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PubMed1978

Chromium (III) thiamin diphosphate: a new probe of enzyme coenzyme--metal ion binding. Interaction with wheat germ pyruvate decarboxylase.

Chromium (III) thiamin diphosphate (CrTDP) is a substitutionally inert complex which is a physical and kinetic probe of the binding mode of metal ion and coenzyme in thiamin diphosphate (TDP) dependent enzymes. CrTDP is prepared by reaction of aquated Cr (III) and TDP and purifed by ion-exchange chromatography. CrTDP binds to the apoenzyme of wheat germ pyruvate decarboxylase, giving an inactive holoenzyme. Chromium (III) ion binds to the apoenzyme in a manner that suggests, in light of the results with CrTDP, that there are two metal ion binding sites. Extension of the use of CrTDP to other enzymes can give specific information about binding and can introduce an active site reporter group

Apoenzymes↗

PubMed1991

Divergence of muscle and liver fructose 2,6-diphosphate in fasted exercising rats.

Previous studies demonstrate that nonexercising muscle may serve as a source of lactate for hepatic gluconeogenesis during long-term exercise. The concentration of fructose 2,6-diphosphate (F-2,6-P2), a signal molecule that accelerates glycolysis, was examined in liver and muscles of fed and fasted resting rats and in fasted rats run for 5, 15, or 30 min at 21 m/min (15% grade). Liver F-2,6-P2 decreased in response to fasting and exercise. White quadriceps (composed predominantly of type IIb fibers) F-2,6-P2 increased from 2.2 +/- 0.1 to 4.5 +/- 0.4 pmol/mg in the fasted rats in response to 30 min of treadmill running. No increase was observed in the red region of the quadriceps (composed of type IIa fibers). The fasted rats also exhibited a threefold increase in glucose 1,6-diphosphate (G-1,6-P2) in the white quadriceps after 30 min of exercise, whereas no significant changes were observed in the red quadriceps or in liver. The increases in F-2,6-P2 and G-1,6-P2 may be important in accelerating glycolysis and enhancing lactate production in muscles that are not glycogen depleted during long-term exercise.

Animals↗

PubMed1992

Control of fructose 2,6-diphosphate in muscle of exercising fasted rats.

This study examined the role of epinephrine in controlling intramuscular signals that may accelerate lactate production in less active muscles during exercise. Sham-operated (sham) or adrenodemedullated (ADM) rats were fasted 24 h and then were killed at rest or after running for 15 or 30 min on a treadmill (21 m/min, 15% grade). One-half of the ADM rats were infused with epinephrine (6 micrograms/h) intravenously (jugular catheter) during exercise. ADM rats exhibited lower blood glucose, blood lactate, white quadriceps muscle content of lactate, glucose 6-phosphate, fructose 6-phosphate, and adenosine 3',5'-cyclic monophosphate (cAMP) during exercise than did sham rats or epinephrine-infused ADM rats. The white quadriceps muscle contents of fructose 2,6-diphosphate (F-2,6-P2) and glucose 1,6-diphosphate (G-1,6-P2) (allosteric activators of glycolysis) were at least two times as high in sham rats and in epinephrine-infused rats as in ADM rats during exercise. We conclude that the exercise-induced rise in epinephrine is responsible for the acceleration of glycolysis in less active muscle during exercise. This effect is likely mediated by epinephrine-induced increases in cAMP, F-2,6-P2, and G-1,6-P2.

Adrenal Medulla↗

PubMed1970

Biosynthesis of cytidine diphosphate diglyceride by human platelets.

Homogenates of human platelets contain an enzyme which catalyzes the formation of cytidine diphosphate diglyceride from cytidine triphosphate and phosphatidic acid. The enzymatic activity could not be dissociated from platelet particles and the greatest specific activity was found in the membrane fraction. The K(m) for cytidine triphosphate was 0.16 mmole/liter and the apparent K(m) for phosphatidic acid was 6.2 mmoles/liter. The pH optimum was 7.0 and the most effective buffers were triethanolamine-HCl and Tris-HCl. The reaction was dependent on the presence of divalent cations, magnesium being the most effective of those investigated. Monovalent cations did not alter the reaction rate. Evidence is presented that the cytidine diphosphate diglyceride produced can serve as a precursor for the synthesis of phosphatidylinositol. No difference was found in the enzymatic activity in platelets from normal subjects and from patients with diseases known to interfere with platelet thromboplastic function.

