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Purine
Skeletal formula with numbering convention
Ball-and-stick molecular model
Space-filling molecular model
Names
IUPAC name
9H-purine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.004.020 Edit this at Wikidata
KEGG
MeSH Purine
UNII
  • InChI=1S/C5H4N4/c1-4-5(8-2-6-1)9-3-7-4/h1-3H,(H,6,7,8,9) checkY
    Key: KDCGOANMDULRCW-UHFFFAOYSA-N checkY
  • InChI=1/C5H4N4/c1-4-5(8-2-6-1)9-3-7-4/h1-3H,(H,6,7,8,9)
    Key: KDCGOANMDULRCW-UHFFFAOYAO
  • c1c2c(nc[nH]2)ncn1
Properties
C5H4N4
Molar mass 120.115 g·mol−1
Melting point 214 °C (417 °F; 487 K)
500 g/L (RT)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Purine is a heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines and their tautomers. They are the most widely occurring nitrogen-containing heterocycles in nature.[1]

Dietary sources

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Purines are found in high concentration in meat and meat products, especially internal organs, such as liver and kidney, and in various seafoods, high-fructose beverages, alcohol, and yeast products.[2][3] Examples of high-purine food sources include anchovies, sardines, liver, beef, kidneys, brains, monkfish, dried mackerel, and shrimp.[3]

Foods particularly rich in hypoxanthine, adenine, and guanine lead to higher blood levels of uric acid.[3] Foods having more than 200 mg of hypoxanthine per 100 g, particularly animal and fish meats containing hypoxanthine as more than 50% of total purines, are more likely to increase uric acid levels.[3] Some vegetables, such as cauliflower, spinach, and peas, have considerable levels of purines, but do not contribute to elevated uric acid levels, possibily due to digestion and bioavailability factors.[3]

Dairy products, soy foods, cereals, beans, mushrooms, and coffee are low-purine foods, characterized specifically by low levels of adenine and guanine comprising more than 60% of purines.[3] A low-purine dietary plan that may reduce the risk of hyperuricemia and gout includes eggs, dairy products, fruits, vegetables, legumes, mushrooms, and soy products.[2][3][4]

Biochemistry

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Purines and pyrimidines make up the two groups of nitrogenous bases, including the two groups of nucleotide bases. The purine bases are guanine (G) and adenine (A) which form corresponding nucleosides-deoxyribonucleosides (deoxyguanosine and deoxyadenosine) with deoxyribose moiety and ribonucleosides (guanosine, adenosine) with ribose moiety. These nucleosides with phosphoric acid form corresponding nucleotides (deoxyguanylate, deoxyadenylate and guanylate, adenylate) which are the building blocks of DNA and RNA, respectively. Purine bases also play an essential role in many metabolic and signalling processes within the compounds guanosine monophosphate (GMP) and adenosine monophosphate (AMP).

In order to perform these essential cellular processes, both purines and pyrimidines are needed by the cell, and in similar quantities. Both purine and pyrimidine are self-inhibiting and activating. When purines are formed, they inhibit the enzymes required for more purine formation. This self-inhibition occurs as they also activate the enzymes needed for pyrimidine formation. Pyrimidine simultaneously self-inhibits and activates purine in a similar manner. Because of this, there is nearly an equal amount of both substances in the cell at all times.[5]

Properties

[edit]

Purine is both a very weak acid (pKa 8.93) and an even weaker base (pKa 2.39).[6]

Purine is aromatic, having four tautomers each with a hydrogen bonded to a different one of the four nitrogen atoms. These are identified as 1-H, 3-H, 7-H, and 9-H (see image of numbered ring). The common crystalline form favours the 7-H tautomer, while in polar solvents both the 9-H and 7-H tautomers predominate.[7] Substituents to the rings and interactions with other molecules can shift the equilibrium of these tautomers.[8]

Notable purines

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There are many naturally occurring purines. They include the nucleotide bases adenine and guanine. In DNA, these bases form hydrogen bonds with their complementary pyrimidines, thymine and cytosine, respectively. This is called complementary base pairing. In RNA, the complement of adenine is uracil instead of thymine.

Other notable purines are hypoxanthine, xanthine, theophylline, theobromine, caffeine, uric acid and isoguanine.

Functions

[edit]

Aside from the crucial roles of purines (adenine and guanine) in DNA and RNA, purines are also significant components in a number of other important biomolecules, such as ATP, GTP, cyclic AMP, NADH, and coenzyme A. Purine (1) itself, has not been found in nature, but it can be produced by organic synthesis.

They may also function directly as neurotransmitters, acting upon purinergic receptors. Adenosine activates adenosine receptors.

