Secondary Metabolites, Biological Activities, and Industrial and Biotechnological Importance of Aspergillus sydowii

Marine-derived fungi are renowned as a source of astonishingly significant and synthetically appealing metabolites that are proven as new lead chemicals for chemical, pharmaceutical, and agricultural fields. Aspergillus sydowii is a saprotrophic, ubiquitous, and halophilic fungus that is commonly found in different marine ecosystems. This fungus can cause aspergillosis in sea fan corals leading to sea fan mortality with subsequent changes in coral community structure. Interestingly, A. sydowi is a prolific source of distinct and structurally varied metabolites such as alkaloids, xanthones, terpenes, anthraquinones, sterols, diphenyl ethers, pyrones, cyclopentenones, and polyketides with a range of bioactivities. A. sydowii has capacity to produce various enzymes with marked industrial and biotechnological potential, including α-amylases, lipases, xylanases, cellulases, keratinases, and tannases. Also, this fungus has the capacity for bioremediation as well as the biocatalysis of various chemical reactions. The current work aimed at focusing on the bright side of this fungus. In this review, published studies on isolated metabolites from A. sydowii, including their structures, biological functions, and biosynthesis, as well as the biotechnological and industrial significance of this fungus, were highlighted. More than 245 compounds were described in the current review with 134 references published within the period from 1975 to June 2023.

Chung et al. stated that the addition of 5-azacytidine (a DNA methyltransferase inhibitor) to the culture of marine sediment-derived A. sydowii obtained from Hsinchu, Taiwan, significantly promoted the production of various metabolites [54]. Investigation of the EtOAc (ethyl acetate) extract of 5-azacytidine-treated culture broth by SiO 2 CC and HPLC yielded new bisabolane sesquiterpenoids 5, 46, and 47, along with 1, 42, 45, and 49, that were assigned based on spectral analyses. The S-configuration of compounds 5 and 46 was assigned using optical rotation comparison, whereas compound 46 ([α]D +1.87) is a methyl derivative of compound 45 ([α]D +7.2) and compound 5 ([α]D +3.9) is C-12 hydroxy analog of compound 1 ([α]D +23) (Figure 3). On the other hand, compound 47 is closely similar to the previously reported compound 8 except for the absence of the C-3 carboxylic group in compound 47 [54]. Compounds 5, 46, and 47 were proposed to be biosynthesized from farnesyl diphosphate (FPP) created from the addition of an IPP (isopentenyl diphosphate) unit to a GPP (geranyl diphosphate) (Scheme 1). Then, cyclization and folding of the carbon chain through an electrophilic attack on double bonds produced the bisabolane nucleus that then underwent a series of carboxylation, hydration, oxidation, and reduction to give compounds 5, 46, and 47 [54]. hydration, oxidation, and reduction to give compounds 5, 46, and 47 [54].   A new bisabolane sesquiterpenoid, compound 15, in addition to compounds 1, 7, 6, 42, 47, 49, 50, and 52, were purified from A. sydowii ZSDS1-F6 EtOAc extract using SiO 2 /Sephadex LH-20/RP-HPLC by Wang et al. [45]. Compound 51 is a new aromatic bisabolene-type sesquiterpenoid with 11S-configuration purified and characterized from the sea-derived A. sydowii SW9 [41]. In 2022, Liu et al. purified a rare iodine-and sulfurcontaining derivative (7S)-4-iodo-flavilane A (54) along with compound 53. Compound 54 is 4-iodinated analog of compound 53 and its absolute S-configuration was proven by ECD analysis [38]. Furthermore, three undescribed cuparene-type sesquiterpenes, labeled 56-58, were isolated from fermented cultured EtOAc extract of the sea sediment-derived A. sydowii MCCC-3A00324 using SiO 2 /RP-18/Sephadex LH-20 CC/HPLC and assigned using spectral and ECD analyses. They represent rare cuparene-type sesquiterpenoids having a C-10 keto group and were discovered for the first time from filamentous fungi [57]. closely similar to the previously reported compound 8 except for the absence of the C-3 carboxylic group in compound 47 [54]. Compounds 5, 46, and 47 were proposed to be biosynthesized from farnesyl diphosphate (FPP) created from the addition of an IPP (isopentenyl diphosphate) unit to a GPP (geranyl diphosphate) (Scheme 1). Then, cyclization and folding of the carbon chain through an electrophilic attack on double bonds produced the bisabolane nucleus that then underwent a series of carboxylation, hydration, oxidation, and reduction to give compounds 5, 46, and 47 [54].

