Structure and biological role of nucleotides, nucleic acids. DNA replication and transcription. Uridine monophosphate what is it Instructions for use

Acute myocardial ischemia and post-ischemic resumption of coronary flow are accompanied by disturbances in the electrical stability of the heart, which is expressed in the development of so-called early ischemic or reperfusion arrhythmias (extrasystole, ventricular tachycardia or ventricular fibrillation). One of the main causes of such rhythm disturbances is the imbalance of K + , Na + and Ca 2+ ions in the ischemic or reperfused myocardium. To a large extent, the change in the intra- and extracellular concentrations of these ions is due to the dysfunction of ion transport systems through the sarcolemma (Na +, K + pump, Ca 2+ pump, ATP-dependent K + channels), the operation of which is ensured by a relatively small fraction of ATP, formed during the process of glycolysis.

During myocardial ischemia, after short-term activation of anaerobic glycolysis, its suppression is observed, primarily due to the inability of glucose to enter the ischemic tissue and the rapid depletion of glycogen reserves in the heart. Already at the 5-10th minute of ischemia, the level of glycogen in the myocardium decreases by 50-75% and is not restored during subsequent reperfusion. A decrease in glycogen reserve during ischemia is one of the factors that increases the likelihood of arrhythmias.

The use of glycogen resynthesis activators opens up certain prospects for the prevention of rhythm disturbances in acute myocardial infarction, administration of thrombolytic drugs, extracorporeal circulation, coronary angioplasty, etc. Such activators can be the nucleoside uridine and its phosphorus esters - uridine-5"-monophosphate (UMP), uridine-5"-diphosphate (UDP), uridine-5"-triphosphate (UTP). Exogenous uridine is actively transported into cardiomyocytes, sequentially converting into UMP, UDP, UTP and uridine-5"-diphosphoglucose, which is a direct substrate for glycogen synthesis. The rate of incorporation of uridine into the intracellular pool of uridine compounds increases significantly with a decrease in coronary current. Exogenous nucleotides can also be incorporated into cardiac muscle either after they are dephosphorylated to uridine, or directly, for example, in the presence of Mg 2+ ions.

The objective of the study was to study the effect of uridine, its mono-, di- and triphosphate on the severity of ventricular arrhythmias during regional ischemia of the left ventricular myocardium and subsequent reperfusion, as well as during cardiac reperfusion after total ischemia.

MATERIAL AND METHODS

The work was performed on Langendorff-perfused hearts of white nonlinear male rats (animal weight 250-280 g). The rats were anesthetized with ether vapor, after which the chest was opened, the heart was removed, washed with a Krebs-Henseleit solution cooled to 4°C and connected to a system for perfusion with a Krebs-Henseleit solution (composition in mmol/l: NaCl - 118.0; KCl - 4.7; CaCl 2 - 2.5; KH 2 PO 4 - 1.2; MgSO 4 - 1.6; NaHCO 3 - 25.0; Na-EDTA - 0.5; glucose - 5.5; pH 7 ,4), oxygenated with a mixture of 95% O 2 and 5% CO 2 at 37 ° C and a constant pressure of 97 cm of water column. After a 15-minute period of stabilization of heart rate, regional ischemia of the left ventricle was simulated by ligating the left coronary artery at the level of the lower edge of the left atrial appendage or total ischemia by stopping the supply of perfusate. After 30 minutes of ischemia, in both cases, coronary flow was restored and reperfusion was carried out for 30 minutes.

Rhythm disturbances were recorded using bipolar electrography in monitoring mode, the number of ventricular extrasystoles (ES), the duration of periods of ventricular tachycardia (VT) and ventricular fibrillation (VF) were assessed. The hearts of animals in the control group were perfused only with Krebs-Henseleit solution; in the experimental groups, uridine, UMP, UDP or UTP (50 μmol/l; Reanal, Hungary) were added to the perfusate. Hearts from 8 animals were used in each group. For statistical analysis, a one-way ANOVA test was used (Microcal Origin 3.5 program). Differences between the values ​​in the control and experimental groups were considered significant at probability values ​​p<0,05.

RESULTS AND DISCUSSION

Control. Occlusion of the left coronary artery led to the development of early arrhythmias (table), which occurred at the 2-3rd minute of ischemia and ceased by the 20-25th minute. 4-5 minutes after removing the ligature, rhythm disturbances were again noted, which continued until the end of the reperfusion period. In case of total ischemia, in the first 2 minutes after stopping the supply of perfusate until the disappearance of heartbeats, only single ES were recorded. 3-4 minutes after the resumption of coronary flow, rhythm disturbances were also observed, mainly in the form of ES and VF, which stopped by the 25-27th minute of reperfusion.

Table.

Frequency of occurrence (%), number (n) of ventricular extrasystoles (ES), duration of periods (sec.) of ventricular tachycardia (VT) and ventricular fibrillation (VF) of isolated perfused rat hearts with 30-minute regional or total ischemia and subsequent 30-minute reperfusion

	Regional ischemia, 30 min.		Reperfusion 30 min.		Total ischemia, 30 min.		Reperfusion 30 min.
	Frequency	n or sec.	Frequency	n or sec.	Frequency	n or sec.	Frequency	n or sec.
Control
ES	100	674±98	100	212±15	50	27±3	88	268±19
ZhT	88	240±28	88	40±10	0	0±0	50	21±4
VF	75	320±57	88	373±37	0	0±0	75	163±13
Uridine
ES	88	147±10*	100	95±11*	63	20±4	75	105±12*
ZhT	50	37±6*	0*	0±0*	0	0±0	0*	0±0*
VF	50	40±5*	63	67±9*	0	0±0	0*	0±0*
UMF
ES	75	162±38*	88	80±7*	75	16±5	38*	32±4*
ZhT	50	29±4*	0*	0±0*	0	0±0	0*	0±0*
VF	0*	0±0*	50	55±12*	0	0±0	25*	8±3*
UDF
ES	88	119±54*	100	202±17	50	18±6	88	159±18*
ZhT	75	105±13*	75	84±11*	0	0±0	38	20±6
VF	63	56±8*	75	305±21	0	0±0	50	148±10
UTF
ES	50	84±9*	100	265±24*	63	30±8	100	353±22*
ZhT	38	25±2*	100	94±9*	0	0±0	75	49±14*
VF	0*	0±0*	88	207±12*	0	0±0	75	195±12*
Note. * - differences from the control group are statistically significant (p<0,05).

Uridine and UMF. When hearts were perfused with a solution containing uridine or UMF for 30 minutes after occlusion of the coronary artery, a decrease in the incidence of ventricular arrhythmias was noted (in the experiment using UMF, VF did not occur) and a significant, compared to the control group, decrease in their severity. Further administration of drugs during the reperfusion period after removal of the ligature prevented the occurrence of VT, contributed to a more than 2-fold decrease in the number of ES, a decrease in the frequency of VF, and reduced its duration by approximately 5 times. A similar effect of uridine and UMF was observed during reperfusion of hearts after 30 minutes of total ischemia (table).

