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Inosinic acid
Inosinic acid
Inosinic acid
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Inosinic acid
Ball-and-stick model of the inosinic acid molecule
Names
IUPAC name
5'-Inosinic acid
Other names
  • IMP
  • Hypoxanthine ribotide
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.004.588 Edit this at Wikidata
E number E630 (flavour enhancer)
MeSH Inosine+monophosphate
UNII
  • InChI=1S/C10H13N4O8P/c15-6-4(1-21-23(18,19)20)22-10(7(6)16)14-3-13-5-8(14)11-2-12-9(5)17/h2-4,6-7,10,15-16H,1H2,(H,11,12,17)(H2,18,19,20)/t4-,6-,7-,10-/m1/s1 checkY
    Key: GRSZFWQUAKGDAV-KQYNXXCUSA-N checkY
  • InChI=1/C10H13N4O8P/c15-6-4(1-21-23(18,19)20)22-10(7(6)16)14-3-13-5-8(14)11-2-12-9(5)17/h2-4,6-7,10,15-16H,1H2,(H,11,12,17)(H2,18,19,20)/t4-,6-,7-,10-/m1/s1
    Key: GRSZFWQUAKGDAV-KQYNXXCUBU
  • O=C3/N=C\Nc1c3ncn1[C@@H]2O[C@@H]([C@@H](O)[C@H]2O)COP(=O)(O)O
Properties
C10H13N4O8P
Molar mass 348.208 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 ?)

Inosinic acid or inosine monophosphate (IMP) is a nucleotide (that is, a nucleoside monophosphate). Widely used as a flavor enhancer, it is typically obtained from chicken byproducts or other meat industry waste. Inosinic acid is important in metabolism. It is the ribonucleotide of hypoxanthine and the first nucleotide formed during the synthesis of purine nucleotides. It can also be formed by the deamination of adenosine monophosphate by AMP deaminase. It can be hydrolysed to inosine.

The enzyme deoxyribonucleoside triphosphate pyrophosphohydrolase, encoded by YJR069C in Saccharomyces cerevisiae and containing (d)ITPase and (d)XTPase activities, hydrolyzes inosine triphosphate (ITP) releasing pyrophosphate and IMP.[1]

Important derivatives of inosinic acid include the purine nucleotides found in nucleic acids and adenosine triphosphate, which is used to store chemical energy in muscle and other tissues.

In the food industry, inosinic acid and its salts such as disodium inosinate are used as flavor enhancers. It is known as E number reference E630.

Inosinate synthesis

[edit]
Main article: Purine metabolism § Biosynthesis

The inosinate synthesis is complex, beginning with a 5-phosphoribosyl-1-pyrophosphate (PRPP). Enzymes taking part in IMP synthesis constitute a multienzyme complex in the cell. Evidence demonstrates that there are multifunctional enzymes, and some of them catalyze non-sequential steps in the pathway.[citation needed]

This figure shows the pathway described: IMP synthesis.

Synthesis of other purine nucleotides

[edit]

Within a few steps inosinate becomes AMP or GMP.[2] Both compounds are RNA nucleotides.[2] AMP differs from inosinate by the replacement of IMP's carbon-6 carbonyl with an amino group. The interconversion of AMP and IMP occurs as part of the purine nucleotide cycle.[3] GMP is formed by the inosinate oxidation to xanthylate (XMP), and afterwards adds an amino group on carbon 2. Hydrogen acceptor on inosinate oxidation is NAD+. Finally, carbon 2 gains the amino group by spending an ATP molecule (which becomes AMP+2Pi). While AMP synthesis requires GTP, GMP synthesis uses ATP. That difference offers an important regulation possibility.

Glutamine-PRPP-amidotransferase

Regulation of purine nucleotide biosynthesis

[edit]

Inosinate and many other molecules inhibit the synthesis of 5-phosphoribosylamine from 5-phosphoribosyl-1-pyrophosphate (PRPP), disabling the enzyme that catalyzes the reaction: glutamine-5-phosphoribosyl-1-pyrophosphate-amidotransferase. In other words, when levels of inosinate are high, glutamine-5-phosphoribosyl-1-pyrophosphate-amidotransferase is inhibited, and, as a consequence, inosinate levels decrease. Also, as a result, adenylate and guanylate are not produced, which means that RNA synthesis cannot be completed because of the lack of these two important RNA nucleotides.