Mono-and Triterpenoids and Sterols
In 2020, the chemical investigation of deep-sea sediment-isolated A. sydowii MCCC-3A00324 by Niu et al. led to the separation of new osmane-type monoterpenoids aspermonoterpenoids A (59) and B (60) by SiO2 CC/HPLC and their structures were determined by spectral, ECD, and specific rotation analyses (Table 2, Figure 4). Compounds 59 and 60 are the first osmane monoterpenes reported from fungi, whereas compound 59 features a novel skeleton, which is possibly derived after the cleavage of the cyclopentane ring and oxidation reaction of the osmane monoterpenoid. They have 4S and 4S/5R/6S configurations, respectively [60].   These metabolites were proposed to be biosynthesized from a GPP that underwent subsequent hydrolysis/oxygenation/cyclization to yield the monocyclic osmane monoterpenoid ring. Then, carbon-carbon bond cleavage of osmane gives intermediate I and its further oxygenation yields compound 59, whilst the osmane oxygenation forms compound 60 [60] (Scheme 2).  These metabolites were proposed to be biosynthesized from a GPP that underwent subsequent hydrolysis/oxygenation/cyclization to yield the monocyclic osmane monoterpenoid ring. Then, carbon-carbon bond cleavage of osmane gives intermediate I and its further oxygenation yields compound 59, whilst the osmane oxygenation forms compound 60 [60] (Scheme 2). Zhang et al. purified and characterized compound 61, a new 29-nordammarane-type triterpenoid, in addition to its known analog, compound 62, from the marine-derived A. sydowii PFW1-13 [48]. Compound 61 is structurally similar to compound 62 with a 1,1,2-trisubstituted ethanol unit instead of a trisubstituted ethenyl unit, suggesting that compound 61 is a C 24 -C 25 hydrated derivative of compound 62 [48]. Its configuration was assigned as 4S/5S/6S/8S/9S/10R/13R/14S/16S/17Z based on comparing its optical rotation (−118.9) with that of compound 62 (optical rotation −105.1) [48]. Wang et al., in 2019, reported the separation of ergosterol derivatives 63-66 from deep-sea water-isolated A. sydowii [55], while compounds 68 and 69 were separated by Li et al.; compound 69 was assumed to be a sterol degradation product [44].

Xanthone and Anthraquinone Derivatives
Xanthones are commonly found in lichen, fungi, plants, and bacteria [61]. In fungi, xanthones are mostly derived from acetyl-CoA through a series of polyketide synthasecatalyzed chemical transformations [62]. These metabolites were found to demonstrate diverse bioactivities.

Xanthone and Anthraquinone Derivatives
Xanthones are commonly found in lichen, fungi, plants, and bacteria [61]. In fungi, xanthones are mostly derived from acetyl-CoA through a series of polyketide synthasecatalyzed chemical transformations [62]. These metabolites were found to demonstrate diverse bioactivities.

Alkaloids
Alkaloids have drawn considerable attention because of their unique structural features and varied bioactivities. Interestingly, alkaloids belonging to various classes were reported from A. sydowii.
Biosynthetically, compounds 103-105 were postulated to be generated through a mixed mevalonic acid/amino acid pathway. Compound 105 is generated from the oxidation of compound 107, which results from mevalonic acid, tryptophan, and alanine. A cyclo(Trp-Pro) is formed from proline and tryptophan and is further oxidized and methylated to produce ethoxylated cyclo(Trp-Pro). Then, the latter reacts with mevalonic acid to yield compound 104 and intermediate I.  (115) and the known compound 110 using SiO2 CC and RP-HPLC from the CH3OH/CH3CN extract of A. sydowii MSX-19583 obtained from spruce litter; the compounds were assigned by spectral and ECD analyses and Marfey's Method (Table 4). Compound 115 is structurally similar to the ditryptophenaline reported in various Aspergillus species and derived from tryptophan and phenylalanine subunits [33].  (115) and the known compound 110 using SiO 2 CC and RP-HPLC from the CH 3 OH/CH 3 CN extract of A. sydowii MSX-19583 obtained from spruce litter; the compounds were assigned by spectral and ECD analyses and Marfey's Method (Table 4). Compound 115 is structurally similar to the ditryptophenaline reported in various Aspergillus species and derived from tryptophan and phenylalanine subunits [33].  A new quinazolinone alkaloid, labeled 124, as well as related alkaloid 125 and triazole analog 134 were separated and characterized from the mycelia EtOAc extract of seawaterderived A. sydowii SW9 using SiO 2 /Rp-18/Sephadex LH-20 CC and spectral analyses ( Figure 9). Compound 124 is an acetyl derivative of 2-(4-hydroxybenzyl)quinazolin-4(3H)one, previously reported from Cordyceps-associated Isaria farinose [41,66].

Phenyl Ether Derivatives
Phenyl ethers are a group of simple polyketides that are widely reported in various Aspergillus species and have shown significant bioactivities (Table 5). in 127 has been replaced by an acetoxy methylene group [65].

