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Vicine
Vicine
Vicine
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Vicine
Names
IUPAC name
2,6-Diamino-5-(β-D-glucopyranosyloxy)pyrimidin-4(1H)-one
Systematic IUPAC name
2,6-Diamino-5-{[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}pyrimidin-4(1H)-one
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.005.283 Edit this at Wikidata
UNII
  • InChI=1S/C10H16N4O7/c11-7-6(8(19)14-10(12)13-7)21-9-5(18)4(17)3(16)2(1-15)20-9/h2-5,9,15-18H,1H2,(H5,11,12,13,14,19)/t2-,3-,4+,5-,9+/m1/s1 checkY
    Key: KGNGTSCIQCLKEH-SYCVNHKBSA-N checkY
  • InChI=1/C10H16N4O7/c11-7-6(8(19)14-10(12)13-7)21-9-5(18)4(17)3(16)2(1-15)20-9/h2-5,9,15-18H,1H2,(H5,11,12,13,14,19)/t2-,3-,4+,5-,9+/m1/s1
    Key: KGNGTSCIQCLKEH-SYCVNHKBBM
  • O=C2\N=C(\N)NC(=C2/O[C@@H]1O[C@@H]([C@@H](O)[C@H](O)[C@H]1O)CO)/N
Properties
C10H16N4O7
Molar mass 304.259 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Vicine is an alkaloid glycoside found mainly in fava beans, which are also called broad beans (Vicia faba).[1] Vicine is toxic in individuals who have a hereditary loss of the enzyme glucose-6-phosphate dehydrogenase. It causes haemolytic anaemia, called favism. The formation of vicine in Vicia faba has been studied, but this natural formation has not yet been found.[2][3]

History

[edit]

Vicine was initially isolated in 1870 from the seeds of Vicia sativa by a method of extraction with sulfuric acid and subsequent precipitation with mercury sulfate (HgSO4). Later vicine was also found in other Vicia species, namely Vicia faba, beet juice and peas. The chemical structure of the compound was built gradually. First the glycosidic nature of the compound was recognized in 1896. The same year the aglycone of vicine, divicine, was isolated. In the beginning of the 20th century the pyrimidine structure was recognized. Despite these initial successes, the correct formula of vicine was determined only in 1953 and it is 2,4-diamino-6-oxypyrimidine-5-(β-D-glucopyranoside).[2]

Metabolism

[edit]

Vicine is an inactive compound in the body. When vicine enters the body through food, it is hydrolysed by intestinal microflora to the highly reactive free radical generating aglycone divicine.[2] Upon hydrolysis, the glucose part of the molecule is split off and that results in the reduced divicine. Divicine is then taken up in the blood through the intestinal epithelium.[4][5]

Adverse effects

[edit]

Adverse effects almost solely occur in humans that suffer from glucose-6-phosphate dehydrogenase deficiency. This deficiency causes a shortage of glutathione in erythrocytes and glutathione is needed for the neutralization of ROS (reactive oxygen species) created by the strongly oxidizing agent divicine.[5] Glucose-6-phosphate dehydrogenase deficiency is a common genetic condition, with a global prevalence of approximately 4.9%, affecting over 400 million individuals worldwide.[5][6] It is important to recognize that glucose-6-phosphate dehydrogenase deficiency can still be life-threatening if not promptly diagnosed and managed. Effective management often includes interventions as blood transfusions, but with appropriate care, full recovery from favism without lasting complications is the expected outcome.[7]

Indications

[edit]

Persons with G6PD deficiency are asymptomatic. An attack of acute haemolytic anaemia can appear out of nowhere and can be very severe and life-threatening. Indications of such a sudden attack of favism are dark urine, pallor, jaundice, abdominal pain and in most cases fever.[5]

Toxicity

[edit]

The β-glycosidic bond between glucose and the hydroxyl group at C5 on the pyrimidine ring are hydrolysed to yield the aglycone of vicine, divicine (2,6-diamino-4,5-dihydroxypyrimidine).[8] These aglycones have a strong oxidising capacity for glutathione.[9] In healthy individuals, this is not a problem, as glutathione can be reduced quickly enough to regenerate it. In individuals with a deficiency for glucose 6-phosphate dehydrogenase (G6PD) however, this results in haemolytic anaemia.[10]

Effects on animals

[edit]