History

[edit]

The word purine (pure urine)[9] was coined by the German chemist Emil Fischer in 1884.[10][11] He synthesized it for the first time in 1898.[11] The starting material for the reaction sequence was uric acid (8), which had been isolated from kidney stones by Carl Wilhelm Scheele in 1776.[12] Uric acid was reacted with PCl5 to give 2,6,8-trichloropurine, which was converted with HI and PH4I to give 2,6-diiodopurine. The product was reduced to purine using zinc dust.

Conversion of uric acid (left) to purine (right) via 2,6,8-trichloropurine and 2,6-diiodopurine intermediates

Metabolism

[edit]
Main article: Purine metabolism

Many organisms have metabolic pathways to synthesize and break down purines.

Purines are biologically synthesized as nucleosides (bases attached to ribose).

Accumulation of modified purine nucleotides is defective to various cellular processes, especially those involving DNA and RNA. To be viable, organisms possess a number of deoxypurine phosphohydrolases, which hydrolyze these purine derivatives removing them from the active NTP and dNTP pools. Deamination of purine bases can result in accumulation of such nucleotides as ITP, dITP, XTP and dXTP.[13]

Defects in enzymes that control purine production and breakdown can severely alter a cell's DNA sequences, which may explain why people who carry certain genetic variants of purine metabolic enzymes have a higher risk for some types of cancer.

Purine biosynthesis in the three domains of life

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Organisms in all three domains of life, eukaryotes, bacteria and archaea, are able to carry out de novo biosynthesis of purines. This ability reflects the essentiality of purines for life. The biochemical pathway of synthesis is very similar in eukaryotes and bacterial species, but is more variable among archaeal species.[14] A nearly complete, or complete, set of genes required for purine biosynthesis was determined to be present in 58 of the 65 archaeal species studied.[14] However, also identified were seven archaeal species with entirely, or nearly entirely, absent purine encoding genes. Apparently the archaeal species unable to synthesize purines are able to acquire exogenous purines for growth.,[14] and are thus analogous to purine mutants of eukaryotes, e.g. purine mutants of the Ascomycete fungus Neurospora crassa,[15] that also require exogenous purines for growth.

Laboratory synthesis

[edit]

In addition to in vivo synthesis of purines in purine metabolism, purine can also be synthesized artificially.

Purine is obtained in good yield when formamide is heated in an open vessel at 170 °C for 28 hours.[16]

This reaction and others like it have been discussed in the context of the origin of life.[17]

Oro and Kamat (1961) and Orgel co-workers (1966, 1967) have shown that four molecules of HCN tetramerize to form diaminomaleodinitrile (12), which can be converted into almost all naturally occurring purines.[18][19][20][21][22] For example, five molecules of HCN condense in an exothermic reaction to make adenine, especially in the presence of ammonia.

The Traube purine synthesis (1900) is a classic reaction (named after Wilhelm Traube) between an amine-substituted pyrimidine and formic acid.[23]

Traube purine synthesis

Prebiotic synthesis of purine ribonucleosides

[edit]

In order to understand how life arose, knowledge is required of the chemical pathways that permit formation of the key building blocks of life under plausible prebiotic conditions. Nam et al. (2018)[24] demonstrated the direct condensation of purine and pyrimidine nucleobases with ribose to give ribonucleosides in aqueous microdroplets, a key step leading to RNA formation. Also, a plausible prebiotic process for synthesizing purine ribonucleosides was presented by Becker et al. in 2016.[25]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Purine

View on Grokipedia
from Grokipedia
Purine is a heterocyclic aromatic organic compound with the molecular formula C5H4N4, characterized by a bicyclic structure consisting of a six-membered pyrimidine ring fused to a five-membered imidazole ring. This core scaffold forms the basis for the purine nucleobases adenine and guanine, which are essential components of nucleic acids, DNA and RNA, comprising half of their nucleotide building blocks. Beyond their role in genetic material, purines are critical in cellular metabolism, serving as precursors for high-energy molecules like ATP (adenosine triphosphate), which powers numerous biochemical reactions, and as cofactors that support cell growth and proliferation. Purines are synthesized de novo in cells through a complex pathway involving contributions from such as , aspartate, and , as well as one-carbon units from tetrahydrofolate and , ultimately assembling the purine ring step by step on a ribose-5-phosphate backbone to form inosine monophosphate (), the first complete purine . is then converted to AMP (adenosine monophosphate) and GMP (guanosine monophosphate), which are further phosphorylated to ADP, ATP, GDP, and GTP for energy transfer and signaling functions. In to biosynthesis, purines participate in salvage pathways that recycle free bases and nucleosides, conserving energy and maintaining nucleotide pools. Extracellular purines, including ATP, ADP, and , act as signaling molecules in purinergic systems, binding to P1 () and P2 (ATP/ADP) receptors on cell surfaces to regulate processes such as , , vascular tone, and immune responses. Dysregulation of can lead to disorders like , caused by from excessive (the end product of purine ), Lesch-Nyhan syndrome due to defects in , or contributions to cancer and neurodegenerative diseases through altered signaling or imbalances. Purines also play roles in and have been detected in , suggesting potential prebiotic significance.