Chromane and Coumarin Derivatives
Citrinin is a polyketide-derived mycotoxin that was first reported in Penicillium citrinum as lemon-yellow particles. Also, other species of Monascus, Penicillium, and Aspergillus genera are found to be capable of producing this toxin [68].
The coculture of two or more different microbes is a useful approach for activating silent biosynthetic genes to accumulate cryptic compounds. In this regard, an investigation on the EtOAc extract of a coculture of A. sydowii EN-534 and P. citrinum EN-535 obtained from the marine red alga Laurencia okamurai using SiO2/Sephadex LH-20/RP-18 CC/preparative TLC (thin-layer chromatography) resulted in the separation of new citrinin analogs 171 and 172, in addition to compounds 169, 170, and 173-176, that were characterized by spectral, optical rotation, ECD, and X-ray analyses (Table 6, Figure 13). Compounds 171 and 172 are a citrinin dimer and citrinin monomer, respectively. The configurations of compounds 171-173 were assigned as 3R/4S/2′R/3′S, 3R/4S/2′R, and 3′S/1S/3R/4S by X-ray and ECD analyses [69]. Further, asperentin B (178), a new asperentin analog, was obtained from the Mediterranean sea sediment-derived A. sydowii EN50, which is closely related to compound 177 but with an additional OH at C-6 [46]; it was proposed to be derived from the hydroxylation of PKS (polyketide synthase) precursor at the aromatic ring [46].

Chromane and Coumarin Derivatives
Citrinin is a polyketide-derived mycotoxin that was first reported in Penicillium citrinum as lemon-yellow particles. Also, other species of Monascus, Penicillium, and Aspergillus genera are found to be capable of producing this toxin [68].
In 2006, Teuscher et al. separated and characterized new hydroxylated, chlorinated diaryl cyclopentenone derivatives 210 and 211 from red alga Acanthophora spicifera-associated A. sydowii using Sephadex LH-20/HPLC and NMR/CD analyses, respectively. These kinds of metabolites were related to diaryl cyclopentenones reported in order Boletales basidiomycetic fungi and involved in conspicuous bluing reactions of fruiting bodies and reported for the first time from ascomycetes [53]. Compound 215 was isolated as enantiomers, involving (+)-(215a) and (−)-(215b), using SiO 2 /RP-18 CC/HPLC from Rhododendron moleaccompanied A. sydowii and elucidated by spectral and CD analyses. They were purified by chiral HPLC and identified to have 7S and 7R configurations, respectively [26].

Other Metabolites
New catechol derivatives 223 and 224 were separated as racemic by Liu et al. and could not be separated into their enantiomers. Compound 224 resembles compound 223, except for the presence of the C-2 COOH group and a 2-methylpentan-1-ol unit, instead of the 2-CH 3 and propionic acid moiety in compound 223 [35] (Table 8, Figure 15). A new chorismic acid analog, labeled 217, was reported by Liu et al. and its 3R/4S/5R/1 S configuration was assigned based on ECD analysis [41]. The same group separated a dibenzofuran derivative, labeled 234, from A. sydowii SCSIO-41301 [35]. Compounds 228-230 and 234 were separated by Niu et al. from the deep-sea sediment-associated A. sydowii MCCC-3A00324 [60].
Anthocyanins belong to the flavonoids family and are generally reported from plant sources. These metabolites have various applications in agro-food industries such as in natural dyes; additionally, their substantial therapeutic human health in treating obesity and improving cardiovascular function are of note [74]. In 2020, Bu et al. reported the capacity of A. sydowii H-1 to produce anthocyanins using metabolomic and transcriptomic analyses [25]. Compounds 242-246 were characterized; compounds 242 and 244 were the most abundant of the identified anthocyanins [25]. Interestingly, cinnamate-4-hydroxylase and chalcone synthase genes were identified as the key genes involved in anthocyanin biosynthesis [25]. This expanded the knowledge of natural anthocyanin biosynthesis by fungi for the first time.
Vascular endothelial cell growth factor (VEGF) is a tumor-secreted protein that stimulates both the migration and growth of vascular endothelial cells; thus, interference with VEGF signaling suppresses tumor growth or blocks angiogenesis [34].

Anti-Mycobacterial, Anti-Microalgal, and Antimicrobial Activities
Infectious illnesses seriously threaten human health worldwide [75,76]. Recently, the increasing recurrence of pathogens' resistance to antimicrobials represents an alarming trend in infectious diseases that results from misuse or overuse of existing antimicrobials and has become a universal health concern [75,76].

Anti-Influenza Virus Activity
The influenza pandemic remains a threat to public health because of its elevated rates of mortality and morbidity. Although vaccination is the primary means for preventing this illness, antiviral medications are an essential adjunct to vaccines for influenza control and prevention [78,79]. In the last several decades, natural products have been subjected to intensive investigations as a possible alternative therapy for the recovery and treatment of influenza. Various reports have demonstrated that developing natural bioactive metabolites has remarkable advantages [78,79]. It is noteworthy that the renowned anti-influenza oseltamivir was synthesized using natural shikimic and quinic acids as starting materials [78,79]. Some reports assessed the anti-influenza potential of A. sydowii-isolated metabolites; these are highlighted below (Table 11).    , respectively). It was found that the C-1 methyl 2-hydroxy-4-oxobutanoate side chain significantly enhanced the antiviral activity (e.g., compound 203 vs. compound 205) and C-3 configuration had less influence on activity (e.g., compound 205 vs. compound 206) [42].