A 10 g vicine /kg diet in laying hens led to reduced feed intake, egg weight, haemoglobin levels and fertility and increased liver weights, liver glutathione levels and plasma lipid levels. A diet with comparable levels of vicine per kg in pigs showed only small effects on protein and energy digestibility.[11]

In another study, laying and broiler hens were fed grains that were soaked for different periods of time, which partly or totally removed vicine. Hens that had had grains with vicine still in them showed a significant decrease in corpuscular haemoglobin, while the others did not.[12]

An in vivo study in rats showed that oral administration of vicine resulted in only small reductions in glutathione concentrations and no mortality. Intraperitoneal administration however, led to a rapid decrease in glutathione followed by death because of anoxia.[13]

References

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Vicine

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Vicine is a naturally occurring , chemically known as 2-[(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)oxy]-6-(hydroxymethyl)oxane-3,4,5-triol (CAS Number: 152-93-2), with the molecular formula C₁₀H₁₆N₄O₇ and a molecular weight of 304.26 g/mol. Found predominantly in the seeds of fava beans ( L.), where it can constitute up to 1.5% of the dry weight, vicine is also present in other legumes such as and in the seeds of bitter melon () at concentrations of 1–2% dry weight. In the , vicine is hydrolyzed by intestinal microflora into its aglycone divicine, a reactive compound that generates free radicals and oxidizes , leading to —known as favism—in individuals with (G6PD) deficiency. This condition affects an estimated 440 million people worldwide as of 2021, particularly in Mediterranean, Middle Eastern, and African populations, and can result in severe complications including hyperbilirubinemia, renal damage, and even death if untreated. Chemically, vicine belongs to the class of β-glucosides, featuring a glucose moiety linked to a base, and it co-occurs with the structurally similar convicine in fava beans, both contributing to the plant's anti-nutritional properties. Upon ingestion, these glycosides are metabolized into divicine and isouramil, potent oxidizing agents that disrupt integrity in G6PD-deficient individuals by depleting cellular antioxidants, a process exacerbated in neonates and infants due to immature enzyme systems. Favism episodes often occur shortly after consuming fava beans or related products, with symptoms including , , and dark urine, and the risk extends to breastfed infants if nursing mothers consume fava beans, as the metabolites can transfer via . Beyond its toxicity, vicine has garnered interest for potential therapeutic applications, including slow-acting hypoglycemic effects observed in studies on bitter melon extracts, positioning it as a non-steroidal agent for managing . Agricultural research has focused on breeding low-vicine faba bean cultivars to enhance and safety for and animal feed, with molecular markers enabling selection of lines containing less than 0.1% vicine-convicine content, thereby reducing favism risk while maintaining crop yield. Recent analyses using liquid chromatography-mass spectrometry (LC-MS/MS) have identified over 100 vicine derivatives in faba beans, including sugar-modified and acid-conjugated forms, highlighting the compound's structural diversity and biosynthetic pathways in plants.

Chemistry

Molecular Structure

Vicine is a with the molecular formula C₁₀H₁₆N₄O₇ and a molecular weight of 304.26 g/mol. The compound is systematically named 2,4-diamino-5-(β-D-glucopyranosyloxy)-1H-. It features a central ring bearing amino groups at the 2- and 4-positions, a tautomeric keto group at the 6-position, and a β-D-glucopyranosyloxy linked via an O-glycosidic bond at the 5-position. This arrangement positions vicine as a analog, with the glucosyl moiety contributing to its glycosidic nature. Early structural proposals for vicine underwent revision, with initial misidentifications corrected in to confirm the current formulation. Vicine shares structural similarity with convicine, a related compound differing in the ring by having a carboxamide group at the 4-position instead of an amino group, while retaining the β-D-glucopyranosyloxy group at the 5-position.