In the pathogenesis of early arrhythmias during acute ischemia or post-ischemic reperfusion of the myocardium, the leading role is played by disruption of the distribution of ions on both sides of the cardiomyocyte membranes. The role of ATP-dependent K+ channels (K ATP channels) of the sarcolemma is especially noted. Activation of these channels occurs when the level of intracellular subsarcolemmal ATP decreases below 3-4 mmol/l and is accompanied by an intense release of K + ions from cardiomyocytes, membrane depolarization, a decrease in the amplitude and duration of the action potential, as well as the rate of repolarization.

These changes lead to disruption of automatism, excitability and conduction in the heart muscle, which creates conditions for the development of arrhythmias both by the re-entry mechanism and in connection with the formation of heterotopic foci of electrical activity. The K ATP channel blocker, the antidiabetic drug glibenclamide, prevents the development of arrhythmias during myocardial ischemia. The imbalance of ions is facilitated by a decrease in the activity of Na + ,K + -ATPase and Ca 2+ -ATPase of the sarcolemma, the substrate for which is also ATP formed during glycolysis.

Impaired ion distribution is aggravated during post-ischemic reperfusion, which is associated with the leaching of K + ions from the extracellular space, the accumulation of Na + and Ca 2+ ions in cardiomyocytes entering through damaged membranes along a concentration gradient, as well as inadequate restoration of ATP levels, despite a sufficient influx of glucose to previously ischemic myocardium.

The antiarrhythmic effect of uridine and UMF is apparently associated with their participation in the resynthesis of myocardial glycogen, activation of glycogenolysis and the formation of the glycolytic fraction of ATP, necessary for normalizing the functioning of ion transport systems. In addition, the product of the catabolism of uridine and UMP is -alanine, which is part of acetyl-CoA in the form of a fragment of pantothenic acid, therefore metabolites of uridine compounds can contribute to the activation of redox processes in the heart. When exogenous UMP is dephosphorylated, uridine is formed, which is able to be transported into cardiomyocytes, having the same effect as the native nucleoside.

UDF and UTF. Uridine di- and triphosphate also had an antiarrhythmic effect in regional ischemia, even slightly superior to the effect of uridine (table). Both compounds, on the one hand, are partially dephosphorylated to uridine, which is captured by the myocardium, and on the other, they act on purine (pyrimidine) P 2U receptors of the endothelium of blood vessels, causing vasodilation due to the formation of endothelial relaxing factor (EDRF), the role of which is performed by nitric oxide (NO). As a result, the antianginal effect of these compounds may manifest itself in the form of a reduction in the infarct area and a weakening of the arrhythmogenic effect of ischemia.

A different situation was observed during post-ischemic reperfusion. UDP and, especially, UTP had a proarrhythmogenic effect in restoring coronary flow after regional or total ischemia. Perhaps the coronary dilatation they cause promotes hyperoxygenation of previously ischemic myocardium and activation of lipid peroxidation with the formation of lysophosphoglycerides, which have arrhythmogenic activity. A similar effect is exerted by the active coronary dilator adenosine, which prevents ventricular arrhythmias during experimental myocardial ischemia, but potentiates the arrhythmogenic effect of post-ischemic reperfusion.

In addition to the vascular endothelium, P 2U receptors are also present on the surface of cardiomyocytes. Their excitation leads to activation of phospholipase C of the sarcolemma and an increase in the level of inositol-1, 4, 5-triphosphate, which is accompanied by an increase in the content of intracellular Ca 2+ and contributes to the occurrence of trace depolarizations and trigger automatism in previously ischemic myocardial tissue.

LITERATURE

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IUPAC name: 1 -(3R, 4S, 5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)pyrimidin-2,4-dione
Other names: uridine
Molecular Formula: C 9 H 12 N 2 O 6
Molar mass: 244.20 g mol-1
Appearance: Solid
Density: 0.99308 g/cm3
Melting point: 167.2 °C (333.0 °F)

Uridine, a nucleoside, contains uracil attached to a ribose ring (known as ribofuranose) via a β-N1-glycosidic bond. Uracil attached to the deoxyribose ring forms deoxyuridine. Uridine is a nucleotide found in large quantities in beer that is used to enhance cell membrane synthesis as well as other neurological purposes. It has potential cognitive enhancing properties, with its effects enhanced by fish oil. Need to know Also known as: uridine diphosphate (UDP), uridine monophosphate (UMP) Variety:

Pseudovitamin

Neotropic remedy

Pairs well with:

Fish oil (Especially with docosahexaenoic acid, as it relates to cognitive performance)

Uridine: instructions for use

Uridine dosage ranges from 500-1,000 mg, with rare human studies using the upper end of this range. Caution is recommended when taking uridine with food, but is not required.

Sources and structure

Sources

Uridine is one of the four main components of ribonucleic acid (RNA); the other three are adenosine, guanine and cytidine. Listed below are foods that contain uridine in RNA form. However, uridine in this form is not bioavailable. It is broken down in the liver and gastrointestinal tract, and food consumption does not increase blood uridine levels. In infants consuming breast milk or commercial infant formula, uridine is present as a monophosphate, and this source of uridine is indeed bioavailable and enters the bloodstream. Consuming foods rich in RNA can lead to increased levels of purines (adenosine and guanosine) in the blood. High levels of purines cause uric acid levels to increase and can worsen or lead to the development of diseases such as gout. Moderate yeast consumption, about 5 grams per day, will provide adequate uridine levels for improved health with minimal side effects.

Note: It has been suggested that the RNA content of yeast products should be chemically reduced if these products are consumed in large quantities (50 g or more per day) as a source of protein. However, such processing is expensive and rarely used.

Harvard researchers report that uridine and EPA/DHA omega-3 fatty acid supplements act as antidepressants in rats.