Anti-Diabetic and Anti-Obesity Activities
A close relation among between diabetes and obesity has been proven [80]. Insulintriggered cellular glucose uptake is a crucial step in glucose regulation and any defect in this mechanism results in insulin resistance [81]. Enhancement of insulin sensitivity is one of the significant hallmarks of anti-diabetic agents. Lipid accumulation in diabetic patients can result in serious effects such as diabetic cardiomyopathy [82]. Hence, efficient antidiabetics should decrease adipocytes' lipid accumulation and facilitate lipid metabolism and burning [54].

Protein Tyrosine Phosphatase Inhibition
Protein tyrosine phosphatases (PTPs) are proven to be substantial new targets for new anti-diabetes [58]. For example, PTP1B (protein tyrosine phosphatase 1B) negatively regulates insulin action in the insulin receptor signaling pathway, SHP1 (SH2-containing protein tyrosine phosphatase 1) negatively controls signaling pathways, which streamlines glucose homeostasis through modulating insulin signaling in muscles and the liver, and CD45 (leukocyte common antigen) is a receptor for some ligands and regulates SHP-1 recruitment [58]. Also, PTP1B has a substantial role in cancer development, inflammation processes, and insulin signaling cascade. Therefore, PTP1B inhibitors are considered drug candidates for treating cancer, diabetes, inflammation processes, and sleeping sickness [46].

Anti-Nematode Activity
Globally, parasitic nematodes cause diseases of major socio-economic significance to humans and animals. They have a long-term impact on human health, especially in children [83]. Indeed, nematodes' resistances to available anti-nematode agents are widespread all over the world [84]. Thus, there is an insistent demand to discover new agents for the effective and sustained control of nematodes.

Industrial and Biotechnological Applications
The discovery and development of effective enzymes for the use of renewable resources as raw materials is a requirement for the transition to a biobased economy. Many enzymes are crucial in efficiently hydrolyzing raw materials by enzymatic means. Exploring the potential of untapped natural habitats is a potent method for overcoming the limited enzymatic toolkit.
A. sydowii was found to be a rich source of enzymes with marked industrial and biotechnological potential, including α-amylases, lipases, xylanases, cellulases, keratinase, and tannases, which are discussed here.

α-Amylase, Tannases, and Lipase Enzymes
Amylases (AAs) are utilized in multiple manufacturing processes, including fermentation, textile, detergent, paper, and pharmaceutical sectors [85]. Given the low cost and wide availability of the starch feedstock used to make food, bioethanol, textile, paper, detergent, and chemicals, there is a significant demand for α-amylase [86]. However, because of advancements in biotechnology, the use of AAs has increased in a variety of sectors such as those of clinical, pharmaceutical, and analytical chemistry, as well as in the food, textile, and brewing industries [85]. The huge industrial demand for AAs to support economically competitive manufacturing processes is still being severely hampered by the cost and effectiveness of AA cocktails [19]. In this regard, it is imperative to generate effective and affordable AAs by using inexpensive sources such as agricultural wastes.
Tannase, an extracellular enzyme belonging to the hydrolase family, is derived from various species of the Aspergillus genus [8,87]. It catalyzes the breakdown of depsides and tannins. Tannase lessens tannins' unwanted effects (astringent and bitter taste), enhancing the flavor qualities of products such as animal feeds and foodstuffs. It is used in various applications, including polyphenolic compound structural elucidation, bioremediating tannin-contaminated wastewaters, gallic acid production, and coffee-flavored soft drink, fruit juice, and instant tea production [20].
In 2020, Albuquerque et al. purified and characterized tannase-acyl hydrolase from A. sydowii SIS-25 derived from Caatinga soil (Serra Talhada, Pernambuco, Brazil) utilizing a polyethylene glycol-citrate aqueous two-phase system. This enzyme removed phenolic components and enhanced the sensory qualities of green tea and produced gallic acid [20].

Bioremediation and Biodegradation
Sustainable development goals (SDGs) target various concerns in our planet such as food security, health, environmental sustainability, bioremediation, climate change, alternative eco-friendly fuel, improving water quality, sustainable food production, and discovering new drugs [88]. Treatment and measurement of various contaminants in water, soil, and air are complicated issues and are linked to the nature of contaminants and their environmental interactions. Reusing wastewater offers a substitute supply for the irrigation of agricultural land that has been used for decades in many nations. Recycling wastewater adheres to circular economy principles by reducing waste and encouraging ongoing resource reuse [89] which potentially assists various national initiatives in promoting sustainable agriculture methods. Creating agricultural systems with minimal required inputs and zero waste contributes to SDG 2 (End hunger) (via sustainable food production), SDG 12 (Responsible consumption and production), SDG 13 (Climate action), and SDG 15 (Sustainable use of terrestrial ecosystems) [90]. Various researches have focused on biologically based methods, relying on natural processes to remove contaminants such as the utilization of microorganisms (bioremediation) such as fungi to remarkably contribute to achieving the SDGs [88].