Applications

[edit]

Inosinic acid can be converted into various salts including disodium inosinate (E631), dipotassium inosinate (E632), and calcium inosinate (E633). These three compounds are used as flavor enhancers for the basic taste umami or savoriness with a comparatively high effectiveness. They are mostly used in soups, sauces, and seasonings for the intensification and balance of the flavor of meat.

See also

[edit]

References

[edit]

Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Inosinic acid

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from Grokipedia
Inosinic acid, also known as inosine 5'-monophosphate (), is a composed of the nucleobase hypoxanthine linked to a sugar moiety with a group esterified at the 5' position, having the molecular formula C₁₀H₁₃N₄O₈P and a molecular weight of 348.21 g/mol. It appears as odorless, colorless or white crystals or powder, freely soluble in and slightly soluble in , with a of 1.0–2.0 in a 5% solution. Inosinic acid serves as a key intermediate in purine nucleotide biosynthesis, acting as the first fully formed nucleotide in the de novo pathway and functioning as a precursor for the synthesis of (AMP) and (GMP). It plays essential roles in cellular metabolism, including as a human , an , and a , primarily located in the , , and mitochondria. Additionally, inosinic acid contributes to the regulation of . Beyond its biological functions, inosinic acid, particularly in the form of its disodium salt (), is widely used as a flavor enhancer in the to impart taste, often in combination with other additives like , and is recognized as (GRAS) by regulatory authorities. It also finds applications in pharmaceuticals as a potential supplement and in biochemical research for studying pathways.

Chemical Characteristics

Molecular Structure

Inosinic acid, also known as inosine 5'-monophosphate (), is a consisting of the base hypoxanthine attached to a β-D- sugar through an N9-C1' β-glycosidic bond, with a monophosphate group esterified to the 5'-hydroxyl of the . The molecular formula of inosinic acid is C₁₀H₁₃N₄O₈P, and its is 348.21 g/mol. Structurally, the hypoxanthine base features a bicyclic purine ring system formed by the fusion of an imidazole ring and a pyrimidine ring, with a keto (oxo) group at the C6 position of the pyrimidine ring and no substituents at C2. The ribose sugar adopts a furanose conformation with hydroxyl groups at C2' and C3', while the phosphate group is linked as a dihydrogen phosphate ester at C5'. The systematic IUPAC name is [(2R,3S,4R,5R)-3,4-dihydroxy-5-(6-oxo-3H-purin-9-yl)oxolan-2-yl]methyl dihydrogen phosphate, commonly expressed as 9-β-D-ribofuranosyl-6-oxopurine-5'-monophosphate. Compared to other major purine nucleotides, inosinic acid (IMP) possesses hypoxanthine, which differs from the adenine base in AMP by replacement of the 6-amino group with a 6-oxo group, and from the guanine base in GMP by the absence of a 2-amino group alongside the 6-oxo group.

Physical and Chemical Properties

Inosinic acid is typically obtained as an odorless white crystalline powder or colorless crystals. It exhibits moderate solubility in water, approximately 70 g/L at 25°C, rendering it freely soluble for most aqueous applications, while it is slightly soluble in ethanol. A 5% aqueous solution displays a pH range of 1.0 to 2.0, reflecting its acidic nature primarily from the phosphate moiety. The compound behaves as a polyprotic weak , with reported pKa values of 2.4 for the first dissociation and 6.4 for the second, influencing its and across pH gradients. These values align with the of monophosphates, where the group dominates acidity. Additionally, the hypoxanthine base contributes a higher pKa around 8.8 associated with the ring , though this is less impactful under physiological conditions. Inosinic acid demonstrates good thermal stability in neutral and weakly acidic aqueous solutions, even at elevated temperatures up to 90°C, but undergoes to and inorganic under strongly acidic conditions or via enzymatic by phosphatases. This reactivity underscores its sensitivity to low pH environments, where facilitates phosphate cleavage. It also exhibits characteristic UV absorption with a maximum at 250 nm in 0.01 N HCl, attributable to the conjugated π-system of the hypoxanthine moiety. Due to its weak acidity, inosinic acid readily forms salts such as , which enhances water solubility and stability for various uses, though the free acid itself maintains structural integrity under standard storage at -20°C.