Uridine in its pure form has been found in the following foods:

In fact, beer is the largest source of uridine. In turn, significant DNA and RNA content (possibly indicative of uridine content) was detected in (relative to dry weight, unless otherwise noted):

Liver (pork and beef): 2.12-2.3% in beef and 3.1-3.5% in pork (RNA); 1.7-2% in beef and 1.4-1.8% in pork (DNA); all in relation to dry weight

Pancreas, largest source of RNA: 6.4-7.8% (pork) and 7.4-10.2% (beef)

Lymph nodes, largest source of DNA: 6.7-7.0% (pork) and 6.7-11.5% (beef)

Fish: 0.17-0.47% (RNA) and 0.03-0.1% (DNA), with herring having the highest RNA content at 1.53%

Baker's yeast (6.62% RNA, 0.6% DNA)

Mushrooms; boletus 1.9-2.4% RNA, champignons 2.05% RNA, chestnut 2.1% RNA, all contain a small amount (0.06-0.1%) DNA

Broccoli 2.06% RNA and 0.51% DNA

Oats 0.3% RNA, undetectable DNA

Chinese cabbage, spinach and cauliflower have the same content of 1.5% RNA and 0.2-0.3% DNA

Parsley 0.81% RNA and 0.27% DNA

Organ meats and, surprisingly, cruciferous vegetables are generally high in RNA and DNA, suggesting they contain uridine. Beer intake at 10ml/kg can increase serum uridine levels by 1.8-fold, which is the same as a similar dose of uridine. (0.05 mg/kg); the alcohol content does not affect absorption and the level of uridine in the urine increases equally. Uridine does not cause an increase in uric acid levels after drinking beer, and inhibition of uric acid synthesis by allopurinol has no effect on serum uridine levels achieved under the influence of beer.

Structure and properties

It was found that uridine, exposed as an aqueous solution to ultraviolet radiation, immediately decomposes and is converted into photohydrates. Unstable in aqueous solution when exposed to ultraviolet radiation

Food interactions

During periods of malnutrition (1600 to 400 kcal of sugar alone; equivalent to a juice diet), plasma uridine can decrease by up to 36% within three days of fasting and decreases by 13% (not significantly) after one day. These results replicate a previous study, with similar results observed in rabbits during fasting.

NucleoMaxX (Mitoknol)

Mitoknol is a proprietary blend of uridine, derived from cane sugar, with a high nucleoside content (17%) with 6g of the total 36g sachet being nucleosides. These sachets contain 0.58g uridine (1.61%) and 5.4g (15%) 2′,3′,5′-tri-O-acetyluridine (TAU), similar in structure to uridine; If the weight of both molecules is taken into account, each sachet contains about 1.7 x 10-2 mol of uridine. Is just a source of uridine and TAU, the latter of which is the better absorbed form of uridine (depot form)

Uridine in the glycolytic pathway

Uridine plays an important role in the glycolytic pathway of galactose. There is no catabolic process for the metabolism of galactose. Thus, galactose is converted to glucose and metabolized in the general glucose pathway. After incoming galactose is converted to galactose-1-phosphate (Gal-1-P), it reacts with UDP-glucose, a glucose molecule attached to a UDP (uridine di-phosphate) molecule. This process is catalyzed by the enzyme galactose-1-phosphate uridyl transferase, and transfers UDP to the galactose molecule. The end result is a UDP-galactose molecule and a glucose-1-phosphate molecule. This process continues to carry out glycolysis of the galactose molecule.

Pharmacology

Bioavailability and Absorption

Uridine is absorbed from the intestine through either facilitated diffusion or specialized uridine transporters. Due to limited absorption, the maximum permissible dose (a dose higher than that indicated causes diarrhea) is 12-15 g/m2 (20-25 g for a man of average height), sharply increasing the serum level to 60-80 micromoles or 5 g/m2 (8.5 g for a man medium height), taken three times a day every 6 hours, which maintains serum concentrations at 50 micromoles; provides biological digestibility of 5.8-9.9%. There are practical limits to the absorption of uridine due to the fact that high doses can cause diarrhea, but these limits are much higher than the standard dosage Mitoknol is a cane sugar extract with a high content (17%) of nucleosides, and a pharmacokinetic study of one “sachet” of the NucleoMaxX brand (36g) taken with 200ml orange juice found that serum uridine levels were increased from a baseline of 5.4-5.8µM to 152+/-29.2µM (Cmax) after 80 minutes (Tmax), with high inter-individual variability observed. Cmax from 116 to 212 micromoles. This study also revealed an initial half-life of 2 hours and a terminal half-life of 11.4 hours, with serum concentrations at 8 and 24 hours falling to 19.3+/-4.7µM and 7.5+/-1.6µM, respectively. This study was later repeated in a related pharmacokinetic study, which yielded similar high Cmax values ​​(150.9 micromoles) at 80 minutes (Tmax), but the observed half-life was 3.4 hours and the mean urinary concentration∞ was 620.8+/-140.5 micromoles; both studies noted high concentrations of uridine in women, which is associated with differences in body weight that disappear after decomposition, leading to equalization. When Mitoknol was compared with uridine alone, both tested for effect on uridine content, a 4-fold increase in absorption was found, with the concentration achieved by Mitoknol exceeding that caused by uridine. The increased bioavailability of Mitoknol may simply be due to its high triacetyluridine (TAU) content, as TAU has 7 times greater bioavailability than an equimolecular amount of uridine due to its lipophilicity and passive diffusion, as claimed in its patent. It is cleaved to uridine by intestinal and plasma esterases, but is resistant to uridine phosphorylase. Mitocnol can be used in situations where it is necessary to achieve high serum uridine concentrations without gastrointestinal side effects due to its high bioavailability

Internal regulation

Serum uridine levels at rest range from 3-8 micromoles. Red blood cells contain the enzyme uridine diphosphate glucose, which is part of the P450 system; if necessary, this enzyme can be lysed to provide pure uridine and glucose in the body when the uridine content is used up.

Neuroscience (Mechanisms)

Movement

Uridine is known to bypass the blood-brain barrier, and is picked up by one of two transporters, one class of which is called equilibrium (SLC29 family; e.g., ENT1, ENT2, and ENT3 transporters), which are low affinity (100–800 micromolar range) and sodium independent, and concentrating (SLC28 family, consisting of ENT4, as well as CNT1, 2 and 3), which are sodium-independent, high-affinity (1-50 micromolar) active transporters.