Blood Platelet Disorders↗

PubMed1988

The evaluation of erythrocyte thiamin diphosphate as an indicator of thiamin status in man, and its comparison with erythrocyte transketolase activity measurements.

HPLC measurement of the major physiological form of thiamin, thiamin diphosphate, in erythrocytes (ETDP) has been assessed as an indicator of thiamin status and compared with erythrocyte transketolase activity (ETKA) before and after activation with exogenous thiamin diphosphate (TDP effect). The comparison was made by following the response of the parameters to incubation of erythrocytes with thiamin and by measurements in alcoholic, elderly and student groups. All parameters were responsive to the thiamin content of their environment, but ETDP was at least as sensitive as TDP effect and more sensitive than ETKA in reflecting thiamin uptake and utilisation by erythrocytes. There was a better correlation between ETDP and ETKA than between ETDP and TDP effect. All the groups showed a significant positive correlation between ETDP and ETKA, but only the elderly and the alcoholic groups showed a significant negative correlation between ETDP and TDP effect. The lack of correlation between ETDP and TDP effect in the student group may be due to the relative imprecision of TDP effect measurements at the lower end of the reference range. ETDP is more stable than ETKA in frozen erythrocytes, is easier to standardise and is not affected by various factors which can influence the enzyme assay. Measurement of ETDP is, therefore, recommended for first line assessment of thiamin status.

Adult↗

PubMed2003

Human uridine diphosphate-glucuronosyltransferase UGT2B7 conjugates mineralocorticoid and glucocorticoid metabolites.

Mineralocorticoid and glucocorticoid hormones are metabolized as glucuronide conjugates. Using labeled [(14)C]uridine diphosphate glucuronic acid and microsomal preparations from human embryonic kidney 293 cells stably expressing the different human and monkey uridine diphosphate glucuronosyltransferase (UGT)2B enzymes, it is demonstrated that the two human allelic variants UGT2B7H((268)) and UGT2B7Y((268)) conjugate aldosterone, its A-ring reduced metabolites (5alpha-dihydroaldosterone and 3alpha,5beta-tetrahydroaldosterone), and both 5alpha- and 5beta-tetrahydrocortisone epimers. The two variants of UGT2B4 also glucuronidate tetrahydroaldosterone, whereas all enzymes tested were inefficient to produce cortisol glucuronide derivatives. Kinetic analyses reveal that UGT2B7 polymorphisms glucuronidate mineralocorticoids with a 5.5- to 20-fold higher affinity than glucocorticoids. For the first time, a significant difference between the two allelic variants of UGT2B7 is described, because UGT2B7H((268)) possesses an 11-fold higher aldosterone glucuronidation efficiency (ratio Vmax((app.))/Km((app.))) than UGT2B7Y((268)). RT-PCR experiments demonstrate the expression of UGT2B7 in human kidney and in renal proximal tubule epithelial cells, suggesting that mineralocorticoids and glucocorticoids are metabolized in their target tissue. Measurement of aldosterone glucuronidation and normalization with the UGT2B protein contents in monkey tissues demonstrate that liver and kidney glucuronidate this hormone with a similar velocity. Immunohistochemical studies performed in monkey kidney cortex reveal a restrictive expression of UGT2B proteins in the epithelial cells of the proximal tubules. Because expression of the mineralocorticoid receptor was detected in the distal tubule epithelial cells, the present data suggest a two-cell mechanism of aldosterone action and metabolism in the kidney.

Aldosterone↗

PubMed2004

Myocardial protection using fructose-1,6-diphosphate during coronary artery bypass graft surgery: a randomized, placebo-controlled clinical trial.

