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At least 199 records · Page 11Linked to original sources
PubMed1994

Reversible unfolding of fructose 6-phosphate, 2-kinase:fructose 2,6-bisphosphatase.

Reversible unfolding of rat testis fructose 6-phosphate,2-kinase:fructose 2,6-bisphosphatase in guanidine hydrochloride was monitored by following enzyme activities as well as by fluorescence methodologies (intensity, emission maximum, polarization, and quenching), using both intrinsic (tryptophan) and extrinsic (5((2-(iodoacetyl)amino) ethyl)naphthalene-1-sulfonic acid) probes. The unfolding reaction is described minimally as a 4-state transition from folded dimer-->partially unfolded dimer-->monomer-->unfolded monomer. The partially unfolded dimer had a high phosphatase/kinase ratio due to preferential unfolding of the kinase domain. The renaturation reaction proceeded by very rapid conversion (less than 1 s) of unfolded monomer to dimer, devoid of any enzyme activity, followed by slow (over 60 min) formation of the active enzyme. The recovery rates of the kinase and the phosphatase were similar. Thus, the refolding appeared to be a reversal of the unfolding pathway involving different forms of the transient dimeric intermediates. Fluorescence quenching studies using iodide and acrylamide showed that the tryptophans, including Trp-15 in the N-terminal peptide, were only slightly accessible to iodide but were much more accessible to acrylamide. Fructose 6-phosphate, but not ATP or fructose 2,6-bisphosphate, diminished the iodide quenching, but all these ligands inhibited the acrylamide quenching by 25%. These results suggested that the N-terminal peptide (containing a tryptophan) was not exposed on the protein surface and may play an important role in shielding other tryptophans from solvent.

Acrylamides↗
PubMed1994

Bovine heart fructose 6-P,2-kinase:fructose 2,6-bisphosphatase mRNA and gene structure.

Previously we described the coding region of bovine heart Fructose 6-P,2-kinase:Fructose 2,6-bisphosphatase as determined from cDNA. We have isolated several overlapping clones and determined the DNAs which encode the entire mRNA of bovine heart bifunctional enzyme, including the 5'- and 3'-noncoding regions. the exon-intron structure of the 27-kb gene was determined and shown to consist of 16 exons. There are one primary and two secondary transcription initiation sites with the coding region beginning at exon 2. Exons 3-7 encode the Fructose 6-P,2-kinase domain, and exons 9-14 encode the Fructose 2,6-biphosphatase domain. Exon 15 is a unique exon for the heart type isozyme and contains the phosphorylation sites for protein kinases A and C. Alternative splicing of this exon accounts for the expression of two heart type isozymes in cardiac muscle. Exon 16 (also unique), 1820 bp long and located 7 kb downstream of exon 15, encodes the short C-terminus of the enzyme and is completely different from that of the rat heart bifunctional enzyme gene.

Amino Acid Sequence↗
PubMed2001

Physiological relevance of fructose 2,6-bisphosphate in the regulation of spinach leaf pyrophosphate:fructose 6-phosphate 1-phosphotransferase.

A major problem in defining the physiological role of pyrophosphate:fructose 6-phosphate 1-phosphotransferase (PFP, EC 2.7.1.90) is the 1,000-fold discrepancy between the apparent affinity of PFP for its activator, fructose 2,6-bisphosphate (Fru-2,6-P2), determined under optimum conditions in vitro and the estimated concentration of this signal metabolite in vivo. The aim of this study was to investigate the combined influence of metabolic intermediates and inorganic phosphate (Pi) on the activation of PFP by Fru-2,6-P2. The enzyme was purified to near-homogeneity from leaves of spinach (Spinacia oleracea L.). Under optimal in vitro assay conditions, the activation constant (Ka) of spinach leaf PFP for Fru-2,6-P2 in the glycolytic direction was 15.8 nM. However, in the presence of physiological concentrations of fructose 6-phosphate, inorganic pyrophosphate (PPi), 3-phosphoglycerate (3PGA), phosphoenolpyruvate (PEP), ATP and Pi the Ka of spinach leaf PFP for Fru-2,6-P2 was up to 2000-fold greater than that measured in the optimised assay and Vmax decreased by up to 62%. Similar effects were observed with PFP purified from potato (Solanum tuberosum L.) tubers. Cytosolic metabolites and Pi also influenced the response of PFP to activation by its substrate fructose 1,6-bisphosphate (Fru-1,6-P2). When assayed under optimum conditions in the gluconeogenic direction, the Ka of spinach leaf PFP for Fru-1,6-P2 was approximately 50 microM. Physiological concentrations of PPi, 3PGA, PEP, ATP and Pi increased Ka up to 25-fold, and decreased Vmax by over 65%. From these results it was concluded that physiological concentrations of metabolites and Pi increase the Ka of PFP for Fru-2,6-P2 to values approaching the concentration of the activator in vivo. Hence, measured changes in cytosolic Fru-2,6-P2 levels could appreciably alter the activation state of PFP in vivo. Moreover, the same levels of metabolites increase the Ka of PFP for Fru-1,6-P2 to an extent that activation of PFP by this compound is unlikely to be physiologically relevant.

