevic, 2017). Mushrooms are rich sources of natural antibiotics
(Sivanandhan, Khusro, Paulraj, Ignacimuthu, & AL-Dhabi, 2017). In
recent years, antimicrobial peptides have gained increased interest due
to their high efficacy and specificity, low drug interaction and toxicity,
and the inability of developing resistance by the microorganisms
(Boparai & Sharma, 2020). To date, several antimicrobial peptides have
been identified in mushrooms (Table 3). Most of them are endogenous
peptides and can easily be divided into three categories, namely anti-
fungal, antibacterial, and antiviral peptides.
Cordymin, an antifungal peptide isolated from the medicinal
mushroom C. militaris, inhibited mycelial growth in Mycosphaerella
arachidicola, Bipolaris maydis, Rhizoctonia solani, and Candida albicans
with the IC50 values of 10 μM, 50 μM, 80 μM, and 0.75 mM, respec-
tively. Additionally, Cordymin displayed a remarkable thermostability
(100 °C), pH stability (6–13), and mental ion stability (unaffected by
10 mM Mg2+ and 10 mM Zn2+) (Wong et al., 2011). Another novel
antifungal peptide with a MW of 17 kDa was isolated from fruiting
bodies of edible mushroom Lentinus squarrosulus. It exhibited strong
antifungal activity against various human fungal pathogen, especially
two clinical isolates Trichophyton mentagrophytes and T. rubrum, with
inhibition zone diameter of 25.7 mm and 22.8 mm, respectively, at a
dosage of 30 µg/disc. However, it was devoid of antibacterial activity
(Poompouang & Suksomtip, 2016).
An antibacterial peptide called plectasin, the first defensin (en-
dogenous peptide antibiotics) to be isolated from a fungus, was ex-
tracted from Pseudoplectania nigrella (Mygind et al., 2005). Re-
combinant plectasin demonstrated potent activity against some gram-
positive bacteria, especially Streptococcus pneumoniae (including strains
that are resistant to conventional antibiotics). The intravenous admin-
istration of 10 mg/kg of BW of Plectasin cured mice with experimen-
tally induced peritonitis and pneumonia, caused by S. pneumoniae, as
effectively as a subcutaneous dose of 70 mg/kg of BW of vancomycin
and intravenous dose of 30 mg/kg of BW of penicillin, respectively.
Moreover, plectasin exhibited extremely low levels of toxicity in mice,
and the maximum tolerated single intravenous dose exceeded 125 mg/
kg of BW. The primary, secondary and tertiary structures of Plectasin
were highly similar to those of the defensins found in scorpions, spiders,
mussels, and dragonflies (Mygind et al., 2005), which demonstrated the
universal connection between live beings and indicates that mushroom
is also an excellent source of antimicrobial defensins. It is important to
note that two antioxidant peptide fractions, one extracted from a G.
lucidum fruiting body (GLF1), and the other from mycelium (GLM1),
also showed remarkable antibacterial activities (Mishra et al., 2018).
The minimal inhibitory concentration (MIC) of GLF1 and GLM1 against
the pathogenic bacteria, Escherichia coli and Salmonella typhi, were
60 μg and 52 μg, and 42 μg and 36 μg, respectively. This indicated that
GLM1 was a better antibacterial peptide fraction than GLF1, which was
the opposite with regards to their antioxidant activity results. Although
their AA sequences were not determined, the presence of hydrophobic
and cationic AAs, two of the major structural characteristics of anti-
bacterial peptides, in these two peptide fractions was confirmed.
Therefore, it was postulated that the generation of ROS and induction of
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Food Research International 134 (2020) 109230
intracellular protein leakage in bacterial cells were the possible me-
chanisms of action. Mishra et al. (2019) found a similar conclusion
regarding antibacterial peptide fractions extracted from the medicinal
mushroom O. sinensis. Like antioxidant peptides, antimicrobial peptides
can also be produced by the enzymatic hydrolysis of mushroom-derived
proteins. Peptides purified from the trypsin hydrolysates of proteins
extracted from A. bisporus inhibited 26.64% of Pseudomonas aeruginosa
growth at 0.25 mg/mL, and the hydrolysates of proteins extracted from
T. claveryi inhibited 27.44% of Bacillus cereus growth at the same con-
centration (Farzaneh et al., 2018).