Physical and Chemical Properties

Vicine appears as a white to off-white crystalline solid at . It exhibits moderate in , with reported values ranging from approximately 1.5 mg/mL at 2°C to higher levels around 10 mg/mL in aqueous solutions at ambient temperatures, increasing further with rising temperature up to 60°C; this is attributed to its polar structure. Vicine is moderately soluble in alcohols such as , as demonstrated by common extraction protocols using these solvents, but it is insoluble in non-polar solvents due to its hydrophilic nature. Vicine demonstrates sensitivity to acidic , which cleaves the to yield divicine, and to enzymatic degradation by β-glucosidases; it remains relatively stable at neutral but undergoes partial degradation during thermal processing, with approximately 19% loss observed upon . Spectroscopically, vicine shows characteristic UV absorption maxima in the range of 260-280 nm attributable to its ring, with peaks at 274 nm in acidic conditions (0.1 N HCl), 275 nm at neutral (6.8), and 269 nm in basic conditions (pH 13); these properties facilitate its detection and quantification in analytical methods such as HPLC-UV. The approximate pKa values for vicine's nitrogens are around 3.2 and 9.6, influencing its ionization and solubility behavior in biological and aqueous media.

Occurrence and Biosynthesis

Natural Sources

Vicine is primarily found in the seeds of fava beans ( L.), where it accumulates predominantly in the cotyledons, reaching concentrations of up to 0.7% of the dry weight in typical cultivars. This serves as a natural defense compound in the , with levels varying widely across collections, from as low as 0.4 mg/g to over 6 mg/g dry seed weight. Vicine is also found in the seeds of bitter melon (), a non-legume cucurbit, at concentrations of 1–2% dry weight. In related species such as common vetch ( L.), vicine occurs at generally lower concentrations, typically around 0.2–8 mg/g dry seed weight, depending on the . Trace amounts have been reported in other legumes, but it is absent or undetectable in major crops like chickpeas (Cicer arietinum), soybeans (Glycine max), lentils (Lens culinaris), and peas (Pisum sativum). The content of vicine in V. faba is highly variable, influenced by genetic factors, environmental conditions such as sowing time and , and seed maturity stage, with concentrations peaking in immature seeds and declining as pods ripen. Wild or traditional varieties generally exhibit higher levels compared to modern cultivated low-vicine breeding lines developed for improved nutritional safety. Vicine often co-occurs with its analog convicine in fava bean seeds, with total vicine-convicine levels ranging from 5 to 15 mg/g dry weight across genotypes.

Biosynthetic Pathway

The biosynthesis of vicine in faba bean (Vicia faba) begins with the purine nucleotide guanosine triphosphate (GTP) as the primary precursor, diverging from earlier assumptions of a pyrimidine origin. The pathway proceeds through intermediates in the riboflavin biosynthesis route, where GTP is converted to 2,5-diamino-6-ribosylamino-4(3H)-pyrimidinone (DARPP) in the initial committed step. This reaction is catalyzed by the enzyme encoded by the VC1 gene, which exhibits GTP cyclohydrolase II activity and also functions bifunctionally in riboflavin production. Subsequent transformations involve hydrolysis of the ribosyl group (potentially mediated by a COG3236 domain-containing enzyme), deamination to form a divicine-like aglycone, and final glycosylation with uridine diphosphate glucose (UDP-glucose) to yield vicine. A parallel branch leads to convicine via a similar glucosylation of isouramil. The gene, identified through gene-to-metabolite correlations, mapping, and complementation studies, represents a pivotal discovery in that elucidates the shared early steps for both vicine and convicine production. Located on , VC1 (also homologous to RIBA1 in other ) shows high sequence conservation but includes variants that disrupt function, such as a 2-bp insertion causing a in low-vicine cultivars, reducing accumulation by 10- to 40-fold. A related , RIBA2, contributes modestly (5-10%) to the pathway flux. Isotope-labeling experiments with 13^{13}C10_{10}, 15^{15}N5_5-GTP confirmed the origin, with labeled vicine incorporating the precursor's atoms efficiently. Expression of VC1 is tightly regulated, peaking during early seed-filling stages in developing seeds, particularly in maternal seed coats where it is upregulated up to eightfold compared to embryos. This temporal and tissue-specific pattern ensures vicine deposition aligns with seed maturation. Genetic variations, including copy number variants (CNVs) ranging from 2 to 5 copies per across genotypes, influence accumulation; however, dosage insensitivity prevails, as only a single VC1 allele is typically expressed per due to mechanisms like allele-specific silencing or epigenetic regulation (e.g., ). High-vicine genotypes express functional alleles (VC1A or VC1C), while low-vicine lines predominantly express the non-functional vc1b, correlating with 5-fold lower transcript levels and minimal vicine content (e.g., ~0.04% dry weight versus 0.5-1% in high accumulators). Evolutionarily, the vicine biosynthetic pathway likely arose as a mechanism in , deterring herbivores and pathogens through the generation of upon ; it induces hemolytic effects in sensitive animals, suggesting selective pressure for its retention in species. Independent evolution is inferred from its presence in distantly related plants like bitter melon (), where analogous pathways protect against .

