AICA ribonucleotide

Last updated
AICA ribonucleotide
Aminoimidazole carboxamide ribonucleotide.svg
Names
IUPAC name
(1R)-1-(5-Amino-4-carbamoyl-1H-imidazol-1-yl)-1,4-anhydro-D-ribitol 5-(dihydrogen phosphate)
Systematic IUPAC name
[(2R,3S,4R,5R)-5-(5-Amino-4-carbamoyl-1H-imidazol-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate
Other names
AICAR, Aminoimidazole carboxamide ribonucleotide, AICA ribonucleotide, ZMP, 5-Amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.019.285 OOjs UI icon edit-ltr-progressive.svg
KEGG
MeSH AICA+ribonucleotide
PubChem CID
UNII
  • InChI=1S/C9H15N4O8P/c10-7-4(8(11)16)12-2-13(7)9-6(15)5(14)3(21-9)1-20-22(17,18)19/h2-3,5-6,9,14-15H,1,10H2,(H2,11,16)(H2,17,18,19)/t3-,5-,6-,9-/m1/s1 Yes check.svgY
    Key: NOTGFIUVDGNKRI-UUOKFMHZSA-N Yes check.svgY
  • InChI=1/C9H15N4O8P/c10-7-4(8(11)16)12-2-13(7)9-6(15)5(14)3(21-9)1-20-22(17,18)19/h2-3,5-6,9,14-15H,1,10H2,(H2,11,16)(H2,17,18,19)/t3-,5-,6-,9-/m1/s1
    Key: NOTGFIUVDGNKRI-UUOKFMHZBG
  • O=P(O)(O)OC[C@H]2O[C@@H](n1cnc(C(=O)N)c1N)[C@H](O)[C@@H]2O
Properties
C9H15N4O8P
Molar mass 338.213 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) is an intermediate in the generation of inosine monophosphate. AICAR is an analog of adenosine monophosphate (AMP) that is capable of stimulating AMP-dependent protein kinase (AMPK) activity. The drug has also been shown as a potential treatment for diabetes by increasing the metabolic activity of tissues by changing the physical composition of muscle. [1]

Contents

Mechanism of action

The nucleoside form of AICAR, acadesine, is an analog of adenosine that enters cardiac cells to inhibit adenosine kinase and adenosine deaminase. It enhances the rate of nucleotide re-synthesis increasing adenosine generation from adenosine monophosphate only during conditions of myocardial ischemia. [2] In cardiac myocytes, acadesine is phosphorylated to AICAR to activate AMPK without changing the levels of the nucleotides. [3] AICAR is able to enter the de novo synthesis pathway for adenosine synthesis to inhibit adenosine deaminase causing an increase in ATP levels and adenosine levels. [4]

Use as a performance-enhancing drug

In 2009, the French Anti-Doping Agency, suspected that AICAR had been used in the 2009 Tour de France for its supposed performance enhancing properties. [5] [6] Although a detection method was reportedly given to the World Anti-Doping Agency, it was unknown if this method was implemented. [7] As of January 2011, AICAR was officially a banned substance in the World Anti Doping Code, [8] and the standard levels in elite athletes have been determined, to interpret test results. [9] [10]

See also

Related Research Articles

<span class="mw-page-title-main">Adenosine</span> Chemical compound

Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building blocks of RNA (and its derivative deoxyadenosine is a building block of DNA), which are essential for all life on earth. Its derivatives include the energy carriers adenosine mono-, di-, and triphosphate, also known as AMP/ADP/ATP. Cyclic adenosine monophosphate (cAMP) is pervasive in signal transduction. Adenosine is used as an intravenous medication for some cardiac arrhythmias.

<span class="mw-page-title-main">Adenosine monophosphate</span> Chemical compound

Adenosine monophosphate (AMP), also known as 5'-adenylic acid, is a nucleotide. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine. It is an ester of phosphoric acid and the nucleoside adenosine. As a substituent it takes the form of the prefix adenylyl-.

<span class="mw-page-title-main">Cyclic nucleotide</span> Cyclic nucleic acid

A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, and a single phosphate group. As can be seen in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) images, the 'cyclic' portion consists of two bonds between the phosphate group and the 3' and 5' hydroxyl groups of the sugar, very often a ribose.

<span class="mw-page-title-main">Adenosine monophosphate deaminase deficiency type 1</span> Medical condition

Adenosine monophosphate deaminase deficiency type 1 or AMPD1, is a human metabolic disorder in which the body consistently lacks the enzyme AMP deaminase, in sufficient quantities. This may result in exercise intolerance, muscle pain and muscle cramping. The disease was formerly known as myoadenylate deaminase deficiency (MADD).

