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Quercetin' /ˈkwɜrsɨtɨn/, a plant-derived secondary metabolite, is the aglycone form of numerous bio-flavonoid O-glycosides such as rutin, isoquercitrin, hyperoside, and quercitrin, found most commonly in citrus fruits, buckwheat, onions, tea, and wine. Quercetin is an organic compound and chemically classified as a flavonoid, a class of polyphenolic pigments molecules containing a basic skeleton of diphenylpropane (C6–C3–C6). Quercetin is biosynthesized from dihydroquercetin, a type of flavanonol that participates in a reaction catalyzed by flavonol synthase. Flavanols have a 2-hydroxyflavone backbone structure and quercetin is distinguished from other flavonols by the distinct positioning of two of its five phenolic -OH groups giving it the structure 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H- chromen-4-one.

Biochemistry

File:Para-coumaryl CoA (2, three malonyl-CoA thioesters (3) chalcone (1).png

Step 2

File:Chalcone (1) (2S)-naringenin (4).png

Step 3

File:Naringenin (4) and dihydrokaempferol.png

Step 4

File:Dihydrokaempferol dihydroquercetin.png

Step 5

File:Dihydroquercetin quercetin.png

Step 6

Enzymatic biosynthesis pathway

The following steps details the biosynthesis pathway for quercetin in model plants, snapdragon, Arabidopsis, maize, and petunia.

Step 1: Phenylalanine is converted to para-coumaryl CoA in a series of steps known as the general phenylpropanoid pathway using phenylalanine ammonia-lyase, cinnamate-4-hydroxylase, and 4-coumaroyl-CoA-ligase.

Step 2: Chalcone synthase, a type III polyketide synthase, catalyzes the condensation of para-coumaryl CoA (2) and three malonyl-CoA thioesters (3) to give chalcone.

Step 3: Chalcone isomerase catalyzes the intramolecular cyclization of chalcone (1) to give (2S)-naringenin (4), a flavanone derivative of many flavonoids.

Step 4: Flavanone 3β-hydroxylase (FHT) catalyzes the B-ring hydroxylation of naringenin (4) to produce dihydrokaempferol, a type of dihydroflavanol.

Step 5: Dihydrokaempferol is converted to dihydroquercetin by the actions of Flavonoid 3′-hydroxylase.

Step 6: Flavonol synthase catalyzes the conversion of dihydroquercetin into quercetin.

Biosynthesis in the rutin degradation pathway

Studies have shown that ''Aspergillus flavus'' can synthesize quercetin through the catabolism of quercetin glycosides, such as rutin and quercitrin. The enzyme quercitrinase, in Aspergillus flavus, catalyzes the reaction between quercitrin/rutin and water to yield L-rhamnose and quercetin.

Quercitrin + H2O ⇌ L-rhamnose + Quercetin

Oxidative properties

Antioxidant properties

Quercetin is classified as an antioxidant because of its capabilities to prevent damage to important cellular components caused by reactive oxygen species (ROS), such as, peroxides and free radicals. Quercetin is an antioxidant molecule that exhibits radical-scavenging activities that aid in the process of removing radicals in biological organisms. The reductive properties of quercetin are attributed to the two phenolic hydroxyl groups, known as catechol group, which function as electron donating groups that are capable of being oxidized by electron deficient molecules in biological organisms such as superoxide anions, perhydroxyl radicals, and chain-propagating lipid peroxyl radicals. In addition to its reductive chemical properties, quercetin and its glycosides are classified as antioxidants because they are capable of inhibiting oxidative enzymes, such as xanthine oxidase, lipoxygenase and NADPH, which play a key role in initiating radical-induced cellular damage in biological organisms. Studies suggest that quercetin can competitively inhibit XO in vivo by acting on XOs molybdenum containing active site. XO inhibition, by the actions of quercetin can prevent XO from catalyzing the reduction of xanthine to Uric acid, which can decrease the rate of superoxide formation.

Prooxidant properties

Quercetin has also been shown to exhibit the paradoxical role of having both antioxidant and pro-oxidant activities. Although quercetin has been shown to promote cellular proliferation and increase total antioxidant capacities in vitro, it has also been shown to exhibit cytotoxic pro-oxidative abilities in vitro at high concentrations which was shown to decrease cellular viability. Quercetin's cytotoxicity is because it can exacerbate the effects oxidative stress when it is oxidized by superoxide to form semiquinone radicals, which can further react to form hydrogen peroxide in vitro.[1][7] Studies also show that quercetin has the ability to spontaneously autoxidize in vitro to generate free radicals such as superoxide and hydrogen peroxide. Research in vitro on quercetin’s carcinogenic pro-oxidant activities showed findings that it could induce oxidative DNA damage in cells that lead to apoptosis.

Medical applications

Quercetin's various metabolic functions makes it a popularly used secondary metabolite in traditional medicine to prevent and treat diseases such as cancer, cardiovascular and nervous diseases, obesity, and chronic inflammation. Due to its antioxidant, anti-tumor and anti-inflammatory activity, quercetin has been studied extensively as a chemoprevention agent in several cancer models, since it is thought to prevent tumor angiogenesis. Previous studies have also supported the merits of quercetin an enhancer of cardiovascular health because it has been shown to encourage blood flow and protects against LDL cholesterol oxidation through its anti oxidative abilities. However, "Quercetin has not been confirmed scientifically as a specific therapeutic for any condition nor approved by any regulatory agency."

Fate of Quercetin

Fate of Quercetin in rodents

Following dietary ingestion in rodents, quercetin undergoes rapid and extensive metabolism that makes the biological effects presumed from in vitro studies unlikely to apply in vivo. Rodents that were intravenously administered with the quercetin aglycone showed a rapid decrease in plasma quercetin concentrations and a lack of accumulation of quercetin in the tissues. These findings suggests that quercetin is quickly metabolized and excreted into the urine following an intravenous injection of the compound in rodents. Recent studies also suggest that monoglucoside derivatives of quercetin, such as isoquercitrin and Q4’G, are hydrolyzed and converted, through the actions of lactose phorizin hydrolase, into quercetin aglycones, which are absorbed at the brush border membranes in the small intestines. Quercetin can also be incorporated into intestinal epithelial cells through a sodium-dependent glucose transporter-1 (SGLT-1) pathway. Quercetin glycoside derivatives that are not monoglucosides such as hyperoside, or glycosides that contain multiple sugars, such as rutin, are deconjugated into quercetin aglycones by intestinal bacteria and subsequently absorbed in the large intestines. In humans, the quercetin aglycones that are absorbed in digestive tract are never present in the blood because they are transported through the lymphatic system to the liver, through the portal vein, immediately metabolized into the following metabolites: quercetin 3′-O-β-d-glucuronide (Q3′GA), quercetin 4′-O-β-d-glucuronide (Q4′GA), quercetin 3-O-β-d-glucuronide (Q3′GA), 3′-O-methyl quercetin 4′-O-β-d-glucuronide, 3′-O-methyl quercetin 3-O-β-d-glucuronide and quercetin 3′-O-sulfate.