Polycyclic Aromatic Hydrocarbons
PAHs (polycyclic aromatic hydrocarbons) are a heterogeneous class of hydrocarbons having two or more fused aromatic rings. In nature, they are formed as a result of organic matter's incomplete decomposition and human activities such as petroleum spilling, waste incineration, home heaters, and the burning of carbon, oil, gas, or wood [91]. Additionally, PhCs (pharmaceutical compounds), a second class of contaminants, have become more significant in recent years as a result of their durability and abundance in surface water bodies and the ineffectiveness of treatment facilities eliminating them [92]. According to Olicón-Hernández et al., these contaminants are hazardous to aquatic life and contribute to microbial resistance's emergence [93]. Numerous studies have focused on the microbial biodegradation of these contaminants, particularly by fungi [93,94], because these pollutants are known for their high toxicity and persistence [94]. It is noteworthy that halophilic fungi are useful in xenobiotic mycoremediation under high-salinity conditions [94].
González-Abradelo et al. studied the potential of A. sydowii EXF-12860 toward the bioremediation of saline wastewaters, containing toxic and persistent PAHs and PhCs. It was stated that A. sydowii may be helpful in lowering the amounts of harmful PAHs and PhCs under high-salinity conditions (>1 M NaCl) during the biotechnological downstream processing of diverse industrial wastewater. It removed 100% of fifteen complex PAHs at 500 ppm in biorefinery wastewater at high salt concentrations. Additionally, it has ecotoxic activity as it demonstrated the same capability to eliminate PhCs. This supported its capabilities for xenobiotic biodegradation in low-water activity [94]. A novel piezo-tolerant and hydrocarbon-oclastic deep-sea sediment-derived A. sydowii BOBA1 demonstrated a marked degradation potential for PAHs in spent engine oil hydrocarbon fractions (71.2 and 82.5% of spent engine oil, respectively) under high-pressure (0.1 and 10 MPa, respectively) culture conditions with a 21-day retention period. This provided insights into the bioremediation of hydrocarbon-contaminated deep-sea environments [95].
Additionally, Birolli et al. stated that A. sydowii CBMAI-935 isolated from a noncontaminated site on the coast of São Sebastião (Brazil) biodegraded anthracene [96]. To biodegrade dieldrin, one of the most widely employed organo-chlorine pesticides, banned due to its long persistence and high toxicity to the environment, Birolli et al. found that A. sydowii CBMAI-935 and A. sydowii CBMAI-933 were capable of growing in the presence of dieldrin, suggesting its high tolerance. It is noteworthy that no biodegradation byproducts were found in the GCMS, revealing that dieldrin could be converted into polar molecules or mineralized, prohibiting the emergence of harmful or durable derivatives [97].

Heavy Metals and Insecticides
Cadmium (Cd) is often used in the electroplating and metallurgical industries and is found in several pesticides, fertilizers, and fungicides [98]. Upon its absorption by both animals and humans, it accumulates in the kidneys and liver, severely harming the renal tubules and resulting in a variety of symptoms such as proteinuria and hyperglycemia [99]. Trichlorfon (TCF) is a broad-spectrum organic phosphorus pesticide that is utilized for controlling pests on a variety of crops [100]. It is an inhibitor of cholinesterase that causes delayed neuropathy in both animals' and humans' nervous systems [98]. Zhang et al. reported that by inoculating A. sydowii into Cd-TCF co-contaminated soil, TCF breakdown was accelerated, and soil enzyme activity was raised. When Brassica juncea (Indian mustard) was planted along with A. sydowii inoculation, maximum TCF degradation and Cd removal efficacy were noted. Brassica juncea is among those hyperaccumulator plant species that are frequently employed for heavy metal phytoextraction from contaminated soil. Thus, using B. juncea and A. sydowii together is a promising strategy to bioremediate soil that has been contaminated with both TCF and Cd [98]. Tian et al. isolated PAF-2, a new strain of A. sydowii from pesticide-contaminated soils, that had potential for the biodegradation of TCF and its degradation [100].
Methyl parathion is an efficient organophosphate acaricide and insecticide that is widely utilized for pest control on a wide variety of crops, but it is extremely toxic. Alvarenga et al. reported the ability of A. sydowii CBMAI-935 to biodegrade this pesticide completely after 20 days. This fungus metabolized this pesticide to its more toxic isomerization and oxidation products isoparathion and methyl paraoxon, which were subsequently metabolized to the less toxic product 1-methoxy-4-nitrobenzene/p-nitrophenol/O,O,Otrimethyl phosphorothioate/O,O,S-trimethyl phosphorothioate/trimethyl phosphate, suggesting A. sydowii CBMAI-935's efficiency in the bioremediation of this pesticide and its toxic forms [103,104].