History

Discovery and Isolation

Vicine was first isolated in 1870 from the seeds of common vetch ( L.) by German chemists Hermann Ritthausen and Wilhelm Kreusler. Their procedure involved extracting the ground seeds with dilute or 80% alcohol, followed by precipitation using to obtain the crude compound. This marked the initial identification of vicine as a distinct substance present in leguminous plants. In the late , vicine was recognized as a based on its chemical behavior and properties, though its full structure remained unclear at the time. By 1914, American chemist Treat B. Johnson isolated vicine from fava beans ( L.), establishing its presence in this species and beginning to connect it to the toxic effects observed in fava bean consumption. These early efforts were driven by investigations into favism, a hemolytic condition known since ancient times—legendarily linked to ' prohibition against eating fava beans in the 6th century BCE, as recorded in classical texts warning of fatal risks for susceptible individuals. Over the , isolation techniques evolved to improve yield and purity. Modern methods typically begin with defatting faba bean seeds to remove , followed by extraction using 80% or similar solvents to solubilize the . The extract is then purified via chromatography, such as reversed-phase (HPLC) on C18 columns with acidic mobile phases like 0.1% in water, achieving purities of up to 90% for analytical and purposes. These advancements have facilitated detailed studies of vicine's role in while minimizing impurities from co-occurring compounds like convicine.

Structural Determination

The determination of vicine's chemical structure progressed through several decades of research, marked by initial inaccuracies that were gradually resolved through experimental analysis. In 1914, P.A. Levene proposed an of C₁₀H₁₄N₄O₆ for vicine, characterizing it as a 3-N-glucoside of 2,5-diamino-4,6-dioxypyrimidine based on and early degradation studies. This formulation, however, was erroneous, as subsequent investigations revealed inconsistencies in the nitrogen linkage and overall composition. Hydrolysis experiments in the intervening years provided critical insights, demonstrating that vicine yielded glucose and a pyrimidine aglycone upon acid or enzymatic breakdown, indicating a rather than the N-linked structure suggested by Levene. These studies highlighted the compound's glucoside nature but failed to pinpoint the exact substitution pattern due to limitations in analytical precision at the time. A pivotal advancement occurred in 1953, when Aaron Bendich and Grace B. Clements definitively established vicine's structure as 2,4-diamino-6-oxypyrimidine-5-β-D-glucopyranoside through a combination of degradative techniques, spectroscopic analysis, and total synthesis. Degradation involved periodate oxidation to confirm the β-glycosidic linkage and the aglycone divicine (2,4-diamino-5,6-dioxypyrimidine), while UV spectroscopy matched vicine's absorption spectra with synthetic analogs like 2,4-diamino-5-ethoxy-6-oxypyrimidine. Synthesis of the proposed structure further validated these findings, resolving prior ambiguities and confirming the O-glycoside at the 5-position. In subsequent decades, modern spectroscopic methods have corroborated and refined this structure. (NMR) has elucidated the precise of the glucopyranoside moiety and the ring protons, while provides molecular weight confirmation (m/z 305 [M+H]⁺) and fragmentation patterns consistent with the . (IR) identifies key functional groups, such as the carbonyl at approximately 1650 cm⁻¹ and O-H stretches from the glucose unit. Vicine's structure is distinguished from that of the related compound convicine through aglycone analysis following hydrolysis: vicine yields divicine, whereas convicine produces isouramil (2-amino-4-hydroxy-6-oxypyrimidine-5-β-D-glucopyranoside's aglycone), reflecting differences in pyrimidine substitution that affect their reactivity and biological effects.

Metabolism

Enzymatic Hydrolysis

Vicine undergoes enzymatic hydrolysis through the action of β-glucosidase enzymes, which cleave the β-glucosidic bond at the C-5 position of its pyrimidine ring, yielding divicine as the aglycone and D-glucose as the sugar moiety. The reaction can be represented as: Vicine+H2O→β-glucosidasedivicine+D-glucose\text{Vicine} + \text{H}_2\text{O} \xrightarrow{\beta\text{-glucosidase}} \text{divicine} + \text{D-glucose}
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