Compared to antifungal and antibacterial peptides, mushroom-de-
rived antiviral peptides are scarce. The human immunodeficiency virus
(HIV) is the causative agent of an acquired immunodeficiency syn-
drome (AIDS), a viral disease that is one of most difficult to treat,
worldwide (Ghafouri, Amini, Khalili, & Sawaya, 2006). Some anti-HIV
peptides that target the HIV-1 reverse transcriptase (RT) (one of the key
enzymes in the HIV life cycle), were isolated from mushrooms. Hot
water extracts of Trametes suaveolens, Lactarius camphoratus, Pleurotus
pulmonarius, Sparassis crispa, Russula paludosa, and P. sajor-caju all
displayed over 50% inhibition of the HIV-1 RT activity at 1 mg/mL,
with the extract of R. paludosa possessing the highest inhibitory activity
(97.6%) (Wang et al., 2007). Thereafter, a 4.5 kDa peptide, with an N-
terminal AA sequence of KREHGQHCEF, was purified from the R. pa-
ludosa water extract. The IC50 value of this peptide was determined to
be as low as 11 μM. Moreover, this peptide was devoid of ribonuclease,
hemagglutinating, protease, antifungal, laccase, and protease inhibitory
activities. Therefore, it was concluded that this peptide did not belong
to any of these classes of proteins. In another study, the inhibitory ac-
tivity of agrocybin, an antifungal peptide isolated from the edible
mushroom Agrocybe cylindracea, on HIV-1 RT inhibitory activity was
evaluated. The IC50 value was 60 μM (Ngai, Zhao, & Ng, 2005). Cor-
dymin, a multifunctional mushroom-derived peptide, also inhibited
HIV-1 RT with an IC50 value of 55 μM (Wong et al., 2011). The peptides
from the ethanol extracts of Lignosus rhinocerus (tiger milk mushroom)
also showed a remarkable HIV-1 RT inhibitory activity (55.56%) at
1 mg/ml (Sillapachaiyaporn & Chuchawankul, 2019). Therefore,
mushroom-derived HIV-1 RT inhibitory peptides may be a potent sup-
plement to anti-HIV drug. However, there is a lack of in vivo data,
probably due to the infectivity of HIV and the unavailability of ap-
propriate and easily accessible animal models.
Mushroom-derived antimicrobial peptides are very different from
antimicrobial proteins as they lack specific bioactivity. Some of them
possess the general characteristics of antimicrobial peptides derived
from other sources, such as amphipathic and cationic properties, which
allow them to bind to the negatively-charged membranes of microbes
with ease. However, most of them do not demonstrate specific me-
chanisms of their inhibitory actions, which is important with regards to
their flexible application. Antimicrobial peptides function in the body,
using different mechanisms, could reduce the likelihood of microbial
resistance (Kim & Wijesekara, 2010). Most of the mushroom-derived
antimicrobial peptides are endogenous and the analysis of their prop-
erties have evidenced that some of them are novel peptides, which
means there may be additional or alternative modes of inhibitory ac-
tions; however, this requires confirmation.
3.4. Other activities of MBAPs
While most researches are focused on the above-mentioned activ-
ities of MBAPs, other beneficial activities have also been reported. The
antitumor and immunostimulatory activities of the previously men-
tioned antioxidant polypeptide, extracted from P. eryngii mycelium,
were also evaluated. It demonstrated significant antitumor activities
and inhibited growth by 61.40% in cervical (Hela-229), 59.20% in
breast (BT-549), and 32.80% in stomach (HGC-27) cancer cells. It also
evidenced significant (p < 0.05) immunostimulatory activities as it
increased macrophage proliferation by 64.70% and increased
J. Zhou, et al.
phagocytosis by 25.08% at 2 mg/mL. Therefore, it was recommended
that this antioxidant peptide should be added to the list of functional
foods as a multifunctional antioxidant (Sun, Hu, & Li, 2017). An anti-
thrombotic tripeptide with a sequence of WGC was isolated from In-
onotus obliquus mycelia. This purified tripeptide exerted a potent pla-
telet aggregation inhibitory activity of 83.3% in mice at a dosage of
20 mg/kg of BW. Furthermore, its inhibitory activity was significantly
higher than that of several scrambled peptides (including WCG, GCW,
GWC, CGW, and CWG) at the same dosage, which suggests that the AA
sequence is vital for functioning (Hyun, Jeong, Lee, Park, & Lee, 2006).