Buffers↗
PubMed1994

The configuration and conformation of di-D-fructose anhydride I. The crystal and molecular structure of 3,4,3',4'-tetra-O-acetyl-6,6'-di (triphenylmethyl)-di-D-fructose anhydride I.

The crystal structure of 3,4,3',4'-tetra-O-acetyl- 6,6'-di(triphenylmethyl)-di-D-fructose anhydride I (1) has been determined by single-crystal X-ray diffraction. The crystals are monoclinic, space group P2(1) with a = 16.399(2), b = 9.091(2), c = 17.946(4) A, beta = 103.66(1) degrees, V = 2600(2) A3, and Z = 2. The structure was refined to R = 0.044 and Rw = 0.051 for 4403 observed reflections. The structure analysis of 1 showed that the previously assigned chemical structure of di-D-fructose anhydride I is undoubtedly alpha-D-fructofuranose beta-D-fructofuranose 1,2':2,1'-dianhydride. The conformations of the furanose rings are E5 with P = 59.8 and tau m = 43.2 degrees for D-fructose 1, and 2T3 with P = -34.39 degrees and tau m = 39.64 degrees for D-fructose 2. The two furanose fragments are linked by a 1,4-dioxane ring in a spiro arrangement. The 1,4-dioxane ring has a chair conformation with Cremer-Pople puckering parameters Q = 0.527 A, phi = 72.2 degrees and the a = 14.2 degrees.

Carbohydrate Conformation↗
PubMed1987

Fructose 2,6-bisphosphate in rat erythrocytes. Inhibition of fructose 2,6-bisphosphate synthesis and measurement by glycerate 2,3-bisphosphate.

The concentration of fructose 2,6-bisphosphate found in freshly isolated erythrocytes was below the limit of detection (20 pmol/ml of packed cells). However, it increased to about 250 pmol/ml of cells when erythrocytes were incubated with glucose at pH 6.9, but not at pH 7.4 or 8.2. This could be explained by variations in the content of glycerate 2,3-bisphosphate, which was found to inhibit 6-phosphofructo-2-kinase, the enzyme responsible for fructose 2,6-bisphosphate synthesis. Glycerate 2,3-bisphosphate was also found to inhibit the potato enzyme (pyrophosphate:fructose-6-phosphate 1-phosphotransferase) used for the measurement of fructose 2,6-bisphosphate.

2,3-Diphosphoglycerate↗
PubMed1995

Fructose-1,6-Bisphosphate Is an Allosteric Activator of Pyrophosphate:Fructose-6-Phosphate 1-Phosphotransferase.

The activity of highly purified pyrophosphate:fructose-6-phosphate 1-phosphotransferase (PFP) from barley (Hordeum vulgare) leaves was studied under conditions where the catalyzed reaction was allowed to approach equilibrium. The activity of PFP was monitored by determining the changes in the levels of fructose-6-phosphate, orthophosphate, and fructose-1,6-bisphosphate (Fru-1,6-bisP). Under these conditions PFP activity was not dependent on activation by fructose-2,6-bisphosphate (Fru-2,6-bisP). Inclusion of aldolase in the reaction mixture temporarily restored the dependence of PFP on Fru-2,6-bisP. Alternatively, PFP was activated by Fru-1,6-bisP in the presence of aldolase. It is concluded that Fru-1,6-bisP is an allosteric activator of barley PFP, which can substitute for Fru-2,6-bisP as an activator. A significant activation was observed at a concentration of 5 to 25 [mu]M Fru-1,6-bisP, which demonstrates that the allosteric site of barley PFP has a very high affinity for Fru-1,6-bisP. The high affinity for Fru-1,6-bisP at the allosteric site suggests that the observed activation of PFP by Fru-1,6-bisP constitutes a previously unrecognized in vivo regulation mechanism.