<span class="mw-page-title-main">Erythropoietin</span> Protein that stimulates red blood cell production

Erythropoietin, also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bone marrow. Low levels of EPO are constantly secreted in sufficient quantities to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO include any anemia, and hypoxemia due to chronic lung disease.

<span class="mw-page-title-main">Protein kinase A</span> Family of enzymes

In cell biology, protein kinase A (PKA) is a family of serine-threonine kinase whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase. PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It should not be confused with 5'-AMP-activated protein kinase.

<span class="mw-page-title-main">Cyclic guanosine monophosphate</span> Chemical compound

Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in response to the binding of membrane-impermeable peptide hormones to the external cell surface. Through protein kinases activation, cGMP can relax smooth muscle. cGMP concentration in urine can be measured for kidney function and diabetes detection.

<span class="mw-page-title-main">Vasodilation</span> Widening of blood vessels

Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, which is the narrowing of blood vessels.

<span class="mw-page-title-main">AMP-activated protein kinase</span> Class of enzymes

5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It belongs to a highly conserved eukaryotic protein family and its orthologues are SNF1 in yeast, and SnRK1 in plants. It consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. In response to binding AMP and ADP, the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis, and modulation of insulin secretion by pancreatic β-cells.

<span class="mw-page-title-main">Inosinic acid</span> Chemical compound

Inosinic acid or inosine monophosphate (IMP) is a nucleotide. 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.

Blood doping is a form of doping in which the number of red blood cells in the bloodstream is boosted in order to enhance athletic performance. Because such blood cells carry oxygen from the lungs to the muscles, a higher concentration in the blood can improve an athlete's aerobic capacity (VO2 max) and endurance. Blood doping can be achieved by making the body produce more red blood cells itself using drugs, giving blood transfusions either from another person or back to the same individual, or by using blood substitutes.

<span class="mw-page-title-main">AMP deaminase</span> Mammalian protein found in Homo sapiens

AMP deaminase 1 is an enzyme that in humans is encoded by the AMPD1 gene.

<span class="mw-page-title-main">Nucleic acid metabolism</span> Process

Nucleic acid metabolism is a collective term that refers to the variety of chemical reactions by which nucleic acids are either synthesized or degraded. Nucleic acids are polymers made up of a variety of monomers called nucleotides. Nucleotide synthesis is an anabolic mechanism generally involving the chemical reaction of phosphate, pentose sugar, and a nitrogenous base. Degradation of nucleic acids is a catabolic reaction and the resulting parts of the nucleotides or nucleobases can be salvaged to recreate new nucleotides. Both synthesis and degradation reactions require multiple enzymes to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.

Performance-enhancing substances, also known as performance-enhancing drugs (PEDs), are substances that are used to improve any form of activity performance in humans. A well-known example of cheating in sports involves doping in sport, where banned physical performance-enhancing drugs are used by athletes and bodybuilders. Athletic performance-enhancing substances are sometimes referred as ergogenic aids. Cognitive performance-enhancing drugs, commonly called nootropics, are sometimes used by students to improve academic performance. Performance-enhancing substances are also used by military personnel to enhance combat performance.

Purine metabolism refers to the metabolic pathways to synthesize and break down purines that are present in many organisms.

In enzymology, an adenosine-phosphate deaminase (EC 3.5.4.17) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">AMPD3</span> Protein-coding gene in the species Homo sapiens

AMP deaminase 3 is an enzyme that in humans is encoded by the AMPD3 gene.

<span class="mw-page-title-main">Acadesine</span> Chemical compound

Acadesine (INN), also known as 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, AICA-riboside, and AICAR, is an AMP-activated protein kinase activator which is used for the treatment of acute lymphoblastic leukemia and may have applications in treating other disorders such as diabetes. AICAR has been used clinically to treat and protect against cardiac ischemic injury. The drug was first used in the 1980s as a method to preserve blood flow to the heart during surgery.

<span class="mw-page-title-main">Purine nucleotide cycle</span>

The Purine Nucleotide Cycle is a metabolic pathway in protein metabolism requiring the amino acids aspartate and glutamate. The cycle is used to regulate the levels of adenine nucleotides, in which ammonia and fumarate are generated. AMP coverts into IMP and the byproduct ammonia. IMP converts to S-AMP (adenylosuccinate), which then coverts to AMP and the byproduct fumarate. The fumarate goes on to produce ATP (energy) via oxidative phosphorylation as it enters the Krebs cycle and then the electron transport chain. Lowenstein first described this pathway and outlined its importance in processes including amino acid catabolism and regulation of flux through glycolysis and the Krebs cycle.