Structure and Properties

Molecular Structure

Purine is a heterocyclic aromatic consisting of a six-membered ring fused to a five-membered ring, forming a bicyclic structure that serves as the core scaffold for various nucleobases. This fused ring system combines the nitrogen-rich frameworks of (a with nitrogens at positions 1 and 3) and (a five-membered ring with nitrogens at positions 1 and 3), resulting in a planar, with four atoms contributing to its . The molecular formula of purine is C₅H₄N₄, with a standard numbering system that assigns positions 1, 3, 7, and 9 to the atoms and positions 2, 4, 5, 6, and 8 to the carbon atoms, starting from the ring and proceeding through the fusion points at C4-C5 and N7-C8. In the predominant 9H-tautomer, the is attached to N9, and the structure includes alternating double bonds, such as C2=N3 in the ring and C4=C5 at the fusion site, along with delocalized electrons across both rings to maintain aromatic stability. Purine exists in multiple tautomeric forms due to the mobility of the among its four sites, but the primary tautomers are the 7H and 9H variants, with the equilibrium in solution strongly favoring the 9H form by a significant margin as determined through matrix isolation and calculations. This preference arises from the energetic stability of the 9H configuration, which better accommodates the aromatic electron distribution in the ring.

Physical Properties

Purine appears as a white to off-white powder under standard conditions. Its molecular formula is C₅H₄N₄, corresponding to a molecular weight of 120.11 g/mol. The compound melts at approximately 214–217 °C, at which point it begins to decompose without a distinct liquid phase. Purine does not have a defined , as it sublimes at elevated temperatures above its . In terms of , purine is highly soluble in , with a reported value of 400 g/L at 20 °C; solubility increases further in hot . It is also soluble in , , acetone, and hot , and it forms salts that enhance solubility in dilute acids and bases. Spectroscopically, purine exhibits characteristic UV absorption maxima at around 220 nm and 263 nm in neutral , which are attributable to its conjugated heterocyclic and are commonly used for its quantitative detection in biochemical assays.

Chemical Properties

Purine displays amphoteric behavior, acting as both a and a due to the presence of atoms in its fused . The pKa value for at the N1 position, reflecting its basicity, is approximately 2.4, while the pKa for at the N9-H, indicating its acidity, is approximately 9.8. These values position purine in a neutral form under physiological conditions, with favored in strongly acidic media and in basic environments. The stability of purine is significantly enhanced by its aromatic character, arising from a delocalized π-electron system across the and rings, which follows with 10 π electrons. This delocalization contributes to the molecule's resistance to and confers planarity to the ring system, minimizing strain and promoting overall thermodynamic stability. In terms of reactivity, purine undergoes primarily at the C8 and C2 positions of the imidazole and pyrimidine rings, respectively, due to the relative at these sites facilitated by the electron-rich aromatic framework. Conversely, occurs at the C6 and C2 positions, particularly when activated by good leaving groups such as , enabling displacement under milder conditions at C6 compared to C2. Purine exhibits a moderate oxidation potential, rendering it susceptible to one-electron oxidation under mild conditions to form radical cations or derivatives like 8-hydroxypurine, often initiated by . This reactivity underscores its role in pathways but also highlights vulnerability to environmental oxidants. Regarding stability in aqueous media, purine remains resistant to at neutral , maintaining structural integrity over extended periods, though it shows sensitivity to strong oxidizing agents that can disrupt the .