Biological Synthesis

De Novo Biosynthesis

De novo biosynthesis of inosinic acid, also known as inosine monophosphate (IMP), occurs through a 10-step enzymatic pathway in the of eukaryotic cells, assembling the ring from simple precursors without recycling existing purines. The pathway begins with the activation of 5-phosphoribosyl-1-pyrophosphate (PRPP) by -PRPP amidotransferase (PPAT, also called PurF in prokaryotes), which catalyzes the first committed step: the transfer of an amino group from to PRPP, yielding 5-phosphoribosylamine (PRA) and releasing and glutamate. This rate-limiting reaction is tightly regulated and sets the foundation for the linear assembly of the base onto the ribose-5-phosphate moiety. Subsequent steps build the imidazole ring and then the pyrimidine ring of the purine structure through additions of , formyl groups from N¹⁰-formyltetrahydrofolate, a second , CO₂, and aspartate, involving ATP-dependent condensations and cyclizations. Key intermediates include glycinamide (GAR), formylglycinamide (FGAR), formylglycinamidine (FGAM), 5-aminoimidazole (AIR), 4-carboxy-5-aminoimidazole (CAIR), 5-aminoimidazole-4-(N-succinylcarboxamide) (SAICAR), and 5-aminoimidazole-4-carboxamide (AICAR). Enzymes such as GAR synthase (part of trifunctional GART), FGAM synthase (PFAS), AIR synthase (part of GART), phosphoribosylaminoimidazole succinocarboxamide synthase (part of bifunctional PAICS), adenylosuccinate lyase (), and AICAR transformylase (part of bifunctional ATIC) drive these transformations, with several enzymes functioning in multifunctional forms to enhance efficiency in humans. The final steps involve of AICAR to formylaminoimidazole-4-carboxamide (FAICAR) and its cyclization to IMP by IMP cyclohydrolase (also part of ATIC). The overall process is energetically demanding, requiring the hydrolysis of six ATP molecules to ADP and inorganic phosphate, along with the consumption of additional cofactors. A simplified net reaction is: PRPP+Gln+Gly+Asp+2HCOO−+CO2+6ATP+H2O→IMP+2Glu+fumarate+PPi+6ADP+6Pi\text{PRPP} + \text{Gln} + \text{Gly} + \text{Asp} + 2 \text{HCOO}^- + \text{CO}_2 + 6 \text{ATP} + \text{H}_2\text{O} \rightarrow \text{IMP} + 2 \text{Glu} + \text{fumarate} + \text{PP}_\text{i} + 6 \text{ADP} + 6 \text{P}_\text{i} This equation highlights the incorporation of nitrogen from and , carbon from and CO₂, and the four-carbon unit from aspartate (which is released as fumarate). To optimize flux and minimize intermediate leakage, the pathway enzymes assemble into a dynamic called the purinosome, which channels substrates and operates in the near and mitochondria for cofactor access. The pathway is subject to end-product inhibition by and downstream purines, ensuring balanced pools.

Salvage and Salvage-Like Pathways

Inosinic acid, also known as inosine monophosphate (), can be synthesized through salvage pathways that recycle pre-existing bases and nucleosides, providing an energy-efficient alternative to de novo biosynthesis. These pathways utilize (PRPP) and specific enzymes to convert free purines into , conserving cellular resources by avoiding the high ATP expenditure required for building purines from simple precursors. The primary salvage route involves the conversion of hypoxanthine to , catalyzed by the enzyme (HGPRT). In this reaction, hypoxanthine reacts with PRPP to form and (PPi), a reversible process that plays a crucial role in purine across various tissues. Hypoxanthine+PRPP⇌IMP+PPi \text{Hypoxanthine} + \text{PRPP} \rightleftharpoons \text{IMP} + \text{PP}_\text{i} Defects in HGPRT activity, such as those causing Lesch-Nyhan syndrome, impair this salvage mechanism, leading to elevated levels of hypoxanthine and due to reduced IMP production. Another significant salvage-like pathway occurs through the of (AMP) to IMP, mediated by AMP deaminase (AMPD), particularly in as part of the nucleotide cycle. This cycle facilitates ammonia production and anaplerosis during intense exercise, converting AMP to IMP to maintain without relying on external purine sources. A minor pathway contributes to IMP formation via the phosphorolysis of to hypoxanthine, catalyzed by (PNP), followed by HGPRT-mediated salvage. This route is important in tissues with high turnover, such as the liver and immune cells, enhancing overall reutilization. Collectively, these salvage and salvage-like pathways underscore the efficiency of recycling, requiring far less energy than , thus supporting pools in non-proliferating cells and during metabolic stress.