Lignocellulosic Biomasses
Due to the acute energy crisis and increased demand for fossil fuels, lignocellulose is widely considered a potential cost-effective, renewable resource for bioethanol production [105,106]. Lignocellulose consists of cellulose, hemicellulose, and lignin. Lignin, which together with hemicellulose and cellulose makes up the majority of a plant's skeleton, is the second-most abundant organic renewable resource on Earth after cellulose [105,106]. The ligninolytic enzymes Lac (laccase), LiP (lignin peroxidase), VP (versatile peroxidase), and Mnp (manganese peroxidase) play a major role in the breakdown of lignin [105,106] and are found among the extracellular enzymes in filamentous fungi. These enzymes play a significant role in bioremediation, as they neutralize or degrade contaminants in the environment [6]. They also have a wide range of uses in the paper, textile, cosmetic, food, chemical, agricultural, and energy industries.
A thermostable, low-molecular-weight xylanase belonging to the glycosyl hydrolase 11 family was purified from A. sydowii MG49 by Ghosh et al. and demonstrated specific efficacy only in the presence of xylan and had no activity in the presence of cellulose or carboxymethyl cellulose [23].
A. sydowii MS-19 isolated from the Antarctic region produced low-temperature lignindegrading enzymes LiP and Mnp. These results suggested that A. sydowii MS-19 could be used as a source of lignocellulosic enzymes [107].
Brandt et al. stated that A. sydowii Fsh102 isolated from shrimp shells showed notable xylanase-producing capacity [109]. Two xylanases I and II belonging to GH-11 (glycoside hydrolases) and GH-10 families, respectively, were characterized and expressed in E. coli. These enzymes can function in a wide pH range and are tolerant of mesophilic temperatures. Both xylanases can be characterized as being extremely interesting for the enzymatic breakdown of xylan-containing biomasses in industrial bioprocesses based on their activity and stability [109]. In another study on A. sydowii SBS-45 culture filtrate, two xylanases (I and II) were purified. They showed optimum activity at 50 • C and 10.0 pH. This activity was boosted by certain metal ions and L-tryptophan [110].
A. sydowii isolated from Indore, India, had the potential to produce cellulases under submerged fermentation. It was found that β-glucosidase, exoglucanase, and endoglucanase were produced at a ratio of 64:27:9, whereas lactose was the best carbon source for inducing cellulase production [113].

Keratinous Wastes
Keratins are components of hooves, wool, horns, nails, hair, and feathers [8,114]. They are insoluble proteins with highly stable polypeptide chains, containing many disulfide bonds [115,116]. According to estimates, the United States, China, and Brazil produce 40 million tons of keratinous waste each year [117]. Also, keratinous waste is produced in millions of tons annually in meat industry slaughterhouses worldwide [115,116]. Normal enzymes such as papain and pepsin that break down proteins cannot break them down. Keratinous waste management utilizing a low-cost solution is needed particularly in underdeveloped nations. These wastes can be broken down by microbial keratinases which are extracellular enzymes secreted by various bacterial and fungal genera [8,114]. They are widely used in different pharmaceutical industries, in treating keratinized skin, calluses, acne, and psoriasis, and in cosmetic products manufacture (e.g., nutritional lotions, anti-dandruff shampoos, and creams) [21,115,116]. Also, they are usually employed in nitrogen fertilizers, feed formulas, and the leather industry, as well as in treating keratin waste-contaminated wastewater [21].
Alwakeel et al. studied the capability of keratinase produced by A. sydowii AUMC-10935 isolated from male scalp hair to degrade keratinous materials from chicken feathers. The enzyme had optimal activity (120 IU/mg) at 50 • C and pH 8.0, which was notably prohibited by EDTA and certain metal ions [21].

Biocatalysis
The pharmaceutical sector is continually looking for new approaches to new therapeutic agent syntheses, which has increased the demand for biocatalytic techniques [118]. Whole microorganism cells are effectively used as catalysts in the stereoselective biotransformation of a variety of chemical molecules. Also, many chemical reactions such as carbonyl ketone reduction, sulfide oxidation, secondary alcohol deracemization, and Baeyer-Villiger reactions were all catalyzed by enzymes from various microorganisms [6]. The whole cell of A. sydowii was investigated as a biocatalyst for various chemical reactions. This was highlighted in the current work.
Whole cells of the marine sponge-derived A. sydowii Gc12 obtained from the South Atlantic Ocean catalyzed the hydrolysis of (R,S)-benzyl glycidyl ether to produce (R)-benzyl glycidyl ether. Derivatives of glycidyl ether are potentially beneficial intermediates in the manufacture of β-adrenergic blockers. A. sydowii Gc12 hydrolases showed regioselectivity in opening the epoxide ring of racemic oxirane [119].
Sponge-associated A. sydowii CBMAI-934 derived from Chelonaplysilla erecta produced oxidoreductase that catalyzed regioselective mono-hydroxylation of (−)-ambrox ® to 1βhydroxy-ambrox. (−)-Ambrox ® , a naturally occurring terpene, was separated from ambergris, a pathological substance formed in the blue whale's intestine. This compound is of great commercial value in the perfume industry as a fixative or fragrant agent [120]. de Paula and Porto investigated progesterone biotransformation by A. sydowii CBMAI-935 associated with marine sponge Geodia corticostylifera. In a good yield, this fungus was able to oxidize progesterone at the C17-site, resulting in the two major products testololactone and testosterone. Additionally, this Baeyer-Villiger reaction-based bio-oxidation revealed the existence of crucial enzymes in this fungus that can aid in related steroid biotransformation [121]. A. sydowii CBMAI-935 only produced 2 ,4-dihydroxy-dihydrochalcone with a yield of 26% from 2 ,4-dihydroxy-dihydrochalcone [122].