Biological Functions

Role in Nucleic Acids

Purines play a central role in the structure and function of nucleic acids, serving as two of the four nucleobases in both DNA and RNA. Adenine, chemically known as 6-aminopurine, and guanine, known as 2-amino-6-oxopurine, are the purine components that integrate into these biopolymers. These bases attach to a sugar moiety—deoxyribose in DNA or ribose in RNA—to form nucleosides such as deoxyadenosine, adenosine, deoxyguanosine, and guanosine. Further phosphorylation of these nucleosides at the 5' position of the sugar yields nucleotides, including deoxyadenosine monophosphate (dAMP), adenosine monophosphate (AMP), deoxyguanosine monophosphate (dGMP), and guanosine monophosphate (GMP), which are the monomeric units polymerized into DNA and RNA strands. The specific base-pairing rules governed by hydrogen bonds ensure the fidelity of genetic information storage and transfer in nucleic acids. In DNA, pairs with via two hydrogen bonds, while pairs with via three hydrogen bonds, contributing to the stability of . In RNA, pairs with uracil through two hydrogen bonds, and continues to pair with using three, facilitating processes like mRNA-tRNA interactions during . This complementary pairing adheres to , which dictate that in double-stranded DNA, the proportion of purine bases ( plus ) equals that of pyrimidine bases ( plus ), resulting in approximately 50% of the bases being purines. Beyond hydrogen bonding, purines contribute to the structural integrity of the through base-stacking interactions. Adjacent bases along the axis engage in π-π stacking, where the planar aromatic rings of purines like and overlap with neighboring bases, providing hydrophobic stabilization and resisting unwinding forces. These stacking interactions, particularly involving purine-purine pairs, enhance the overall rigidity and thermal stability of the helical structure, complementing the specificity of base pairing to maintain the genetic blueprint.

Roles in Metabolism and Signaling

Purines play essential roles in cellular energy metabolism through their incorporation into nucleoside triphosphates such as (ATP) and (GTP), which serve as universal energy currencies. The high-energy phosphoanhydride bonds in these molecules enable the storage and transfer of energy for endergonic processes, including , , and mechanical work. For instance, the hydrolysis of ATP to (ADP) and inorganic (P_i) releases energy via the reaction ATP → ADP + P_i, with a standard free energy change (\Delta G^{\circ'}) of approximately -30.5 kJ/mol under physiological conditions. Similarly, GTP hydrolysis powers specific reactions, such as protein synthesis during , highlighting the complementary functions of these purine-based triphosphates in maintaining cellular . Beyond energy transfer, purines contribute to redox metabolism as components of key coenzymes. (NAD^+), which contains the purine base , functions as an carrier in catabolic pathways like , the tricarboxylic acid cycle, and fatty acid oxidation, facilitating hydride transfer in two-electron reactions. Flavin adenine dinucleotide (FAD), also featuring , participates in flavoprotein-mediated oxidations, such as those in the and , where it accepts electrons to form FADH_2. These coenzymes link purine structures to the regulation of oxidative processes essential for ATP production and . In cellular signaling, purine derivatives act as critical second messengers that amplify extracellular signals. (cAMP), derived from ATP, mediates responses to hormones like and epinephrine by activating , which phosphorylates targets to influence , , and activity. (cGMP), formed from GTP, regulates pathways involving and , modulating relaxation, phototransduction in vision, and vascular through activation of protein kinase G. These cyclic nucleotides enable rapid, localized , distinguishing purines' dynamic regulatory roles from their structural functions in nucleic acids, where they primarily facilitate base pairing. Purines also function in protective and salvage mechanisms, with serving as a potent in like humans that lack uricase activity. neutralizes , mitigating in conditions such as and neurodegeneration, thereby contributing to evolutionary adaptations in metabolic resilience. Additionally, hypoxanthine, a purine intermediate, is central to the salvage pathway, where it is recycled by to form , conserving energy and preventing wasteful . The involvement of purines in these processes underscores their evolutionary conservation as hubs in core metabolic networks. Purine metabolism genes have undergone selective pressures across mammals, enhancing oxidative stress adaptation and integrating into universal pathways like energy production and signaling, which trace back to early cellular life forms. This conservation reflects purines' foundational role in linking , balance, and environmental responsiveness across diverse organisms.

Metabolism

Biosynthesis

Purine nucleotides are synthesized endogenously through two primary pathways: the de novo biosynthesis pathway, which constructs the purine ring from simple precursors, and the salvage pathway, which recycles free purine bases. The de novo pathway is a 10-step process that begins with phosphoribosyl pyrophosphate (PRPP) and culminates in the formation of inosine monophosphate (IMP), the first purine nucleotide. This pathway requires six enzymes in eukaryotes, including glutamine-PRPP amidotransferase (also known as PRPP amidotransferase), which catalyzes the committed first step by transferring an amide group from glutamine to PRPP, forming phosphoribosylamine (PRA); glycinamide ribonucleotide (GAR) transformylase, which adds a formyl group in the third step; and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, which performs the final formylation in the 10th step. The process consumes six high-energy phosphate bonds equivalent to ATP molecules per IMP produced, highlighting its metabolic cost. The salvage pathway provides a more energy-efficient alternative by reutilizing purine bases derived from dietary sources or nucleotide degradation. Key enzymes include (HGPRT), which catalyzes the conversion of hypoxanthine to and guanine to (GMP) using PRPP, and adenine phosphoribosyltransferase (APRT), which converts to (AMP). These reactions conserve PRPP and bypass the energy-intensive de novo assembly, making salvage particularly important in tissues with high nucleotide turnover, such as the . Variations in purine biosynthesis exist across biological domains. In , the pathway is often organized into the , a coordinated that facilitates efficient and expression under varying conditions. Eukaryotes perform entirely in the , with enzymes forming dynamic complexes known as purinosomes to enhance efficiency. In , the pathway exhibits greater variability, including distinct amidotransferases for the initial step and alternative enzymes for certain transformations, such as non-homologous versions of AIR carboxylase and SAICAR synthetase, reflecting adaptations to extreme environments. Regulation of purine biosynthesis primarily occurs through feedback inhibition at early steps to prevent overproduction. The rate-limiting enzyme, PRPP amidotransferase, is allosterically inhibited by binding of AMP and GMP to separate regulatory sites, with synergistic effects when both are present; also exerts milder inhibition. This end-product inhibition balances nucleotide pools according to cellular needs. serves as a precursor, being converted to AMP via adenylosuccinate synthetase and lyase or to GMP via IMP dehydrogenase and GMP synthetase.