Phospholipids

Uridine plays the role of a nutrient medium in the synthesis of phosphatidylcholine in the Kennedy cycle (also known as the cytidine diphosphate choline pathway; phosphatidylethanolamine is also produced in this way). In this method, choline kinase catalyzes choline into phosphocholine, consuming an ATP molecule in the process, it has negligible affinity (thus most cellular choline is immediately converted to phosphocholine), and although this is not the only possible way to produce phosphocholine (the breakdown of sphingomyelin also produces phosphocholine), it is the most advanced route and first step in phosphocholine synthesis through the Kennedy cycle, with phosphocholine concentration being directly influenced by increasing choline uptake. In other zones, phosphocholine cytidylyltransferase converts cytidine triphosphate to cytidine diphosphate choline plus pyrophosphate (using previously created phosphocholine as a source of choline). This stage is the slowest and rate-limited in the Kennedy cycle, but its activity determines all phosphocholine synthesis. Typically, cell cultures are high in phosphocholine and low in cytidine diphosphate choline, with the rate limit at this stage being determined by the availability of cytidine triphosphate. This enzyme is also negatively regulated by brain phospholipids, and these are the main mechanisms that mediate phospholipid homeostasis and prevent excess phospholipid synthesis. Ultimately, choline phosphotransferase (not to be confused with carnitine palmitoyltransferase, which has a similar abbreviation) transports phosphocholine from cytidine diphosphate choline to diacyglycerol. Also involved is an enzyme called choline-ethanolamine phosphotransferase, which has dual specificity for cytidine diphosphate choline and cytidine diphosphate ethanolamine (and especially the latter), donating phosphocholine to diacyglycerol ultimately creating phospholipids like phosphatidylcholine (other enzymes using cytidine diphosphate ethanolamine create phosphatidylethanolamine instead). This enzyme is not stimulated by incubation with uridine, but is stimulated by neural growth factor (NGF). Uridine and cytidine are converted to phospholipids by the Kennedy cycle, the above cycle being rate-limited immediately following the CCT enzyme. Ensuring that the enzyme acts on cytidine is what determines the rate. Uridine is used as a nutrient medium from which cytidine diphosphate choline is synthesized (albeit before a rate-limited step) indirectly through cytidine. Providing cytidine (synthesized from uridine) is rate limited in the above process, while providing additional cytidine to cells or brain slices with sufficient choline concentration accelerates the synthesis of cytidine diphosphate choline. Uridine demonstrated a similar property by converting to cytidine by first converting to uridine triphosphate (UTP) and then to cytidine triphosphate, which was confirmed in a living model. While uridine produces 5 micromolar UTP, it stimulates maximal 50 micromolar synthesis of cytidine diphosphate choline in vitro; The production of cytidine diphosphate choline from uridine has been confirmed in vivo by oral administration of uridine. Addition of uridine or cytidine to cell cultures will increase the level of cytidine in the cells and overcome the rate limit, leading to the production of phospholipids. In terms of intervention, one study in healthy men taking 500mg uridine once daily for a week reported an increase in total brain phosphomonoester levels (6.32%), primarily due to an increase in total brain phosphoethanolamine levels (7.17%), with an increase phosphatidylcholine in the uridine group did not reach statistical significance. An increase in phosphoethanolamine levels has been found in other areas due to cytidine diphosphate choline, but the latter is not always accompanied by an increase in phosphoethanolamine. Regarding phosphatidylcholine, it has been hypothesized that growth failure is associated with rapid accumulation of phosphatidylcholine in phospholipid membranes; the hypothesis is related to a previous study that noted a decrease in phosphatidylcholine concentrations by uridine or uridine prodrugs. Oral ingestion of uridine increases levels of brain phospholipid precursors in healthy individuals, particularly phosphatidylethanolamine. Although an increase in phosphatidylcholine cannot be excluded, it has not been reliably detected in humans

P2 receptors

P2 receptors are a metaclass of receptors that respond to extracellular purines and pyrimidines (such as ATP) and promote what is known as purinergic neurotransmission. This class of receptors is similar in structure to adenosine receptors (to the extent that they are usually called the same) and is divided into the P2Y and P2X classes (which differ in that P2Y receptors are G-protein coupled, while P2X is a ligand -gated ion channels). Uridine is an agonist of P2 receptors, particularly the P2Y subclass, which comprise the eight known human P2Y receptors (1,2,4,6 and 11-14) and the remainder of the non-mammalian receptors, with phosphorylated uridine having an affinity primarily for receptors P2Y2, and to a lesser extent with P2Y4, P2Y6 and P2Y14. The nervous system is also represented by seven P2X receptors, seemingly unrelated to uridine. Uridine has its own set of receptors that it can affect, namely the P2 receptors, where it has a greater effect on P2Y2, P2Y4, P2Y6 and P2Y14. When not used as a feedstock for phospholipid synthesis, uridine acts as a novel neurotransmitter through purinergic receptors. P2Y2 receptors have structural elements that promote interaction with integrins and the growth of control receptors, and activation of these receptors leads to activation of neural growth factor signaling /tropomyosin receptor kinase A and is mainly neuroprotective.

Synapsis

Uridine has a beneficial effect on synaptic function by increasing the level of brain phosphatidylcholine, which is a component of dendrite membranes. It is hypothesized to benefit people suffering from decreased synaptic function or regulation, as in Alzheimer's disease, where decreased synaptic function is a consequence of common beta-amyloid compounds having toxic effects on neuronal synapses and dendritic spines. By providing phosphatidylcholine, uridine presumably promotes the formation of membranes and dendrites, which may contribute to synaptic function. Studies examining synaptic construction under the influence of uridine have tended to look at dendritic spines due to the difficulty of quantifying synaptic function per se, and dendritic spines represent the most reliable biomarker due to the fact that 90% of dendrites form a synapse. Feeding animals a combination of uridine, choline and omega-3 fatty acids (from fish oil) resulted in an increase in synaptic formation and function and demonstrated improvements in a group of people (n=221) with mild Alzheimer's disease.

Axon growth

Purines and pyrimidines increase cellular differentiation in neurons, with uridine leading to increased neuronal differentiation and sprouting by activating neural growth factor signaling through its receptor tropomyosin receptor kinase A (widely known to increase neuronal growth) through its effects on its own receptor P2Y2 . Removal of the P2Y2 receptor prevents appropriate neural growth factor signaling through tropomyosin receptor kinase A, with the two receptors acting on each other as in coimmunoprecipitation. In this sense, P2Y2 agonists increase neural growth factor signaling by increasing neuronal proliferation due to neuronal sensitivity to the factor, as has been found with the P2Y2 agonist uridine (triphosphate). Activation of the P2Y2 receptor promotes the action of neural growth factor through its own receptor (tropomyosin receptor kinase A), and ultimately leads to P2Y2 receptor agonists increasing factor-induced neuronal growth. 6 weeks, but not 1 week, feeding 330mg/kg (1mmol/kg) uridine to aging rats increased levels of neurofilament -70 (+82%) and neurofilament-M (+121%), two cytoskeletal proteins involved in axonal growth and used as biomarkers, which was previously induced in vitro by neural growth factor in differentiated PC12 neuronal cells by uridine when axonal growth was detected. Notably, an in vitro study found that uridine can act through the P2Y receptor to increase axonal growth.