Journal Article↗
PubMed1992

Enzymes Catalyzing the Reversible Conversion of Fructose-6-Phosphate and Fructose-1,6-Bisphosphate in Maize (Zea mays L.) Kernels.

The significance of the glycolytic and gluconeogenic conversion of fructose-6-phosphate and fructose-1,6-bisphosphate on sugar metabolism was investigated in maize (Zea mays L.) kernels. Maximum extractable activities of the pyrophosphate (PPi) dependent phosphofructokinase, fructose-1,6-bisphosphatase, and the ATP-dependent phosphofructokinase were measured in normal and four maize genotypes, which accumulate relatively more sugars and less starch, to determine how these enzymes are affected by the genetic lesions. Normal endosperm accumulated more dry matter than the high sugar/low starch genotypes, but protein contents did not differ greatly among the genotypes. Mutation of several starch biosynthetic enzymes had little impact on the activities of PPi-dependent phosphofructokinase, fructose-1,6-bisphosphatase, and ATP-dependent phosphofructokinase, despite the altered capacity of the cell to synthesize starch. The PPi-dependent phosphofructokinase appeared to be more active toward glycolysis in all genotypes studied. Activity of the PPi-dependent phosphofructokinase in shrunken (low sucrose synthase genotype) did not differ from the activity in other genotypes, suggesting that the gluconeogenic production of PPi may not be the primary role of the enzyme. As expected, shrunken kernels contained more sugars and less starch than normal kernels throughout kernel development except at the very early stages. Developmental profiles of normal kernels also showed marked changes in the PPi-dependent phosphofructokinase activity, whereas the level of ATP-dependent phosphofructokinase activity remained relatively steady during kernel development. In addition, the ATP-dependent phosphofructokinase, and not the PPi-dependent phosphofructokinase, appeared to correlate more closely with respiration rate. These findings suggest that glycolysis catalyzed by the ATP-dependent phosphofructokinase may serve primarily to support energy production, and glycolysis catalyzed by the PPi-dependent phosphofructokinase may contribute mainly to generation of biosynthetic intermediates.

Journal Article↗
PubMed1985

The phosphoenolpyruvate-dependent fructose-specific phosphotransferase system in Rhodopseudomonas sphaeroides. Mechanism for transfer of the phosphoryl group from phosphoenolpyruvate to fructose.

The phosphoenolpyruvate-dependent fructose-specific phosphotransferase system in Rhodopseudomonas sphaeroides is a membrane-bound complex of two enzymes, an integral membrane protein EII and a soluble factor SF. In media of high ionic strength the binding constant of SF to the membranes is 55 nM. Phosphorylation of SF, the first step in the reaction sequence, has no influence on the binding. The second step is the transfer of the phosphoryl group from SF to EII. The physical existence of both phosphorylated SF and EII is demonstrated and it is shown that the phosphoryl group is donated to the next species in the reaction sequence. The molecular mass of SF is 110 kDa. EII is almost completely extracted from the membrane as a dimer. The molecular mass of the monomer is 55 kDa. Both SF and EII possess thiols that are essential for catalysis. The thiol on EII is protected against inactivation by N-ethylmaleimide in the phosphorylated state. Kinetic experiments show that the binding site for fructose on EII is induced by phosphorylation of EII ('ping-pong' mechanism). The affinity constants of the phosphotransferase complex for phosphoenolpyruvate and fructose at infinite concentration of the other substrate are 25 microM and 8 microM, respectively. The fructose phosphorylation rate equation is given as a function of the concentration of the two enzymes and the two substrates.

Autoradiography↗
PubMed1991

Molecular cloning of the DNA and expression and characterization of rat testes fructose-6-phosphate,2-kinase:fructose-2,6-bisphosphatase.