Nanoparticle Synthesis
Nanoparticles (NP) have attracted great interest recently because of their apparent applications in different fields such as biosensors, biomedicine, cosmetics, drugs, photocatalysis, animal dietary supplements, biolabeling, etc. [130]. Conventional NP synthesis approaches are not environment-friendly and are cost-intensive. Therefore, the development of biocompatible, environment-friendly, and non-toxic protocols in nanostructure biosynthesis is a wealthy area for scientific research, wherein the use of microbes could be an auspicious alternative [131,132]. Fungi are more effective organisms for these purposes than other microbes because of their special features, including their greater growth capacity, greater potential to produce a variety of enzymes, richness in mycelial branching, ability to accumulate different metals, and capacity to grow in harsh environments [133].
A. sydowii derived from Bhavnagar coast water (Gulf of Khambhat, India) had a remarkable intra/extracellular capacity to biosynthesize gold nanoparticles with variable sizes depending on gold ion concentration [52]. Additionally, silver NPs were biosynthesized by Wang et al. using soil-derived A. sydowii culture supernatants. These NPs revealed an in vitro antiproliferative capacity against MCF-7 (human breast adenocarcinoma cell line) and HeLa cells and efficient antifungal potential versus various clinical pathogenic fungi [134].
Zhang et al. prepared magnetic chitosan microsphere-immobilized A. sydowii by utilizing the cross-linking of γ-Fe 2 O 3 magnetic chitosan nanocomposites with A. sydowii through the instant gelation method. This microsphere demonstrated marked Cu adsorp-tion capacity (19.21 mg/g) and good regeneration properties after four cycles, suggesting its potential application as a biosorbent for treating heavy metal-contaminated water [51].
The AgNPs synthesized by Nayak and Anitha from dune-associated A. sydowii had significant antimicrobial potential versus selected bacterial stains; its combination with vancomycin and ampicillin showed enhanced activity (by sevenfold against Shigella sp. and by sixfold against B. cereus and S. aureus [50]).
Organic waste and heavy metal removal from wastewater have always been a major concern for the environment. In order to simultaneously remove trichlorfon and cadmium from an aqueous solution, Zhang et al., in 2020, created magnetic chitosan beads-immobilized A. sydowii [49]. The beads demonstrated considerable trichlorfon and cadmium removal capabilities, as well as outstanding four-cycle recyclability. As a result, the beads are appropriate and efficient for removing cadmium and trichlorfon simultaneously from wastewater [49].

Conclusions
Fungi have been subjected to much research due to their significance as wealth generators for various enzymes and bio-metabolites, as well as being intriguing for applications in agricultural, industrial, and pharmaceuticals fields.
A. sydowii is a globally distributed fungus that was found to have the capacity to biosynthesize diverse classes of metabolites. In the current work, 246 metabolites were separated from A. sydowii in the period from 1975 to 2023 ( Figure 16). Most of these metabolites were reported from 2017 to 2022. from an aqueous solution, Zhang et al., in 2020, created magnetic chitosan beads-immobilized A. sydowii [49]. The beads demonstrated considerable trichlorfon and cadmium removal capabilities, as well as outstanding four-cycle recyclability. As a result, the beads are appropriate and efficient for removing cadmium and trichlorfon simultaneously from wastewater [49].