Catecholamine

A diet of aging rats supplemented with 2.5% disodium uridine (500 mg/kg, or 330 mg/kg uridine, with the human equivalent being about 50 mg/kg) did not affect resting dopamine levels in rat neuronal slices, but did increase K+-evoked dopamine release , while 1 and 6 weeks of administration increased the average dopamine level by 11.6-20.5% without a difference in the temporary decrease in action potential, while without affecting the concentration of DOPAC or HVA. Uridine supplementation increases the level of dopamine released from activated neurons without significantly affecting overall dopamine levels

Cognitive process and cognition

One open-label study using the trade name Cognitex (50mg uridine 5"-monophosphate strongly mixed with 600mg alpha-glycerylphosphorylcholine, 100mg phosphaditylserine, 50mg pregnenolone, 20mg vinpocetine and others) at a dosage of 3 capsules daily for 12 weeks found improvements in short-term spatial memory, recognition, recall, attention and organizational abilities, which increased further after more than 10 weeks of treatment.

Alzheimer's disease

Uridine may help treat Alzheimer's disease by maintaining synaptic connections that are weakened in Alzheimer's disease. By promoting synaptic proliferation, uridine may be used therapeutically for Alzheimer's disease. One study noted significant improvement in Alzheimer's disease symptoms in rats with accelerated β-amyloid production (and thus predisposed to Alzheimer's disease), but was largely confounded using other nutrients to ensure the effect of uridine. Experimental data regarding uridine to date are inconclusive and do not allow us to evaluate the effectiveness of uridine.

Bipolar disorder

In a 6-week study of uridine in an open-label study of bipolar disorder in children, it was noted that 500 mg twice daily (1,000 mg total) was associated with an improvement in depressive symptoms compared with baseline (from a mean of 65.6 on the Children's Depression Rating Scale to 27.2). with effectiveness within a week); manic symptoms were not assessed. Triacetyluridine (TAU) was used in a study of adult bipolar disorder, 18g daily for 6 weeks, and significant improvement in depressive symptoms was noted.

Condition of the cardiovascular system

Heart tissue

Uridine is capable of providing an immediate cardioprotective effect during myocardial ischemia, the preload of which is eliminated by blocking mitochondrial potassium channels (via 5-hydroxydecanoate); This means that uridine preload preserves the levels of energy metabolites (ATP, creatine phosphate and uridine) and further reduces lipid peroxidation.

Fat mass and obesity

Lipodystrophy

Lipodystrophy is a localized loss of fat mass, usually observed during HIV therapy with nucleoside reverse transcriptase inhibitors. In a multicenter study, uridine was associated with an increase in limb fat (seen as the endpoint of normalization of lipodystrophy) after 24 weeks, but the effect did not last longer than 48 weeks; uridine was well tolerated and did not have a negative effect on the virological response. These unfortunate results were replicated in a double-blind study in which uridine as NucleoMaxX (the drug's trade name) had a beneficial effect on mitochondrial RNA but a negative effect on mitochondrial DNA and no effect on limb fat; all of this was accompanied by an increase in systematic inflammation (measured using interleukin-6 and C-reactive protein), although another study confirmed significant improvements in fat mass with a similar study regimen. There have been mixed results regarding lipodystrophy in people undergoing standard HIV therapy.

Interaction with cancer

Pancreas cancer

Activation of the P2Y2 receptor by uridine triphosphate increases proliferation of the pancreatic cancer cell line PANC-1, which was mimicked by a selective receptor agonist and mediated by protein kinase C-dependent activation of protein kinase B.

Aesthetic medicine

Hair

During the early anagen phase of hair growth, an increase in uridine accumulation in dermal papilla cells and hair matrix cells has been noted compared to the resting (telogen) phase in vitro, which extends to other nucleotides (such as thymidine and cytidine); it is assumed that this indicates an increased rate of RNA and DNA synthesis under conditions of spontaneous growth of hair cells. To date, there is no research as to whether uridine accumulation is the cause of rate limitation in this case, nor is the role of exogenous uridine in acting as a breeding ground for DNA synthesis conclusive. Uridine accumulates in hair cells during the growth phase (anagen), but it has not been established whether uridine is used as a nutrient medium for DNA/RNA synthesis, as mentioned above, or whether it is advisable to take uridine. It has been noted that the P2Y1 and P2Y2 receptors ( the latter of which is the target of uridine) appear in hair cells during anagen, with P2Y2 receptors expressed in living cells at the edge of the outer integument/core of the hair, and P2Y1 receptors in the epithelial root sheath and bulb; P2X5 receptors were found inside and outside the epithelial root sheath and pith, while P2X7 receptors were not detected. P2Y2 receptors were discovered early and are no longer present in the developed hair papilla, and due to uridine's role as an agonist of this receptor in promoting keratinocyte proliferation, it has been hypothesized that uridine may stimulate hair cell differentiation. It is theoretically possible, but not proven in practice, that uridine may act through the P2Y2 receptor to differentiate hair cells at the beginning of the growth phase (anagen).

Interactions with nutrients

Kholin

Choline and uridine have effects on neuronal function, and orally administered choline can increase phosphocholine levels in the brain of rats and humans, with a 3-6% increase in serum choline levels resulting in a 10-22% increase in brain phosphocholine levels. Taking uridine increases cytidine diphosphate choline levels in the brain.

Docosahexanoic acid

List of used literature:

Almeida C, et al. Composition of beer by 1H NMR spectroscopy: effects of brewing site and date of production. J Agric Food Chem. (2006)

Thorell L, Sjöberg LB, Hernell O. Nucleotides in human milk: sources and metabolism by the newborn infant. Pediatric Res. (1996)

Inokuchi T, et al. Effects of allopurinol on beer-induced increases in plasma concentrations of purine bases and uridine. Nucleosides Nucleotides Nucleic Acids. (2008)

Shetlar MD, Hom K, Venditto VJ. Photohydrate-Mediated Reactions of Uridine, 2"-Deoxyuridine and 2"-Deoxycytidine with Amines at Near Neutral pH. Photochem Photobiol. (2013)

Eells JT, Spector R, Huntoon S. Nucleoside and oxypurine homeostasis in adult rabbit cerebrospinal fluid and plasma. J Neurochem. (1984)

Nucleo CMP forte

Compound

1 capsule contains cytidine-5-monophosphate disodium 5 mg, uridine-5-trisodium phosphate, uridine-5-diphosphate disodium, uridine-5-monophosphate disodium only 63 mg (corresponding to 1.33 0 mg of pure uridine).
Excipients: citric acid, Na citrate dihydrate, Mg stearate, Aerosil 200, mannitol.