Role in Metabolism

Conversion to Other Purine Nucleotides

Inosinic acid, also known as inosine monophosphate (IMP), serves as a central intermediate and branch point in , where it is converted to either (AMP) or (GMP) to support balanced production of these for synthesis and other cellular processes. This divergence allows cells to regulate the relative levels of and based on metabolic demands. The conversion of to AMP proceeds in two enzymatic steps. First, adenylosuccinate synthetase (ADSS) catalyzes the of IMP with L-aspartate and GTP to form adenylosuccinate, GDP, and inorganic phosphate (P_i), a reaction that is GTP-dependent and represents the committed step in adenine nucleotide formation: [IMP](/page/Imp)+Asp+GTP→adenylosuccinate+GDP+Pi\text{[IMP](/page/Imp)} + \text{Asp} + \text{GTP} \rightarrow \text{adenylosuccinate} + \text{GDP} + \text{P}_\text{i} Subsequently, adenylosuccinate lyase () cleaves adenylosuccinate to yield AMP and fumarate, releasing the latter as a that can enter the : adenylosuccinate→AMP+fumarate\text{adenylosuccinate} \rightarrow \text{AMP} + \text{fumarate} In the parallel pathway to GMP, IMP is first oxidized by inosine monophosphate dehydrogenase (IMPDH), which uses NAD⁺ as a cofactor to produce xanthosine monophosphate (XMP), NADH, and H⁺: IMP+NAD++H2O→XMP+NADH+H+\text{IMP} + \text{NAD}^+ + \text{H}_2\text{O} \rightarrow \text{XMP} + \text{NADH} + \text{H}^+ This step is rate-limiting in guanine nucleotide biosynthesis. XMP is then aminated by GMP synthetase (GMPS) using glutamine, ATP, and water to form GMP, AMP, pyrophosphate (PP_i), and glutamate: XMP+ATP+glutamine+H2O→GMP+AMP+PPi+glutamate\text{XMP} + \text{ATP} + \text{glutamine} + \text{H}_2\text{O} \rightarrow \text{GMP} + \text{AMP} + \text{PP}_\text{i} + \text{glutamate} IMP also plays a key role in the cycle, particularly in , where AMP is deaminated to IMP by AMP deaminase during contraction, facilitating release to buffer and support energy production by replenishing intermediates via fumarate. This cycle helps maintain pools under high-energy demand, preventing excessive degradation.

Regulation and Physiological Functions

The biosynthesis of inosinic acid () is tightly regulated through feedback inhibition mechanisms to maintain . The glutamine-PRPP amidotransferase (PPAT), which catalyzes the first committed step in the de novo purine pathway, is allosterically inhibited by IMP, AMP, and GMP binding to distinct sites on the . This inhibition is synergistic, requiring the presence of all three for maximal suppression, thereby preventing overproduction when purine levels are adequate. At the branch point where IMP diverges to form either AMP or GMP, cross-regulation ensures balanced production of and . The conversion of IMP to AMP via adenylosuccinate synthetase is inhibited by AMP accumulation but stimulated by GTP, which serves as an energy source for the reaction. Conversely, the pathway from IMP to GMP, initiated by IMP , is inhibited by GMP but activated by ATP. These reciprocal stimulations promote synthesis of the opposing nucleotide when one is abundant, avoiding imbalances in the pool. Beyond biosynthesis, IMP plays key physiological roles in cellular processes. In RNA, IMP serves as a precursor to through the incorporation of AMP (derived from IMP) and subsequent enzymatic of to by enzymes, influencing and regulation. In energy metabolism, particularly in , IMP functions within the purine nucleotide cycle to facilitate ATP regeneration during intense contraction; AMP is deaminated to IMP, which is then reconverted to AMP via aspartate and fumarate interconversions, supporting ammonia production and TCA cycle anaplerosis. IMP levels are dynamically regulated by , which equilibrates 2 ADP ⇌ ATP + AMP, influencing AMP availability for to IMP under energy stress. In ischemic tissues, ATP depletion leads to IMP accumulation via increased AMP deaminase activity, serving as a biochemical signal of and contributing to degradation products like hypoxanthine. Imbalances in IMP-related are associated with pathological conditions. Overproduction of purines, including excessive de novo IMP synthesis due to defects like superactive PRPP synthetase, contributes to and by elevating levels. Additionally, derivatives derived from IMP catabolism exhibit immunomodulatory effects, such as suppressing pro-inflammatory TNF-α and enhancing anti-inflammatory IL-10 production in endotoxemia models.