We have isolated and sequenced two overlapping cDNA fragments which could encode the complete amino acid sequence of rat testis fructose-6-phosphate,2-kinase:fructose-2,6-bisphosphatase. Northern blot analysis revealed that the major 2-kilobase mRNA isolated from rat testis hybridized with a cDNA fragment. A full length cDNA, which encoded a protein of 468 amino acids, was constructed and expressed in Escherichia coli. The expressed protein, purified to homogeneity, showed a Mr of 55,000 by gel electrophoresis under denaturing conditions, compared to the deduced Mr of 54,023. Fru-6-P,2-kinase:Fru-2,6-bisphosphatase with the same Mr 55,000 was also present in rat testis extract. The active enzyme was a dimer as judged by molecular sieve filtration. The expressed enzyme was bifunctional with specific activities of 90 and 22 milliunits/mg of the kinase and the phosphatase activities, respectively. Various kinetic constants of the expressed fructose 6-P,2-kinase were KmFru 6-P = 85 microM and KmATP = 270 microM, and those of fructose 2,6-bisphosphatase were KmFru 2,6-P2 = 21 microM and KiFru 6-P = 3.4 microM. The enzyme was phosphorylated by Fru-2,6[2-32P]P2 and also by protein kinase C, but not by cAMP-dependent protein kinase, which is in contrast to the liver and heart isozymes.

Amino Acid Sequence↗
PubMed1989

Purification and characterization of rat skeletal muscle fructose-6-phosphate,2-kinase:fructose-2,6-bisphosphatase.

Fructose-6-phosphate,2-kinase:fructose-2,6-bis-phosphatase from rat skeletal muscle has been purified to homogeneity, and its structure and kinetic properties have been determined. The Mr of the native enzyme was 100,000 and the subunit Mr was 54,000. The apparent Km values of fructose-6-P,2-kinase for Fru-6-P and ATP were 56 and 48 microM, respectively. The apparent Km value for Fru-2,6-P2 of fructose-2,6-bis-phosphatase was 0.4 microM, and the Ki for Fru-6-P was 12.5 microM. The enzyme was bifunctional, and the phosphatase activity was 2.5 times higher than the kinase activity. The enzyme was not phosphorylated by cAMP-dependent protein kinase. The amino acid composition of the skeletal muscle enzyme was similar to that of the rat liver enzyme, and the carboxyl terminus sequence (His-Tyr) was the same as that of the liver enzyme. The tryptic peptides generated from the liver and skeletal muscle enzymes were identical except for two peptides. A peptide corresponding to nucleotides 14-28 of the rat liver enzyme was not detected in the skeletal muscle enzyme. A peptide whose amino acid sequence was Thr-Ala-Ser-Ile-Pro-Gln-Phe-Thr-Asn-Ser-Pro-Thr-Met-Val-Ile-Met-Val-Gly-Leu-Pro - Ala-Arg was also isolated. This peptide was the same as that of rat liver enzyme (nucleotides 31-52) containing the phosphorylation site except in the muscle enzyme two amino terminus amino acids, Gly-Ser(P), have been altered to Thr-Ala. Thus, the rat skeletal muscle enzyme is very similar in structure to the rat liver enzyme except for the lack of possibly one peptide and the lack of a phosphorylation site by the substitution of the target Ser with Ala.

Amino Acid Sequence↗
PubMed1978

[Behavior of various blood constituents (glucose, fructose, insulin, lactate, pyruvate, free fatty acids, inorganic phosphate) and half-life of monosaccharides in the plasma after i.v. infusion of glucose, fructose, galactose and invert sugar solutions in ruminants. 2. Studies in cattle].

Monosaccharides were intravenously injected to eight adult heads of cattle, between 380 kg and 670 kg in live weight, to study, in the context of stress endurance, the half-life values of the sugars as well as monosaccharide effects upon concentrations of various blood components. The fructose concentration in the blood plasma went up temporarily following the infusion of glucose solution. Fructose infusion usually caused only little rise of the glucose concentration in blood plasma, with hypoglycaemia occurring quite often towards the end of an experimental period. The half-life values of sugar in blood plasma were between twelve and 29 and those of fructose between ten and 17 minutes. The rate of fructose conversion was higher than that of glucose conversion, but values were identical in some cases. The pyruvate concentration in the blood and the insulin level in blood plasma went up in response to infusion of monosaccharide solutions. Urine excretion of monosaccharides following invert sugar infusion was less than half of that in response to glucose infusion.