UNLABELLED: In vitro and in vivo studies suggest that fructose-1,6-diphosphate (FDP), an intermediary glycolytic pathway metabolite, ameliorates ischemic tissue injury through increased high-energy phosphate levels and may therefore have cardioprotective properties in patients undergoing coronary artery bypass graft (CABG) surgery. We designed a randomized, placebo-controlled, double-blinded, sequential-cohort, dose-ranging safety study to test 5 FDP dosage regimens in patients (n = 120; 60 FDP, 60 control) undergoing CABG surgery. Of these dosage regimens, 3 produced no benefit, 1 produced improved cardiac function, and 1 required adjustment as a result of metabolic acidosis. This suggests that we achieved the intended effect of a dose-ranging study. The expected response was observed in patients treated with 250 mg/kg FDP IV before surgery and 2.5 mM FDP as a cardioplegic additive (n = 15). These patients had lower serum creatine kinase-MB levels 2, 4, and 6 h after reperfusion (P < 0.05), fewer perioperative myocardial infarctions (P < 0.05), and improved postoperative cardiac function, as evidenced by higher left ventricular stroke work index (LVSWI) 6, 12, and 16 h (P < 0.01) and cardiac index (CI) at 12 and 16 h (P < 0.05) after reperfusion. Overall efficacy of FDP was tested across all regimens that included IV FDP (n = 88; 44 FDP, 44 control) using 2 (FDP versus placebo) x 3 (dose size) factorial analyses. Area-under-curve (AUC) analysis demonstrated a significant increase in CI (AUC-16h, P = 0.013) and LVSWI (AUC-16h, P = 0.003) and reduction in CK-MB levels (AUC-16h, P < 0.05) in FDP-treated patients. The internal consistency of this dataset suggests that FDP may provide myocardial protection in CABG surgery and supports previous laboratory and clinical studies of FDP in ischemic heart disease. IMPLICATIONS: Fructose-1,6-diphosphate (FDP) may increase high-energy phosphate levels under anaerobic conditions and therefore ameliorate ischemic injury. A dose-ranging safety study for FDP was conducted in patients undergoing coronary artery surgery. Preischemic provision of FDP significantly improved cardiac function and reduced perioperative ischemic injury. These myocardial protective effects may improve patient outcome after cardiac surgery.

Aged↗

PubMed1996

Proteolytic release of dehydrodolichyl diphosphate synthase from pig testis microsomes.

Pig testicular dehydrodolichyl diphosphate synthase was released in a soluble form out of microsomes by controlled proteolysis with trypsin or papain. Approximately 25% of the microsomal enzyme activity was recovered in the 115,000 x g supernatant fraction when the microsomes were treated with trypsin at 4 degrees C for 1 h. Similar proteolytic release of microsomal enzyme was also observed with the treatment with papain. The K(m), optimal pH, Mg2+ dependency, and ion strength dependency of the enzyme released by trypsin were similar to those of the microsomal enzyme. The microsomal enzyme was active even in the absence of detergents, while the released enzyme required detergents for activity. Gel filtration of the released enzyme gave a peak of dehydrodolichyl diphosphate synthase activity, which appeared between 150-kDa and 50-kDa molecular mass markers.

Alkyl and Aryl Transferases↗

PubMed1998

Overexpression of an archaeal geranylgeranyl diphosphate synthase in Escherichia coli cells.

An archaeal geranylgeranyl diphosphate synthase was overexpressed in Escherichia coli cells as fusion proteins. These fusion proteins retained their thermostability and had higher specific activity than did a partially purified native enzyme Previously reported. We purified 24.3 mg of MBP (maltose-binding protein)-fusion protein and 5.4 mg of GST (glutathione S-transferase)-fusion protein from a one-liter culture of E. coli. The MBP-fusion proteins existed in dimer, tetramer, octamer, or dodecamer form, and their product specificities were altered according to the oligomerization. The MBP-fusion protein has protease-sensitive sites in the portion corresponding to geranylgeranyl diphosphate synthase.