Conclusions
Fungi have been subjected to much research due to their significance as wealth generators for various enzymes and bio-metabolites, as well as being intriguing for applications in agricultural, industrial, and pharmaceuticals fields.
It was found that the coculture of this fungus with other microbes, as well as the modification of the culture media, significantly promoted the production of structurally varied metabolites, suggesting avenues of further research using these approaches for activating A. sydowii's silent biosynthetic genes toward the accumulation of various substantial compounds.
These metabolites were assessed for different bioactivities, including cytotoxic, antimicrobial, antioxidant, antiviral, anti-obesity, anti-inflammation, immunosuppression, anti-diabetic, protein tyrosine phosphatase 1B (PTP1B) inhibition, and anti-nematode activities ( Figure 18). This fungus was collected from different sources such as cultures, plants, marine environments (water, sea mud, sediment, gorgonian sea fans, algae, sponge, and driftwood), and liverworts. Most of the reported studies were carried out on A. sydowii isolated from marine sources. It is remarkable that this fungus has many enzymatic systems, which may help to explain why its metabolites are so diverse. Future studies will be useful in understanding the enzymes and genes responsible for the manufacture of these metabolites.
It was found that the coculture of this fungus with other microbes, as well as the modification of the culture media, significantly promoted the production of structurally varied metabolites, suggesting avenues of further research using these approaches for activating A. sydowii's silent biosynthetic genes toward the accumulation of various substantial compounds.
Compounds 195 and 196 displayed potent antioxidant activity. Compounds 67, 187, 192, and 239 demonstrated powerful cytotoxic potential. Compounds 2, 3, and 110 had notable antibacterial efficacy. Compounds 80, 81, 92, 94, and 234 displayed potent antiinfluenza virus activity. Furthermore, compound 45 was found to possess anti-diabetic and anti-obesity capacities through promoting glucose consumption and suppressing lipid accumulation, whereas compound 178 had a potent PTP1B inhibition capacity compared to suramin, suggesting its possible application in anti-diabetic and anti-sleeping sickness therapeutic agents.
Despite the large number of metabolites, biological evaluation has only been conducted for a limited number of them, mainly in vitro, and there is a lack of pharmacological investigations that focus on studying the possible action mechanisms of the active metabolites. Therefore, mechanistic and in vivo studies are recommended to clarify and validate potential mechanisms for the active metabolites. Moreover, studies on the structure-activity relationships of these metabolites should be carried out. Despite the large number of metabolites, biological evaluation has only been conducted for a limited number of them, mainly in vitro, and there is a lack of pharmacological investigations that focus on studying the possible action mechanisms of the active metabolites. Therefore, mechanistic and in vivo studies are recommended to clarify and validate potential mechanisms for the active metabolites. Moreover, studies on the structure-activity relationships of these metabolites should be carried out.
Additionally, molecular dynamic and docking studies could be employed to investigate the possible bioactivities of the untested metabolites.
On the other side, many of the tested metabolites displayed no notable effectiveness in some of the tested activities. Therefore, estimation of other possible bioactivities and molecular dynamic and docking studies, as well as derivatization of these metabolites, should clearly be the target of future research.
For further production of structurally varied metabolites by this fungus, cocultivation techniques should be considered an area for future investigation. In addition, exploring the biosynthetic pathways of these bio-metabolites is required and could enable the rational engineering or refactoring of these pathways for industrial purposes. Further, identification of the biosynthetic genes responsible for these metabolites may provide the opportunity to discover A. sydowii's genetic potential for discovering novel metabolites by metabolic engineering, which could lead to more affordable and novel pharmaceutics.
According to the published reports, A. sydowii can produce diverse types of enzymes with potential biotechnological and industrial applications. Research that focuses on engineering enzymes in such a way for maximum activity and stability under appropriate conditions is desirable. Recombinant DNA technology and engineering of proteins are required to improve the industrial production of these enzymes. A. sydowii can withstand high-salinity conditions, pointing to its biotechnological and industrial relevance. It was proven that this fungus adsorbed heavy metals and degraded pesticides, agrochemicals, and contaminants. As a result, A. sydowii might serve as an environmentally safe tool for Additionally, molecular dynamic and docking studies could be employed to investigate the possible bioactivities of the untested metabolites.
On the other side, many of the tested metabolites displayed no notable effectiveness in some of the tested activities. Therefore, estimation of other possible bioactivities and molecular dynamic and docking studies, as well as derivatization of these metabolites, should clearly be the target of future research.
For further production of structurally varied metabolites by this fungus, cocultivation techniques should be considered an area for future investigation. In addition, exploring the biosynthetic pathways of these bio-metabolites is required and could enable the rational engineering or refactoring of these pathways for industrial purposes. Further, identification of the biosynthetic genes responsible for these metabolites may provide the opportunity to discover A. sydowii's genetic potential for discovering novel metabolites by metabolic engineering, which could lead to more affordable and novel pharmaceutics.
According to the published reports, A. sydowii can produce diverse types of enzymes with potential biotechnological and industrial applications. Research that focuses on engineering enzymes in such a way for maximum activity and stability under appropriate conditions is desirable. Recombinant DNA technology and engineering of proteins are required to improve the industrial production of these enzymes. A. sydowii can withstand high-salinity conditions, pointing to its biotechnological and industrial relevance. It was proven that this fungus adsorbed heavy metals and degraded pesticides, agrochemicals, and contaminants. As a result, A. sydowii might serve as an environmentally safe tool for bioremediation and for converting hazardous materials into useful products. The minor reports described NP synthesis utilizing this fungus. These biosynthesized NPs possessed antiproliferative and antimicrobial potential as well as biosorbent capacity for treating heavy metal-and pesticide-contaminated water. However, the synthesized NPs using A. sydowii are limited to silver, γ-Fe 2 O 3 magnetic chitosan nanocomposites, and chitosan beads-immobilized A. sydowii. Therefore, future research should focus on developing protocols for implementing the biosynthesis of other types of NPs such as carbides, metal oxides, and nitrides using this fungus and their bio-evaluation, which could be a promising area for more anticipated beneficial effects.
Despite the large number of published studies on A. sydowii, mycologists, biologists, and chemists still need to conduct more extensive research to fully understand the potential of this fungus and its secondary metabolites.