References

  1. Zarembo, Alan (1 August 2008). "'Exercise pill' could take the work out of workouts". Los Angeles Times. Retrieved 21 January 2012.
  2. Kristiansen, Steen B.; Solskov, Lasse; Jessen, Niels; Løfgren, Bo; Schmitz, Ole; Nielsen-Kudsk, Jens Erik; Nielsen, Torsten T.; Bøtker, Hans Erik; Lund, Sten (2009). "5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside increases myocardial glucose uptake during reperfusion and induces late pre-conditioning: Potential role of AMP-activated protein kinase". Basic & Clinical Pharmacology & Toxicology. 105 (1): 10–16. doi: 10.1111/j.1742-7843.2009.00402.x . PMID   19486332. S2CID   3062525 .
  3. Zhang, Li; Frederich, Markus; He, Huamei; Balschi, James A. (2006). "Relationship between 5-aminoimidazole-4-carboxamide-ribotide and AMP-activated protein kinase activity in the perfused mouse heart". American Journal of Physiology. Heart and Circulatory Physiology. 290 (3): H1235–H1243. doi:10.1152/ajpheart.00906.2005. PMID   16258030. S2CID   18273128 .
  4. Longnus, Sarah L.; Wambolt, Richard B.; Parsons, Hannah L.; Brownsey, Roger W.; Allard, Michael F. (2003). "5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) stimulates myocardial glycogenolysis by allosteric mechanisms". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 284 (4): R936–R944. doi:10.1152/ajpregu.00319.2002. PMID   12626360. S2CID   19608127 .
  5. Cooke, Nicole (11 March 2015). "Nicole Cooke: CIRC report is admirable but authorities must do more on drugs". The Guardian. Retrieved 13 March 2015. There will always be new drugs, such as the weight-loss drug Aicar, which enables riders to shed up to 7kg and yet still maintain their power output. Obviously, it takes time to develop tests for these but it needs to be agreed that retrospective testing can secure sanctions.
  6. Niiler, Eric (10 March 2015). "Doping spreading to amateur cyclists: Report". Seeker. Retrieved 13 March 2015. The commission, formed in 2013 by the sport's governing body, interviewed 174 experts, riders, doctors and team officials. It found a flood of new substances or methods used to enhance blood oxygen capacity include Aicar, Xenon gas, ozone therapy, ITPP, Gas6, Actovegin, various forms of EPO such as CERA, 'Eprex', EPO zeta, EPO Retacrit, Neorecormon, and Albumina. Most of these are used to help patients with severe anemia or blood disorders.
  7. Simms, Daniel (27 July 2009). "AFLD president suspects new drugs in peloton". Cyclingnews. Retrieved 17 March 2012.
  8. "Important changes made to the World Anti-Doping Code". Cyclingnews. 20 December 2010. Retrieved 17 March 2012.
  9. Thomas, Andreas; Beuck, Simon; Eickhoff, Jens Christian; Guddat, Sven; Krug, Oliver; Kamber, Matthias; Schänzer, Wilhelm; Thevis, Mario (2010). "Quantification of urinary AICAR concentrations as a matter of doping controls". Analytical and Bioanalytical Chemistry. 396 (8): 2899–2908. doi:10.1007/s00216-010-3560-8. PMID   20225061. S2CID   25220894.
  10. Cycling Independent Reform Commission (February 2015). "Report to the President of the Union Cycliste Internationale" (PDF). Union Cycliste Inernationale. Archived from the original (PDF) on 18 March 2015. p. 57: The core elements to achieve performance enhancement through doping in cycling have remained the same over the years: firstly, increasing the blood's oxygen carrying capacity, and, secondly, stimulating muscle growth and aiding muscle recovery. Over the years riders have adapted the substances and methods used to achieve these goals in response to: (i) the type of substances available and accessible on the pharmaceutical market (e.g., various EPO generations); (ii) specific drug detection capabilities of laboratories, (e.g., the switch from EPO to blood transfusions or to ozone therapy, or even towards the so-called 'oxygen in a pill' in the form of GW1516 and AICAR); and (iii) other anti-doping tools, such as the ABP which has led to micro-dosing (see below).