Animals↗
PubMed1986

Inhibition of fructose bisphosphatase and stimulation of phosphofructokinase by a stable isosteric phosphonate analog of fructose 2,6-bisphosphate.

We describe the synthesis of a mixture of D-manno- and D-gluco-2,5-anhydro-1-deoxy-1-phosphonohexitol 6-phosphate via a Horner-Emmons reaction of 2,3,5-tri-O-benzyl-beta-D-arabinofuranose followed by phosphorylation of the equivalent 6-position and subsequent deprotection. This mixture inhibits fructose-1,6-bisphosphatase; the concentration required for half-maximal effect in the presence of 25 microM AMP is approximately 6 microM. The mixture of analogs also stimulates 6-phosphofructo-1-kinase from rabbit liver; the concentration required to reach one-half Vmax was found to be ca. 25 microM at 0.25 mM fructose 6-phosphate and 50 microM AMP. These analogs have replaced the labile anomeric phosphate of fructose 2,6-bisphosphate with a stable methylenephosphonate, and could be of great interest due to their appropriate physiological effects and their chemical stability.

Adenosine Monophosphate↗
PubMed1989

The site of substrate and fructose 2,6-bisphosphate binding to rabbit liver fructose-1,6-bisphosphatase.

The binding site(s) in rabbit liver fructose-1,6-bisphosphatase for the active site binding ligand, fructose 6-phosphate, and the inhibitor, fructose 2,6-bisphosphate, have been investigated by using nuclear magnetic resonance spectroscopy. The distance from a nitroxide spin label to the bound ligands and the distance from the structural metal site to the bound ligands are about the same within experimental error. These data indicate that the two ligands probably bind at the active site in the rabbit liver enzyme.

Animals↗
PubMed1984

Fructose 1,6-bisphosphatase in the diagnosis of chronic hepatitis. I. Activity measurements of fructose 1,6-bisphosphatase in human serum.

In this communication, we propose a method for the determination in human serum of fructose 1,6-bisphosphatase based on parallel measurements of enzyme activities in presence of 1-p-bromotetramisole oxalate and adenosine 5'-monophosphate. The employment of these specific inhibitors renders the discrimination between specific and non-specific activities feasible. A regression analysis identifies fructose 1,6-bisphosphatase (EC 3.1.3.11) as the origin of the specific and alkaline phosphatase (EC 3.1.3.1) as the source of the non-specific fructose 1,6-bisphosphate dephosphorylating activities. This procedure lends itself to the diagnosis using serum samples of 'piecemeal' necrosis in liver disease.

Adenosine Monophosphate↗
PubMed1984

Biphasic effect of fructose 2,6-bisphosphate on the liver fructose-1,6-bisphosphatase: mechanistic and physiological implications.

Fructose 2,6-bisphosphate has been claimed to be both a substrate analogue and an allosteric inhibitor of fructose-1,6-bisphosphatase. The results reported here show that fructose 2,6-bisphosphate can be both an inhibitor and an activator of the enzyme, depending on the substrate concentration. This biphasic behaviour at saturating concentrations of substrate can only be due to an allosteric effect. In addition to the mechanistic implication it is possible that this finding may have physiological meaning.

Animals↗
PubMed1990

Structure refinement of fructose-1,6-bisphosphatase and its fructose 2,6-bisphosphate complex at 2.8 A resolution.