1 ampoule with lyophilized powder contains cytidine-5-monophosphate disodium 10 mg, uridine-5-trisodium phosphate, uridine-5-diphosphate disodium, uridine-5-monophosphate disodium only 6 mg (corresponding to 2.660 mg of pure uridine).
Excipients: mannitol; solvent: water, Na chloride.

pharmachologic effect

Nucleo c.m.f. forte contains pyrimidine nucleotides - cytidine-5-monophosphate (CMP) and uridine-5-triphosphate (UTP), which are necessary components in the treatment of diseases of the nervous system.
Phosphate groups are necessary in the body for the reaction of monosaccharides with ceramides, which results in the formation of cerebrosides and phosphatidic acids, which mainly make up sphingomyelin, the main component of the myelin sheath of nerve cells, as well as for the formation of glycerophospholipids. Sphingolipid and glycerophospholipids provide demyelination of nerve fibers, regeneration of axons and myelin sheath in case of damage to the peripheral nervous system and help restore the correct conduction of nerve impulses, and also restore trophism of muscle tissue. As a result, mobility and sensitivity improve, inflammation, pain and numbness decrease.
Also, cytidine 5-monophosphate and uridine 5-triphosphate are precursors of DNA and RNA - nucleic acids necessary for the processes of cellular metabolism and protein synthesis. UTP is also an energy source during muscle fiber contraction.

Indications for use

Neuralgia, neuritis nervus trigeminus (nervus facialis), plexitis, osteoarticular neuralgia (lumbago, lumbodynia, lumboischialgia, radiculopathy), intercostal neuralgia and herpes zoster, metabolic neuralgia (consequences of alcohol addiction, complications of diabetes (polyneuropathy)), ganglionitis, vertebrogenic pain syndrome, Bell's palsy, myopathy, carpal tunnel syndrome.

Mode of application

Nucleo c.m.f. forte capsules
The drug can be used by adults and children.
Adults: 1 to 2 capsules twice daily; Children are prescribed 1 capsule twice a day from the age of 5, can be taken before or after meals.
The course of treatment is at least 10 days. If indicated, the drug can be extended up to 20 days.

Nucleo c.m.f. forte ampoules for intramuscular administration
Before administration, it is necessary to dissolve the powder with the supplied solvent. Adults, as well as elderly people and children under 14 years of age are prescribed 1 injection once every 24 hours. Children from 2 to 14 years old are prescribed 1 injection every 48 hours.
The course of treatment lasts from three to six days, then continue oral administration of the drug from 1 to 2 capsules twice a day for 10 days. If indicated, the drug can be extended up to 20 days.

Side effects

Not described.

Contraindications

An allergic reaction to the components of the drug may occur.
Age under two years is a contraindication to the use of Nucleo c.m.f. forte.

Pregnancy

Taking the drug is not contraindicated, but it is necessary to evaluate the ratio of the real benefits of taking the drug and the potential risk to the intrauterine fetus, since there is no information regarding the safety of use during pregnancy.

Overdose

The drug is low-toxic, the likelihood of overdose is very low even if the therapeutic dose is exceeded.

Release form

Capsules, blister 30 pcs.
To prepare a solution for injection - lyophilized powder (61 mg of active substance) in 2 ml ampoules; No. 3 per pack.

Storage conditions

Store at room temperature (no more than 30 degrees Celsius).

Information about the drug is provided for informational purposes only and should not be used as a guide to self-medication. Only a doctor can decide to prescribe the drug, as well as determine the dose and methods of its use.

4.2.1. Primary structure of nucleic acids called sequence of arrangement of mononucleotides in a DNA or RNA chain . The primary structure of nucleic acids is stabilized by 3",5" phosphodiester bonds. These bonds are formed by the interaction of the hydroxyl group in the 3" position of the pentose residue of each nucleotide with the phosphate group of the neighboring nucleotide (Figure 3.2),

Thus, at one end of the polynucleotide chain there is a free 5"-phosphate group (5"-end), and at the other there is a free hydroxyl group in the 3" position (3"-end). Nucleotide sequences are usually written in the direction from the 5" end to the 3" end.

Figure 4.2. The structure of a dinucleotide, which includes adenosine 5"-monophosphate and cytidine 5"-monophosphate.

4.2.2. DNA (deoxyribonucleic acid) found in the cell nucleus and has a molecular weight of about 1011 Da. Its nucleotides contain nitrogenous bases adenine, guanine, cytosine, thymine , carbohydrate deoxyribose and phosphoric acid residues. The content of nitrogenous bases in a DNA molecule is determined by Chargaff’s rules:

1) the number of purine bases is equal to the number of pyrimidine bases (A + G = C + T);

2) the amount of adenine and cytosine is equal to the amount of thymine and guanine, respectively (A = T; C = G);

3) DNA isolated from cells of different biological species differ from each other in the specificity coefficient:

(G + C) / (A + T)

These patterns in the structure of DNA are explained by the following features of its secondary structure:

1) a DNA molecule is built from two polynucleotide chains connected to each other by hydrogen bonds and oriented antiparallel (that is, the 3" end of one chain is located opposite the 5" end of the other chain and vice versa);

2) hydrogen bonds are formed between complementary pairs of nitrogenous bases. Thymine is complementary to adenine; this pair is stabilized by two hydrogen bonds. Cytosine is complementary to guanine; this pair is stabilized by three hydrogen bonds (see figure b). The more G-C pairs in a DNA molecule, the greater its resistance to high temperatures and ionizing radiation;

Figure 3.3. Hydrogen bonds between complementary nitrogenous bases.

3) both DNA strands are twisted into a helix that has a common axis. The nitrogenous bases face the inside of the helix; In addition to hydrogen interactions, hydrophobic interactions also arise between them. The ribose phosphate moieties are located along the periphery, forming the core of the helix (see Figure 3.4).

Figure 3.4. DNA structure diagram.

4.2.3. RNA (ribonucleic acid) is found predominantly in the cytoplasm of the cell and has a molecular weight in the range of 104 - 106 Da. Its nucleotides contain nitrogenous bases adenine, guanine, cytosine, uracil , carbohydrate ribose and phosphoric acid residues. Unlike DNA, RNA molecules are built from a single polynucleotide chain, which can contain sections that are complementary to each other (Figure 3.5). These regions can interact with each other, forming double helices alternating with non-helical regions.

Figure 3.5. Scheme of the structure of transfer RNA.

Based on their structure and function, there are three main types of RNA:

1) messenger RNA (mRNA) transmit information about the structure of the protein from the cell nucleus to ribosomes;

2) transfer RNAs (tRNAs) transport amino acids to the site of protein synthesis;

3) ribosomal RNA (rRNA) are part of ribosomes and participate in protein synthesis.

AMP, GMP and IMP inhibit key reactions of their synthesis. Two enzymes: PRDF synthetase and amidophosphoribosyltransferase are inhibited only with a simultaneous increase in the concentration of AMP and GMP, while the activity of adenylosuccinate synthetase and IMP dehydrogenase decreases only with an increase in the amount of the final product formed in each branch of the metabolic pathway. AMP inhibits the conversion of IMP to adenylosuccinate, and GMP inhibits the conversion of IMP to xanthosine-5"-monophosphate (KMP), thus ensuring a balanced content of adenyl and guanyl nucleotides.