ATP-Binding Cassette Transporters↗

PubMed2004

Bacillus subtilis ypgA gene is fni, a nonessential gene encoding type 2 isopentenyl diphosphate isomerase.

We previously identified the fni gene of Streptomyces sp. strain CL190 as type 2 isopentenyl diphosphate (IPP) isomerase, which needs both FMN and NADPH for enzyme activity. An fni gene homolog, ypgA, was detected in the database of the Bacillus subtilis genome. However, the ypgA product was about 140 amino acids shorter in the N-terminal than the Streptomyces fni gene product. A database search found three new putative start codons in 129, 225, and 411 bases upstream of the original start codon of the ypgA gene. The longest gene product, which was named ypgA3, showed the most significant homology to the Streptomyces fni gene product. The ypgA3 gene was expressed with an N-terminal His-tag in Escherichia coli and the purified soluble protein was characterized in detail. The ypgA3 protein converted IPP to its isomer dimethylallyl diphosphate in the presence of both FMN and NADPH. The enzyme also catalyzed the reverse reaction in the presence of both the cofactors. Disruption of the ypgA3 gene was not lethal to B. subtilis. These results indicate that Bacillus ypgA3 gene is fni, a nonessential gene encoding type 2 IPP isomerase.

Amino Acid Sequence↗

PubMed1989

Camptothecin hypersensitivity in poly(adenosine diphosphate-ribose) polymerase-deficient cell lines.

Mutant cell lines, derived from the Chinese hamster V79 cell line, deficient in poly(adenosine diphosphate-ribose) polymerase activity, and previously shown to be resistant to topoisomerase II inhibitors, were found to be hypersensitive to camptothecin, a topoisomerase I inhibitor. In all the cell lines, camptothecin induced dose-dependent protein-associated DNA single-strand breaks and sister chromatid exchanges. The increased sensitivity to camptothecin-induced cytotoxicity was not associated with an increase in DNA single strand breaks or sister chromatid exchanges. These results suggest the absence of any direct causal relation between (1) camptothecin induced sister chromatid exchanges and cytotoxicity or (2) camptothecin induced DNA strand breaks and cytotoxicity. The hypersensitivity of these mutant cell lines to camptothecin suggests that poly(adenosine diphosphate-ribose) polymerase is involved with topoisomerase I in modulating camptothecin induced cytotoxicity.

Animals↗

PubMedDate not supplied

[Fructose-1,6-diphosphate aldolase and ketose-1-phosphate aldolase isoenzyme spectra in the kidneys normally and in uranyl acetate poisoning].

Activities of both aldolases were distinctly decreased in acute kidney insufficiency, caused by administration of uranyl acetate. The decrease in the activity of fructose-1,6-diphosptate aldolase was more distinct which led to alteration in ratio between fructose -1,6-diphosphate and ketose-1-phosphate aldolases. The isozyme spectra of the enzymes were also altered. Isozymes of fructose-1,6-diphosphate aldolase AB2 and of ketose-1-phosphate aldolase form 22 possessed the same electrophoretic mobility but their relative activity was increased 2-3-fold under conditions of the acute kidney insufficiency. At the same time, the more electrophoretically mobile isozymes were not detected.

Acetates↗

PubMed2000

[Determination of fructose-1,6-diphosphate with aldolase-DNPH by the colorimetric method].

This paper presents a modified method of enzymatic assay for Fructose-1,6-diphosphate(FDP). FDP is split to dihydroxyacetone phosphate (DAP) and glyceraldehyde-3-phosphate (GAP) by the action of aldolase. DAP is hydrolyzed at room temperature to free triose. Under alkaline conditions, the free triose is reacted with 2,4-dinitrophenylhydrazine (DNPH), yielding a 2,4-dinitrophenylhydrazine derivative which dissolve in alkali forming a purple color mixture, with maximum absorption at 540.nm. It is proportional to the contents of FDP. Because the method depends on the colorimetric determination of triose formed from fructose-1,6-diphosphate only by aldolase, glycerophosphate dehydrogenase/triosephosphate isomerase (GDH/TIM) and reduced nicotinamide adenine dinucleotide (NADH) which usually applied in multienzymatic method, are omitted in the modified method. The method is specific, convenient and accuracy for the determination of FDP.