Catabolism and Uric Acid Formation

Purine catabolism involves the sequential degradation of purine to nucleosides and then to free bases, ultimately leading to as the primary end product in humans. This process begins with the dephosphorylation of such as (AMP) to by , followed by the deamination of to by adenosine deaminase (ADA). is then converted to hypoxanthine via phosphorolysis catalyzed by purine nucleoside (PNP). Similarly, (GMP) follows a parallel path through to , which is deaminated to by guanine deaminase. Hypoxanthine is oxidized to xanthine by xanthine oxidase (XO), and xanthine is further oxidized to uric acid by the same enzyme, marking the terminal steps of purine breakdown. XO catalyzes these reactions using molecular oxygen as the electron acceptor, producing hydrogen peroxide (H₂O₂) as a byproduct in each step, with two molecules of H₂O₂ generated overall during the conversion of hypoxanthine to uric acid. Some catabolic intermediates, such as hypoxanthine and guanine, can be briefly recycled into nucleotides via salvage pathways. Species exhibit significant variations in purine due to differences in the enzyme (uricase). In humans and other hominoid primates, functional uricase is absent, resulting in as the end product, which is less soluble than further metabolites. Birds and reptiles also excrete as their primary nitrogenous waste, aiding in . In contrast, most other mammals possess active uricase, which oxidizes to the more soluble for excretion. In humans, approximately 70% of daily uric acid production arises from endogenous turnover of nucleic acids and , with the remainder from dietary sources. Uric acid is primarily excreted via the kidneys, accounting for about 70% of total elimination, while the intestines handle the rest through bacterial degradation. Imbalances in this catabolic pathway can lead to , defined by serum uric acid levels exceeding 6.8 mg/dL—the saturation threshold at physiological and temperature—which promotes monosodium urate formation and .

Sources and Synthesis

Dietary Sources

Purines and their derivatives, such as and , are naturally occurring compounds found in various foods, particularly those of animal origin, though plant-based sources also contribute in smaller amounts. High-purine foods are often energy-dense and include organ meats and certain , which can significantly influence levels upon . Organ meats represent some of the richest dietary sources of purines, with values typically ranging from 100 to 400 mg per 100 g. For instance, beef liver contains approximately 220–231 mg/100 g, while beef has about 112–174 mg/100 g. , another high-purine category, often exceeds 200 mg/100 g; anchovies provide around 239–321 mg/100 g, and sardines are similarly elevated at 210–480 mg/100 g depending on preparation. Yeast extracts, used in products like spreads and broths, can contain even higher levels, up to 600–1000 mg/100 g, making them potent sources. Moderate-purine foods include red meats and , generally providing 50–150 mg/100 g. cuts range from 77 to 123 mg/100 g, and is comparable at 50–140 mg/100 g. such as beans and lentils fall in a similar range of 50–100 mg/100 g, with dry black mung beans reaching up to 222 mg/100 g in some varieties, though most are lower. Low-purine options, suitable for restricting intake, encompass products, most , and grains, all typically under 50 mg/100 g. and cheeses contain less than 10 mg/100 g, while vegetables like or may reach 20–50 mg/100 g but are still considered minimal contributors. Grains such as or provide negligible amounts, often below 20 mg/100 g. In typical Western diets, daily purine intake averages 600–1000 mg, primarily from , , and processed foods. These dietary purines are absorbed mainly in the as via concentrative nucleoside transporters, before being metabolized to in the liver and other tissues. This exogenous input supplements the endogenous purine pool, with ultimately yielding as the primary end product.
CategoryExamplesPurine Content (mg/100 g)
HighBeef liver, anchovies, yeast extracts200–1000
ModerateBeef, chicken, lentils50–150
Low, , <50