"Spare" pathways for the synthesis of purine nucleotides play a significant role during periods of active tissue growth, when the main synthesis pathway from simple precursors is not able to fully provide nucleic acids with substrates (Fig. 10.31). At the same time, activity increases:

hypoxanthine-guanine phosphoribosyltransferase(HGPRT), which catalyzes the conversion of nitrogenous bases: hypoxanthine and guanine into nu-

Hypoxanthine

cleotides – IMP and GMP using PRDF as a phosphoribose donor;

adenine phosphoribosyltransferase (AFRT), which synthesizes AMP from adenine and PRDP;

adenosine kinase (AKase), which converts adenosine into AMP by transportingγ-phosphate residue of ATP to the 5"-hydroxyl group of ribose nu-

cleoside

Catabolism of purine nucleotides. Hyperuricemia and gout

In humans, the catabolism of purine nucleotides ends with the formation uric acid. Initially, nucleotides hydrolytically lose a phosphate residue in reactions catalyzed by phosphatases or nucleotidases. Adenosine is deaminated adenosine deaminase with the formation of inosine. Purine nucleoside phosphorylase breaks down nucleosides to free bases and ribose-1-phosphate. Then xanthine oxidase- aerobic oxidoreductase, the prosthetic group of which includes iron ions (Fe3+), molybdenum and FAD, converts nitrogenous bases into uric acid. The enzyme is found in significant quantities in the liver and intestines and oxidizes purines with molecular oxygen (Fig. 10.32). Uric acid is removed from the human body mainly through urine and some through feces. It is a weak acid and in biological fluids is found in an undissociated form in complex with proteins or in the form of a monosodium salt - urate. Normally, its concentration in blood serum is 0.15–0.47 mmol/l or 3–7 mg/dl. From 0.4 to 0.6 g of uric acid and urates are excreted from the body daily.

A common disorder of purine catabolism is hyperuricemia, which occurs when the concentration of uric acid in the blood plasma exceeds normal levels. Due to the poor solubility of this substance, against the background of hyperuricemia, gout develops - a disease in which crystals of uric acid and urate are deposited in articular cartilage, ligaments and soft tissues with the formation of gouty nodes or tophi, causing inflammation of the joints and nephropathy. Gout affects 0.3 to 1.7% of the world's population. Men's serum urate levels are twice as high as women's, so they suffer from gout 20 times more often than women. The disease is genetically determined and is caused by:

– defects in PRDF synthetase associated with hyperactivation or resistance of the enzyme to inhibition by the final products of synthesis;

– partial loss of hypoxanthine guanine phosphoribosyltransferase activity, which ensures the recycling of purines.

With a complete loss of hypoxanthine-guanine phosphoribosyltransferase activity, a severe form of hyperuricemia develops - syndrome

Section 10. Metabolism of nitrogen-containing compounds
		Adenosine	Guanosine
			H3PO4
		H3PO4
Ribose 1-phosphate
		Hypoxanthine
		H2O + O2	H2O2H2O
			H2 O2
			Uric acid

Rice. 10.32. Catabolism of purine nucleotides:

1 - nucleotidase or phosphatase; 2 - adenosine deaminase;

3 - purine nucleoside phosphorylase; 4 - guanase; 5 - xanthine oxidase

Lesha-Nyhan, in which neurological and mental abnormalities are observed. The disease is inherited as a recessive trait linked to the X chromosome and occurs only in boys.

Gout is treated with allopurinol, a structural analogue of hypoxanthine. Xanthine oxidase oxidizes the drug into oxypurinol, which binds firmly to the active center of the enzyme and stops the catabolism of purines at the hypoxanthine stage, which is 10 times more soluble in body fluids than uric acid.

Biosynthesis and catabolism of pyrimidine nucleotides. Orotaciduria

Unlike the synthesis of purine nucleotides, in which the nitrogenous base is formed on a ribose-5-phosphate residue, the pyrimidine ring is initially assembled from simple precursors: glutamine, aspartate and CO2. Then it interacts with PRDP and turns into uridine-5"-monophosphate - UMP (Fig. 10.33).

Biological chemistry

HCO3-

Uridine-5"-monophosphate

Glutamate

Carbamoyl phosphate

COO-

COO-

Orotidine 5"-monophosphate

Carbamoyl aspartate

COO-NAD+

NADH + H+ O C

COO-

4 Orotate

Dihydroorotate

Amide group

N 1 6 5

2 3 4

Rice. 10.33. Origin of the atoms of the pyrimidine ring and synthesis of UMP:

I - KAD enzyme: 1 - carbamoylphosphate synthetase P; 2 - aspartate transcarbamoylase; 3 - dihydroorotase; 4 - Dihydroorotate dehydrogenase;

II - UMP synthase: 5 - orotate phosphoribosyltransferase, 6 - OMP decarboxylase

The synthesis of UMP occurs in the cytosol of cells and includes 6 stages catalyzed by 3 enzymes, two of which are multifunctional. At the first stage, carbamoyl phosphate is synthesized from Gln and CO2 using 2 ATP molecules. When Asp is added to carbamoyl phosphate and H2O is removed, a cyclic compound is formed - dihydroorotate, which is the product of the first polyfunctional protein - the CAD enzyme. The name KAD is made up of the initial letters of the enzymatic activities possessed by individual catalytic domains:

carbamoylphosphate synthetase P (CPS P), aspartate transcarbamoylase and dihydroorotase . Dihydroorotate is further oxidized to orotate under the action of NAD-dependent dihydroorotate dehydrogenase and with the participation of the second bifunctional enzyme - UMP synthases turns into UMF.

UMP forms UTP in two stages:

the first stage is catalyzed by UMP kinase, UMP + ATP → UDP + ADP,

and the second is NDP kinase with broad substrate specificity UDP + ATP → UTP + ADP,

CTP is formed from UTP under the action of CTP synthetase, which, using the energy of ATP, replaces the keto group of uracil with the amide group of Gln:

UTP + Glu + ATP → CTP + Glu + ADP + H3 PO4.

Regulation of the synthesis of pyrimidine nucleotides is carried out allosterically via a negative feedback mechanism:

– UTP inhibits the activity of CPS P in the composition KAD enzyme;

– UMP and CMF suppress the activity of the second polyfunctional enzyme - UMP synthases;

– accumulation of CTP reduces the activity of CTP synthetase.

Spare pathways in the synthesis of pyrimidine nucleotides do not play such a significant role as in the synthesis of purine nucleotides, although the following are found in cells:

pyrimidine phosphoribosyltransferase, catalyzing reaction: Pyrimidine + PRDP → Pyrimidine monophosphate + H 4 R 2 O 7 (U or C) (UMF or CMF), uridine kinase, converting a nucleoside into a nucleotide:

Uridine + ATP → UMP + ADP, and uridine phosphorylase, capable of reversing the nucleoside degradation reaction:

uracil + ribose-1-phosphate → uridine + H3 PO4.