Colorimetry↗

PubMed2000

Antineoplastic agents 463. Synthesis of combretastatin A-3 diphosphate prodrugs.

A new and more efficient synthesis of combretastatin A-3 (2a) was completed (8.4% overall yield) starting from methyl gallate and isovanillin with aldehyde 5 and phosphonium salt 8 as key intermediates. Conversion of combretastatin A-3 (2a) to a series of diphosphate prodrugs (10a-l) was readily achieved. Both the diphosphate sodium (10a) and potassium salts (10c) displayed aqueous solubility in excess of 220 mg/ml at room temperature and good cancer cell line inhibitory activity.

Anisoles↗

PubMed2001

Fructose-1,6-diphosphate-added total parenteral nutrition in septic animals and stressed patients.

OBJECTIVE: To investigate the roles of fructose-1,6-diphosphate (FDP)-added total parenteral nutrition (TPN) in septic animals and stressed patients. METHODS: Thirteen adult dogs were randomly assigned to one of two study groups 6 hours after the induction of severe intra-abdominal infection. Group TPN (n = 6) received 70 kcal.kg-1.d-1 of nonprotein calorie (NPC) and 0.56 g.kg-1.d-1 of nitrogen. 1 g/kg of FDP was also infused to the animals in group TPN + FDP (n = 7) everyday. In the clinical study, the control group received routine TPN, while the study group (n = 16) was treated with TPN plus FDP (5 g, two times a day) for 7 days. RESULTS: In dogs with TPN support, plasma ATP levels were not changed significantly, while the value in the TPN + FDP group increased significantly from 0.18 mumol/L to 0.46 mumol/L at 24 h and 0.51 mumol/L at 48 h (P < 0.01). Muscular ATP increased markedly in the TPN + FDP group. Muscular creatine phosphate values were not significantly changed in the TPN group, but the values increased in the TPN + FDP group from 4.06 mumol/g.wt at the beginning to 4.93 mumol/g.wt at 24 h and 5.60 mumol/g.wt at 48 h (P < 0.05), with a cytochrome oxidase increase in immunohistochemistry stain. In the clinical study, plasma ATP levels increased and urinary 3-methylhistidine production significantly decreased with an improved value for positive accumulative nitrogen balance in the FDP-infused group. CONCLUSION: Our results suggest that total parenteral nutrition support with the supplement of fructose-1,6-diphosphate has a positive role in body energy production and protein metabolism in septic animals and stressed patients.

Adenosine Triphosphate↗

PubMed2003

Effects of sodium magnesium fructose diphosphate on free calcium concentration and nitric oxide synthase activity of ischemic synaptosome.

AIM: To study the effects of sodium magnesium fructose diphosphate (SMFD) on free calcium concentration and nitric oxide synthase activity of ischemic synaptosome, so as to explore the protective mechanisms of SMFD on cerebral ischemia. METHODS: The synaptosomes from normal rat brain were prepared by phase partition and cultured with oxygen-glucose deprivation to establish ischemic synaptosome model. The intrasynaptosomal free calcium concentration and nitric oxide synthase activity were detected separately after the synaptosomes were co-incubated with SMFD (1.3 mmol.L-1) or fructose-1, 6-diphosphate (FDP, 4.0 mmol.L-1) for 60 min. RESULTS: SMFD decreased the free calcium concentration and reduced the activity of nitric oxide synthase (NOS) of ischemic synaptosomes. Its effects were more powerful than those of FDP. CONCLUSION: SMFD may protect neurons from ischemic injury by preventing intracellular Ca2+ overload and inhibiting the activity of nitric oxide synthase.