Laboratory Synthesis

The laboratory synthesis of purine primarily relies on classical organic methods that construct the fused imidazole-pyrimidine ring system through targeted ring closures, with the Traube synthesis serving as the foundational approach. Introduced by Wilhelm Traube in 1900, this method begins with the preparation of 4,5-diaminopyrimidine precursors, which are then condensed with formic acid or its derivatives under heating in acidic conditions to form the five-membered imidazole ring and complete the purine structure. The reaction typically achieves yields of 50-70% when performed at elevated temperatures around 100-150°C for several hours, making it efficient for small-scale production despite the need for multi-step precursor synthesis involving nitrosation and reduction. This route has been widely adopted for its simplicity and versatility in introducing substituents at key positions, such as C6 or C2, by modifying the pyrimidine starting material. Alternative chemical routes to purine diverge by prioritizing imidazole ring construction first, followed by fusion with pyrimidine components. For instance, 4,5-diaminoimidazole derivatives can be cyclized with carboxylic acid equivalents or orthoesters to build the six-membered ring, offering flexibility for N7-substituted purines that are challenging via pyrimidine-first methods. Ring closure strategies on pyrimidine derivatives, beyond the Traube variant, often employ urea or cyanogen bromide to bridge adjacent amino groups, enabling the synthesis of hypoxanthine or xanthine analogs as intermediates en route to unsubstituted purine. These pathways typically proceed in 40-60% overall yields across 3-5 steps, depending on substituent complexity, and are favored when imidazole stability or specific isotopic labeling at N7-N9 is required. Modern laboratory methods have expanded purine synthesis to include solid-phase techniques, particularly for nucleoside derivatives used in pharmaceutical screening and oligonucleotide assembly. In solid-phase approaches, purine bases or their precursors are anchored to resins like Merrifield or polystyrene, allowing sequential addition of ring components via nucleophilic substitutions and cyclizations, followed by facile cleavage to yield purine nucleosides in 70-90% purity after HPLC. This enables parallel synthesis of libraries with varied C8 or N9 modifications, streamlining research into antiviral agents. Complementing these, chemoenzymatic strategies leverage purine nucleoside phosphorylase (PNP) to reversibly couple purine bases with ribose-1-phosphate under aqueous, physiological conditions, achieving regioselective β-glycosylation with yields exceeding 80% for analogs like inosine. Such biocatalytic methods reduce solvent use and enhance stereocontrol compared to purely chemical routes. These synthetic protocols are indispensable for generating isotopically labeled purines, critical for NMR spectroscopy and metabolic tracing in biochemical investigations. In the Traube synthesis, incorporation of ¹³C- or ¹⁵N-formic acid derivatives allows site-specific labeling at C2 or N positions with enrichments >95%, facilitating studies of and dynamics. Similarly, chemoenzymatic routes using labeled bases with PNP enable efficient production of [¹⁵N]-adenosine for labeling, with overall processes scalable to milligram quantities for research applications.

Prebiotic Synthesis

The prebiotic synthesis of purines refers to abiotic chemical processes that could have generated these heterocyclic compounds under conditions mimicking the or extraterrestrial environments, contributing to the origins of life. In 1961, Juan Oró reported the synthesis of through the of (equivalent to HCN) in at neutral pH and 70–90 °C, yielding up to 0.5% after several days of heating. This process involves oligomerization of HCN to form intermediates such as 5-aminoimidazole-4-carbonitrile, followed by cyclization, and has been replicated under varied conditions including UV irradiation to simulate primordial atmospheric . Variants of the , which typically produces sugars from , have been adapted for purine synthesis by incorporating HCN, , and under thermal or photochemical conditions. For instance, heating —a plausible prebiotic derived from HCN —at 160–180 °C in the presence of catalysts like yields and other purines in yields of 1–4%, alongside pyrimidines. These reactions occur in neutral to basic aqueous media ( 7–9) at 80–100 °C or in icy matrices simulating cometary environments, with low overall yields (0.1–1%) but potential scalability through repeated wet-dry cycles that concentrate reactants and drive equilibrium. The 5-aminoimidazole-4-carboxamide intermediate, central to these pathways, links cyanide-derived units into the purine ring, providing a conceptual bridge to more complex ribonucleotides. More recent studies (2021) have demonstrated photochemical coproduction of purine ribonucleosides and deoxyribonucleosides from and under UV irradiation, achieving combined yields up to 15% for ribonucleosides. The formation of purine ribonucleosides, which attach to the purine base, addresses a key challenge in prebiotic chemistry by utilizing intermediates to stabilize and select for the correct sugar configuration. Photochemical routes have advanced this, as shown in experiments where thio-modified purine precursors react with under UV light (254 nm) at pH 8–10, producing and in up to 15% yield, alongside deoxyribonucleosides up to 50% yield from a single precursor, with stereoselective β-ribofuranosyl attachment via radical recombination mechanisms. These conditions mimic shallow evaporation or ice photolysis, enabling ribose incorporation without free sugars, and highlight how activation could have facilitated nucleoside assembly in cycles of hydration and . The relevance of prebiotic purine synthesis extends to , with purines detected in carbonaceous chondrites like the , which fell in 1969. Recent analyses (as of 2024) detect purines at higher concentrations than earlier reports, with total purines up to 1.3 ppm and individuals like and in the range of 10–100 ppb, suggesting extraterrestrial delivery to . These findings support models where cometary or meteoritic impacts provided purine precursors, potentially seeding hydrothermal vents or surface pools for further abiotic assembly into life's building blocks.