During catabolism, cytidyl nucleotides hydrolytically lose their amino group and are converted into UMP. When inorganic phosphate is cleaved from UMP and dTMP using nucleotidase or phosphatase and ribose with the participation of phosphorylases, nitrogen bases remain - uracil and thymine. Both heterocycles can undergo hydrogenation with the participation of NADPH-dependent dihydropyrimidine dehydrogenase and hydrolytic cleavage to form β-ureidopropionic acid from dihydrouracil, and β-ureidopropionic acid from dihydrothymic acid.

on - β-ureidobutyric acids. Further hydrolytic cleavage of ureid derivatives ends with the formation of CO2, NH4 and β-alanine or β-aminobutyric acid.

Among the disorders of pyrimidine nucleotide metabolism, only one rare hereditary disease has been described - orotaciduria, which occurs as a result of a mutation in the gene of the second polyfunctional enzyme - UMP synthase. In this case, the conversion of orotate to UMP is disrupted, large amounts of orotate (up to 1.5 g per day) are excreted in the urine. A deficiency of pyrimidine nucleotides develops. To treat this disease, uridine or cytidine is used in doses of 0.5 to 1 g per day, which are converted by nucleoside kinase into UMP or CMP, bypassing the impaired reaction.

Formation of deoxyribonucleotides

Typically, the intracellular concentration of deoxyribonucleotides is very low, but during the S phase of the cell cycle it increases, providing DNA synthesis with substrates. Two enzyme complexes are involved in the formation of deoxyribonucleotides: ribonucleotide reductase And thymidylate synthase.

The reduction of all ribonucleotides into deoxy derivatives is catalyzed by the ribonucleotide reductase complex, which includes the ribonucleotide reductase, reducing protein - thioredoxin and enzyme - thioredoxin reductase, involved in the regeneration of thioredoxin with the help of NADPH (Fig. 10.34).

Ribonucleotide reductase is an allosteric enzyme whose activity depends on the concentration of individual dNTPs, and dATP is an inhibitor of the reduction of all ribonucleotides. This circumstance explains the occurrence of severe forms immunodeficiencies with a decrease in the activity of purine catabolism enzymes: adenosine deaminase or purine nucleoside phosphorylase(Fig. 10.32). Deficiency of these enzymes leads to the accumulation of dATP and dGTP in B and T lymphocytes, which allosterically inhibit ribonucleotide reductase and deprive DNA precursors. DNA synthesis decreases and cells stop dividing.

The synthesis of thymidyl nucleotides is catalyzed by the thymidylate synthase complex, which includes thymidylate synthase, catalyzing the inclusion of a one-carbon radical into the dUMP molecule, dihydrofolate reductase, ensuring the reduction of H2-folate to H4-folate with the participation of NADPH, and serine oxymethyltransferase, carrying out the transfer of the hydroxymethyl group of Ser to H4 -folate with the formation of N5 N10 -methylene-H4 -folate (Fig. 10.35). In the human body, dUMP is formed from dCDP by dephosphorylation and subsequent hydrolytic deamination.

Among the “spare” synthesis routes, the following are of particular importance:

thymine phosphorylase, converting thymine to thymidine: Thymine + Deoxyribose-1-phosphate → Thymidine + H3 PO4 and

thymidine kinase, which catalyzes the phosphorylation of thymidine. Thymidine + ATP → dTMP + ADP.

	Ribonucleotide
Nucleoside-	reductase		Deoxynucleoside-
diphosphates			diphosphates
(NDF)			(dNDF)
Thioredoxin		Thioredoxin
NADP+			NADPH + H+

Thioredoxin

reductase

Rice. 10.34. Reduction of ribonucleoside diphosphates into deoxy derivatives.

The reducing agent for ribonucleotides in the form of NDP is thioredoxin, the sulfhydryl groups of which are oxidized during this reaction. Oxidized thioredoxin is reduced by thioredoxin reductase with the participation of NADPH

N 5, N 10 - methylene-H 2 - folate

H4 - folate

Serin-

hydroxymethyltransferase

NADPH + H+

Rice. 10.35. Synthesis of thymidine-5"-monophosphate.

Thymidylate synthase not only transfers the methylene group of N5 N10 - methylene-H4 -folate to the 5th position of the pyrimidine base of dUMP, but also reduces it to a methyl radical, taking two hydrogen atoms from H4 -folate, therefore replenishing the reserves of N5 N10 -methylene H4 -folate requires the work of two more enzymes: dihydrofolate reductase and serine oxymethyltransferase

Use of nucleotide synthesis inhibitors as antiviral and antitumor drugs

Analogues of nitrogenous bases, nucleosides and nucleotides are widely used in medical practice as drugs (Table 10.3). They can:

– inhibit certain enzymes involved in the synthesis of nucleotides or nucleic acids;

– become involved in growing RNA or DNA chains and stop the chains from growing.

Table 10.3

Some antitumor and antiviral drugs

Connections	Mechanism of action	Application area
5-fluorouracil	Converts to ribo- and deoxyribon-		solid
	cleotides that inhibit thymidine	tumors
	lat synthase and RNA chain growth	Gastrointestinal tract, mammary
		forests, lungs, etc.
Methotrexate	Structural analogue of folic acid,	Chemotherapy
	inhibits dihydrofolate reductase,
	disrupts the synthesis of purine nucleotides and
	conversion of dUMP to dTMP
Thioguanine	Antimetabolite, disrupts DNA synthesis and	Treatment of acute leukemia
	mitosis in tumor cells	goats and chronic
		th myeloid leukemia
Acyclovir	Transforms into the corresponding NTF		herpes
(acyclo-guanosine)	and stops viral DNA synthesis	infections
Cidovudine	Phosphorylated in body cells with
(thymidine analogue) the presence of common intermediate products in metabolic pathways; the possibility of interconversion of substances through common metabolites; use of general coenzymes; the existence of a common path of catabolism and a unified system for the release and use of energy (respiratory chain); using similar regulatory mechanisms. In Fig. Figure 11.1 provides a general diagram of the main metabolic pathways of carbohydrates, proteins and fats described in previous chapters. 11.1. Compartmentalization and regulation of metabolic pathways A significant role in the control of metabolism is played by the division of metabolic processes into separate compartments of cells (Table 11.1). Table 11.1 Compartmentalization of major metabolic pathways Compartment Metabolic process Cytosol Glycolysis Gluconeogenesis Pentose phosphate pathway Lipid biosynthesis Biosynthesis of purines and pyrimidines Mitochondria Citrate cycle Rice. 11.1. Metabolism Integration