Animals↗

PubMed2004

[Protective effects of fructose-1,6-diphosphate on brain damage caused by febrile seizures in rats].

OBJECTIVE: Febrile seizure (FS) is a pediatric emergency. The reiterative attacks of FS may result in brain damage to various extents. Fructose-1,6-diphosphate, serving as a cellular energy substance, has been applied to clinical practice for many years and has shown its importance in adjuvant treatment of diseases with myocardial damage. This study aimed to explore the potentiality of protecting rats' brain damage caused by febrile seizure with fructose-1,6-diphosphate (FDP). METHODS: Thirty 21-day-old male Sprague-Dawley (SD) rats were randomly divided into febrile seizure group (FS), sodium chloride solution (NS) control group and FDP intervention group (FD). Febrile seizure was induced by hyperthermal bath at 45 degrees C in the present study. No intervention treatment was given to rats in FS group before febrile seizure. Thirty minutes before febrile seizures, rats in FD group were given peritoneal injection of FDP at a dose of 25 mg per 100 g of body weight, whereas the same volume of 0.9% sodium chloride solution was injected into peritoneum of rats in NS group. Manifestations of seizure and differences in seizure latency, duration of seizure and seizure severity were observed in all the 3 groups. Samples of rat brain were prepared for electron microscopy in order to understand the characteristics of the ultrastructural changes in mitochondria, interspace of neuronal synapses and neurons of hippocampal region CA(1). RESULTS: Data collected from this study indicated that peritoneal injection of FDP at 25 mg per 100 grams of body weight 30 minutes before febrile seizures could result in improvement of the clinical manifestation of the rats caused by febrile seizures. Specifically speaking, the seizure latency was prolonged, the duration of seizures was shortened and severity of seizure was reduced. Analysis of variance and q-test on the data collected from the 3 groups revealed that there were significant differences between FD group and the other two groups (P < 0.05), yet no significant difference was found between FS group and NS group (P > 0.05). Electron microscopic observations on brain specimens revealed that FDP could relieve mitochondrial degeneration and edema. FDP could also reduce neuronal degeneration and necrosis in hippocampal region CA(1) (the percentages of neuronal degeneration and necrosis in the 3 groups were respectively 13% for FD group, 28% for FS group and 30% for NS group). There was a significant difference between FD group and the other two groups (P < 0.05), FDP treatment could prevent interspace of neuronal synapses from enlarging (the mean interspace was 6.47 +/- 0.37 micro m for FD group, 7.60 +/- 0.36 micro m for FS group and 7.53 +/- 0.40 micro m for NS group. The difference between FD group and the other two groups was significant (P < 0.01). CONCLUSION: FDP could lead to prolonged seizure latency, shorter duration of seizures and mitigation of seizures severity. FDP could also reduce neuronal degeneration and necrosis and prevent the interspace of neuronal synapses from enlarging in hippocampal region CA(1). The present study suggests that FDP can protect brain of rat from damages caused by febrile seizures.

Animals↗

PubMedDate not supplied

[Features of thiamine diphosphate-dependent enzyme inhibition by oxodihydrothiochrome and its phosphorylated derivatives].

Anticoenzyme action of new derivatives of thiamine: oxodihydrothiochrome and its mono- and diphosphoric esters has been studied in the experiments on mice. It is shown that the given compounds exert an inhibiting action on transketolase and pyruvate dehydrogenase and do not change activity of 2-oxoglutarate dehydrogenase in the animal organism. Antivitamin effect of the studied inhibitors is observed with the lower doses and in the earlier terms as compared with the other known inhibitors of thiamine-diphosphate-dependent enzymes. The preparations inhibit activity of the yeast pyruvate-decarboxylase by the mixed (with respect to thiamine-diphosphate) type (Ki for oxodihydrothiochrome and its mono- and diphosphoric esters: 2.3 x 10(-3), 7.2 x 10(-4), 5.6 x 10(-5) M, respectively). Possible mechanisms of the action of the mentioned compounds as thiamine antimetabolites are discussed.

Animals↗