The structures of the native fructose-1,6-bisphosphatase (Fru-1,6-Pase), from pig kidney cortex, and its fructose 2,6-bisphosphate (Fru-2,6-P2) complexes have been refined to 2.8 A resolution to R-factors of 0.194 and 0.188, respectively. The root-mean-square deviations from the standard geometry are 0.021 A and 0.016 A for the bond length, and 4.4 degrees and 3.8 degrees for the bond angle. Four sites for Fru-2,6-P2 binding per tetramer have been identified by difference Fourier techniques. The Fru-2,6-P2 site has the shape of an oval cave about 10 A deep, and with other dimensions about 18 A by 12 A. The two Fru-2,6-P2 binding caves of the dimer in the crystallographically asymmetric unit sit next to one another and open in opposite directions. These two binding sites mutually exchange their Arg243 side-chains, indicating the potential for communication between the two sites. The beta, D-fructose 2,6-bisphosphate has been built into the density and refined well. The oxygen atoms of the 6-phosphate group of Fru-2,6-P2 interact with Arg243 from the adjacent monomer and the residues of Lys274, Asn212, Tyr264, Tyr215 and Tyr244 in the same monomer. The sugar ring primarily contacts with the backbone atoms from Gly246 to Met248, as well as the side-chain atoms, Asp121, Glu280 and Lys274. The 2-phosphate group interacts with the side-chain atoms of Ser124 and Lys274. A negatively charged pocket near the 2-phosphate group includes Asp118, Asp121 and Glu280, as well as Glu97 and Glu98. The 2-phosphate group showed a disordered binding perhaps because of the disturbance from the negatively charged pocket. In addition, Asn125 and Lys269 are located within a 5 A radius of Fru-2,6-P2. We argue that Fru-2,6-P2 binds to the active site of the enzyme on the basis of the following observations: (1) the structure similarity between Fru-2,6-P2 and the substrate; (2) sequence conservation of the residues directly interacting with Fru-2,6-P2 or located at the negatively charged pocket; (3) a divalent metal site next to the 2-phosphate group of Fru-2,6-P2; and (4) identification of some active site residues in our structure, e.g. tyrosine and Lys274, consistent with the results of the ultraviolet spectra and the chemical modification. The structures are described in detail including interactions of interchain surfaces, and the chemically modifiable residues are discussed on the basis of the refined structures.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed2003

Preparation and reactivity of a novel disaccharide, glucosyl 1,5-anhydro-D-fructose (1,5-anhydro-3-O-alpha-glucopyranosyl-D-fructose).

A novel disaccharide, glucosyl 1,5-anhydro-D-fructose (1,5-anhydro-3-O-alpha-glucopyranosyl-D-fructose, GAF) was enzymatically prepared from 1,5-anhydro-D-fructose (1,5-AF) and cyclomaltoheptaose (beta-cyclodextrin). Cyclodextrin glucanotransferase transferred various sizes of maltooligosaccharide to 1,5-AF. Glucoamylase digested the maltooligosyl chain of the products to a glucosyl residue giving a final product, GAF. An NMR analysis of GAF elucidated that the glucose residue was linked to C-3 of the 1,5-AF residue with an ether linkage. Reactivity on the aminocarbonyl reaction of GAF with bovine serum albumin was lower than that of 1,5-AF, but was higher than that of glucose.

Animals↗
PubMed1994

Crystal structure of fructose-1,6-bisphosphatase complexed with fructose 2,6-bisphosphate, AMP, and Zn2+ at 2.0-A resolution: aspects of synergism between inhibitors.

The crystal structure of fructose-1,6-bisphosphatase (Fru-1,6-Pase; EC 3.1.3.11) complexed with Zn2+ and two allosteric regulators, AMP and fructose 2,6-bisphosphate (Fru-2,6-P2) has been determined at 2.0-A resolution. In the refined model, the crystallographic R factor is 0.189 with rms deviations of 0.014 A and 2.8 degrees from ideal geometries for bond lengths and bond angles, respectively. A 15 degrees rotation is observed between the upper dimer C1C2 and the lower dimer C3C4 relative to the R-form structure (fructose 6-phosphate complex), consistent with that expected from a T-form structure. The major difference between the structure of the previously determined Fru-2,6-P2 complex (R form) and that of the current quaternary T-form complex lies in the active site domain. A zinc binding site distinct from the three binding sites established earlier was identified within each monomer. Helix H4 (residues 123-127) was found to be better defined than in previously studied ligated Fru-1,6-Pase structures. Interactions between monomers in the active site domain were found involving H4 residues from one monomer and residues Tyr-258 and Arg-243 from the adjacent monomer. Cooperativity between AMP and Fru-2,6-P2 in signal transmission probably involves the following features: an AMP site, the adjacent B3 strand (residues 113-118), the metal site, the immediate active site, the short helix H4 (residues 123-127), and Tyr-258 and Arg-243 from the adjacent monomer within the upper (or lower) dimer. The closest distance between the immediate active site and that on the adjacent monomer is only 5 A. Thus, the involvement of H4 in signal transmission adds another important pathway to the scheme of the allosteric mechanism of Fru-1,6-Pase.

Adenosine Monophosphate↗