Notable Purines and Derivatives

Nucleobases

The primary purine nucleobases are adenine and guanine, which serve as essential components in the genetic material of DNA and RNA. These compounds share the core purine ring structure—a fused imidazole and pyrimidine ring—but differ in their substituents, influencing their chemical properties and roles in base pairing. Adenine, systematically named 6-aminopurine, has the molecular formula C₅H₅N₅. It exhibits a characteristic ultraviolet absorption maximum at approximately 260 nm, attributable to its conjugated π-electron system. Adenine is sparingly soluble in water (about 0.5 g/L at 20°C) but readily soluble in acidic solutions due to protonation of the imidazole nitrogen. Guanine, known as 2-amino-6-oxopurine, possesses the molecular formula C₅H₅N₅O. It displays absorption with a maximum around 275 nm in neutral conditions, shifting in acidic media. is even less soluble in (approximately 0.21 g/L at 20°C) than , reflecting its tendency to form hydrogen-bonded aggregates. A key structural difference lies in their tautomeric preferences: adenine predominantly adopts the amino form at the 6-position (with the exocyclic -NH₂ group), while guanine favors the keto form at the same position (with a C=O group and N1-H). These preferences stabilize the canonical Watson-Crick base pairing in nucleic acids, where pairs with or uracil, and with . Rare tautomeric shifts can lead to mutations but are minimized under physiological conditions. Adenine and guanine occur exclusively as the major purine bases in DNA and RNA across all known organisms, comprising variable proportions depending on sequence composition (e.g., GC content influences stability). Minor purine bases, such as isoguanine (2-hydroxy-6-aminopurine), are exceedingly rare and typically arise from synthetic or prebiotic processes rather than standard biosynthesis. Relevant derivatives include hypoxanthine, formed by of (replacement of the 6-amino group with oxo), and , which results from of or oxidation of hypoxanthine at the 2-position. These compounds are intermediates in purine but lack direct roles in genetic coding.

Methylated and Other Derivatives

Methylated purine derivatives, particularly those based on the core (2,6-dioxopurine), exhibit diverse pharmacological activities due to modifications that influence their , receptor binding, and metabolic interactions. N- at various positions on the ring enhances lipophilicity, thereby improving and potency while altering ; for instance, sequential increases membrane permeability but can reduce aqueous compared to the parent . These derivatives arise from the purine pathway through enzymatic N-, primarily catalyzed by S-adenosylmethionine-dependent methyltransferases such as xanthosine methyltransferase and 7- methyltransferase, which sequentially add methyl groups to xanthosine or intermediates. Caffeine, or 1,3,7-trimethylxanthine, is a prominent that acts as an , promoting and reducing by blocking A1 and A2A receptors in the . It occurs naturally in beans at 0.9-1.5% dry weight and in tea leaves at approximately 3-4% dry weight, contributing to the beverage's psychoactive effects. Theophylline (1,3-dimethylxanthine) and theobromine (3,7-dimethylxanthine) share similar methylation patterns on the xanthine scaffold, conferring bronchodilator properties through phosphodiesterase inhibition and adenosine antagonism, which relax smooth muscle in airways. Theophylline additionally exhibits cardiotonic effects by increasing cyclic AMP levels, aiding in the treatment of asthma and chronic obstructive pulmonary disease, while theobromine provides milder cardiac stimulation and vasodilatory actions. Other notable derivatives include allopurinol, a hypoxanthine analog that inhibits xanthine oxidase, preventing the conversion of xanthine to uric acid and thereby reducing hyperuricemia in gout patients. In contrast, 6-mercaptopurine functions as an anticancer purine analog that is metabolized to thioinosinic acid, disrupting de novo purine synthesis and incorporating fraudulent nucleotides into DNA, which inhibits replication in leukemic cells.