Practical Applications

As a Food Additive

Inosinic acid, also known as inosine 5'-monophosphate (IMP; E630), and its disodium salt, (E631), are widely used as flavor enhancers in the to impart taste. These additives were first identified for their umami properties in by Japanese chemist Shintaro Kodama, who isolated 5'-inosinate from dried flakes as a key contributor to savory flavor in traditional broth. Commercially, is primarily produced through microbial of sugars using bacteria such as Corynebacterium stationis or coryneform bacteria like Brevibacterium species, which convert precursors into IMP under controlled conditions. Traditionally, it has also been extracted from meat or fish processing byproducts, where ATP breakdown yields IMP during drying or cooking. As enhancers, and exhibit strong synergy with (MSG), amplifying the savory flavor by a factor of 7-8 times compared to either compound alone, allowing lower overall additive levels for effective taste enhancement. This combination is commonly applied in processed foods such as soups, snack foods, sauces, and to intensify meat-like flavors without incorporating actual , typically at low concentrations to achieve desired amplification. Disodium inosinate holds (GRAS) status from the for use as a agent in foods, with no established limit due to its low profile. Acute oral toxicity studies in rats report an LD50 exceeding 15 g/kg body weight, indicating minimal risk at typical dietary exposures.

In Medicine and Research

In medicine, inhibitors of inosine monophosphate dehydrogenase (IMPDH), the enzyme that converts () to xanthosine monophosphate in the purine biosynthesis pathway, have been developed as agents. , a potent IMPDH inhibitor, is the of mycophenolate mofetil, which is widely used to prevent by selectively depleting in lymphocytes, thereby suppressing T- and B-cell proliferation. Clinical studies have demonstrated that effectively reduces IMPDH activity in peripheral blood mononuclear cells, correlating with efficacy in transplant patients. Additionally, IMPDH inhibitors like exhibit antiviral properties by limiting availability for , with applications explored in treating infections such as in immunocompromised individuals. Purine nucleoside analogs, such as the acyclic purine nucleoside analog acyclovir, which mimics (a downstream product from IMP via GMP), have been utilized in antiviral therapies. For instance, acyclovir inhibits DNA polymerase after , serving as a cornerstone treatment for infections. These analogs leverage the purine scaffold of endogenous purine nucleotides to interfere with viral nucleotide incorporation. In research, IMP serves as a critical standard and substrate in nucleotide assays, particularly for measuring IMPDH activity, which is essential for evaluating and drug effects on guanine nucleotide synthesis. Radiolabeled is employed in metabolic tracing studies to quantify purine flux, revealing abnormalities in de novo and salvage pathways in conditions like autism-associated hyperuricosuria, where conversion of labeled to and nucleotides is impaired. These tools have advanced understanding of purine dysregulation in neurological and proliferative disorders. Emerging research explores IMP's therapeutic potential in , with administration suppressing clinical signs in experimental autoimmune (EAE), an animal model of (MS), by modulating immune responses and promoting recovery. Relatedly, —the dephosphorylated product of IMP—has shown promise in clinical trials for MS, where oral supplementation elevates serum levels (a downstream ) to exert neuroprotective effects, with phase II studies demonstrating tolerability and modest improvements in neurological function as of 2013 data. Preclinical studies further indicate that , derivable from IMP, promotes axon regrowth and functional recovery after and by activating intracellular pathways like Mst3b signaling. A key limitation in IMP's clinical application is its rapid hydrolysis in vivo by phosphatases, converting it to and inorganic , which reduces and necessitates strategies or formulations to enhance stability and delivery. This metabolic lability underscores the need for targeted delivery systems in therapeutic contexts.

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