In addition to antioxidant activity, the papain hydrolysate of proteins
extracted from M. esculenta also demonstrated antidiabetic and tyr-
osinase inhibitory activities in vitro. It inhibited α-glucosidase and α-
amylase by 30.56% and 34.93%, respectively, at 2.0 mg/mL. It also
inhibited tyrosinase, a key rate-limiting enzyme that catalyzes the
synthesis of melanin in the body, by 23.34% at 3.0 mg/mL. Note-
worthy, it was found that not only the antioxidant activity, but also the
antidiabetic and tyrosinase inhibitory activities of the hydrolysate, was
enhanced after selenization (Zhang et al., 2019). In another study,
proteins extracted from mushroom foot were firstly treated by ultra-
high-pressure (400 MPa, 10 min), and then hydrolyzed by alkaline
protease. After ultrafiltration, the fraction with a MW less than 3 kDa
showed the highest in vitro activity regarding the activation of enzymes
for alcohol metabolism, specifically activating alcohol dehydrogenase
(ADH) by 70.79% (EC50 = 6.237 mg/mL) and aldehyde dehydrogenase
(ALDH) by 71.35% (EC50 = 7.04 mg/mL). Finally, nine peptides were
identified, two of which (namely, IPLH and IPIVLL) were artificially
synthesized. The EC50 values for IPLH regarding the activation of ADH
and ALDH were 3.42 mg/mL and 4.45 mg/mL, respectively, while the
EC50 values for IPIVLL were 5.75 mg/mL and 6.16 mg/mL, respectively
(Zhao et al., 2017). These two peptides are rich in Leu, Ile, and Pro,
which are crucial to alcohol metabolism (Yu, Li, He, Huang, & Zhang,
2013).
4. Limitations and future perspectives
Mushrooms, rich in a high quantity of high-quality proteins, are a
promising source of BAPs. At present, many antihypertensive, anti-
oxidant, antimicrobial, anticancer, and other BAPs have been dis-
covered from various mushrooms and most of them are endogenous
peptides. In contrast to the large number of BAPs isolated from animals
and plants, only a few BAPs extracted from mushrooms are known, to
date. Of the thousands of mushroom species, 140,000 have been re-
cognized as fungal species, about 2,000 of them are edible, approxi-
mately 200 of them have traditionally been gathered as food or medi-
cine (Erjavec et al., 2012), and less than half of them have been studied.
Among them, A. bisporus, C. sinensis and G. lucidum are three of the
commonly consumed and cultivated species and have been therefore
studied most often. Many other bioactive functions, such as a choles-
terol-lowing activity, have been identified in many other foods
(Boachie, Yao, & Udenigwe, 2018; Karami & Akbari-adergani, 2019),
but remain to be reported with regards to MBAPs. Hence, mushrooms
are a potentially rich and enormous, but relatively untapped, source of
BAPs. It is well known that the chemical structures of peptides are
closely related to their activities and mechanisms of action (Karami &
Akbari-adergani, 2019). However, some of the present research, espe-
cially regarding an antioxidant activity, has only been conducted on
peptide mixtures, without purification and identification, let alone in-
vestigating the mechanisms of action. Noteworthy, some MBAPs have
demonstrated multiple bioactive functions, but only the fundamental
functions have been studied without any detailed information to verify
whether the different functions are affected by the same peptide
(multifunctional peptide) or by different peptides. Some reports suggest
that the activities are not specific and may exhibit other additional
properties. For instance, antitumor or antioxidant activity may possibly
be associated with an immunomodulating property, and vice versa
10
Food Research International 134 (2020) 109230
(Reis et al., 2017). Moreover, if the peptide AA sequence is unknown, it
is impossible to realize the application of peptides as therapeutic aids
by enzymatic or chemical synthesis, or by recombinant DNA tech-
nology, to reduce the cost.
In conclusion, many achievements have been made regarding
MBAPs, especially in terms of antihypertensive peptides. Nevertheless,
most mushrooms continue to be consumed in their natural forms and
commercial products that make use of MBAPs are very rare. As this field
is relatively undeveloped, more in-depth studies, such as in vivo testing
and the investigation of the underlying mechanism of action, should be
the focus of future research.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgement
This work was funded by National Natural Science Foundation of
China (Grant No. 31701195), Guangdong Technological Innovation
Strategy of Special Funds (Key Areas of Research and Development
Program, grant number 2018B020205003), GDAS’ Special Project of
Science and Technology Development (grant number 2017GDASCX-
0201), the 1000-Youth Elite Program, the 111 Project, and New
Zealand-China Scientist Exchange Programme (2019).
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