History

Discovery and Early Characterization

The initial characterization of purine derivatives emerged from investigations into urinary calculi and in the late , driven by efforts to understand the composition of kidney stones and related pathological deposits. In 1776, Swedish chemist isolated a white, crystalline powder from human urinary calculi, marking the first extraction of , a key oxidized purine derivative central to these conditions. This discovery laid the groundwork for later purine studies, as was recognized as a primary component in tophi and calculi associated with . Early 19th-century analyses expanded on these findings, linking purine-related compounds to natural sources beyond human pathology. In 1844, German chemist Julius Bodo Unger isolated a compound from that he initially identified as ; in 1846, he correctly identified it as , a crystalline substance with distinct properties. Precipitation tests, involving and other reagents, were among the initial analytical methods used to separate and characterize these bases from complex mixtures. By 1885, extracted from pancreatic tissue, further revealing the prevalence of purine-like structures in biological materials. The term "purine" and its structural framework were formalized in the late through systematic degradation studies of these derivatives. In 1884, German chemist coined the name "purine" for the hypothetical parent compound derived from by removal of oxygen atoms, establishing it as a bicyclic nitrogenous base. Fischer synthesized the purine compound itself in 1898, confirming its structure. Fischer's team employed , a method refined by in the 1830s, to determine the empirical formula for purine, confirming its composition through quantitative measurement of carbon, , and oxides produced upon burning. This , combined with synthetic degradations, provided the first clear structural insights into the purine ring system.

Key Biochemical Insights

In the mid-20th century, significant advances in purine biochemistry illuminated the de novo biosynthesis pathway, primarily through the work of John M. Buchanan and his collaborators in the 1950s. Using pigeon liver extracts and radioactively labeled precursors, Buchanan's team demonstrated that purines are assembled step-by-step from simple molecules like , , , aspartate, and CO₂, culminating in the formation of (IMP) as a key intermediate. This elucidation established the 10-step enzymatic pathway, highlighting the role of (PRPP) as the initial substrate and revealing regulatory mechanisms that prevent overproduction in cells. Foundational genetic studies in the 1940s, including Salvador E. Luria and Max Delbrück's demonstration of random mutations in bacteria, enabled the isolation of purine auxotrophs—mutants unable to synthesize purines and requiring external supplementation for growth. These bacterial models, refined in subsequent decades, confirmed the conservation of purine biosynthetic genes across organisms and facilitated mapping of the pathway through complementation and isotopic labeling experiments. Nobel Prize-winning discoveries further underscored purines' central role in nucleic acid dynamics. In 1959, Arthur Kornberg was awarded for isolating DNA polymerase I from Escherichia coli, an enzyme that incorporates purine nucleotides (dATP and dGTP) into growing DNA strands during replication, proving the semiconservative mechanism proposed by Watson and Crick. Complementing this, the 1978 Nobel Prize to Werner Arber, Hamilton O. Smith, and Daniel Nathans recognized restriction enzymes, which cleave DNA at specific purine-containing recognition sequences (e.g., GAATTC for EcoRI), enabling precise manipulation of purine-rich genomic regions and revolutionizing molecular cloning. Links to human diseases emerged prominently in the 1960s, with the identification of Lesch-Nyhan syndrome in 1964 as a heritable disorder characterized by , neurological deficits, and self-injurious behavior due to near-complete deficiency of (HGPRT), an crucial for purine salvage. The enzymatic basis was confirmed in 1967, showing HGPRT's role in recycling purine bases into nucleotides, with mutations leading to toxic purine accumulation and overproduction. Concurrently, , a inhibitor, was introduced in the mid-1960s as the first effective therapy for purine-related , reducing formation by up to 70% in and Lesch-Nyhan patients without disrupting essential purine synthesis. Post-2000 advancements have leveraged purines in cutting-edge tools. CRISPR-Cas9 systems, developed in the 2010s, often target purine-rich motifs, such as structures or purine-enriched protospacer adjacent motifs (PAMs) like NGG, enabling precise editing of genes; for instance, orthologs with affinity for purine-rich PAMs have expanded targeting efficiency in therapeutic applications. In , purine analogs have facilitated expanded genetic codes, with unnatural base pairs (e.g., dTPT3-dNaM, a purine-like pair) incorporated into E. coli genomes in , allowing replication of up to eight building blocks and encoding novel for protein engineering. The era, catalyzed by the Project's completion in , revealed the high conservation of genes across eukaryotes, with approximately 52% sequence identity for adenylosuccinate synthase (ADSS) between humans and , underscoring evolutionary pressures on this pathway for and . This conservation has informed studies, highlighting how disruptions in shared purine pathways contribute to metabolic disorders across species.

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