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PubMed1975

[Thiamine and thiamine pyrophosphate in obsese patients during partial and total fasting (author's transl)].

The development of vitamin B1 (thiamine) deficiency was investigated in 17 obese patients in the course of a 1000 calory diet or during total fasting for a fortnight. Compared with normal persons no changes of concentrations of total thiamine, TPP, and pyruvate in the blood; thiamine excretion in the urine, or activiation coefficient of the eryhrocyte transketolase (alphaETK) were observed during the reducing diet. However, during a fortnight's total fasting all values decreased significantly to those of thiamine deficiency. The thiamine pyrophosphate (TPP) levels in the blood dropped from the 1st to the 14th day, whereas the alphaETK rose accordingly and the pyruvate levels showed a delayed rise. Total thiamine content of the blood and thiamine excretion in the urine only showed significantly different values when comparing the 1st and the 14th day. There was no dependency of thiamine excretion on urinary output. Clinical symptoms of thiamine deficiency could be demonstrated in no case.

Diet, Reducing↗
PubMed1981

[99mTc-pyrophosphate myocardial scintigraphy in patients with chronic stable angina pectoris (author's transl)].

In 66 patients suffering on chronic stable angina pectoris myocardial scintigrams with 99mTc-pyrophosphate were evaluated. Patients who had former infarcts or infarct signs in ECG were excluded. 16 normal subjects were used as controls. In all normal subjects and in 35 patients with chronic A.P. a normal myocardial scintigram could be obtained. In the remaining 31 patients a localized myocardial tracer accumulation could be seen. There was a correlation between the tracer accumulation and the limitted left ventricular function. No correlation was found between the severity and the number of involved coronary arteries and a positive scintiphoto. The mechanism of the tracer accumulation is discussed. The results of this investigation show that a positive myocardial scintigram does not prove a myocardial infarction. It is a sign for a insufficiency of the contractility of the left ventricle, probably due to under perfusion.

Angina Pectoris↗
PubMed1988

Technetium 99m pyrophosphate quantitation of skeletal muscle ischemia and reperfusion injury.

The study of ischemia and reperfusion injury in the extremity has been hampered by lack of an accurate method of measuring skeletal muscle injury. We used a bilateral isolated in vivo canine gracilis muscle model in 15 anesthetized dogs. The experimental muscles had 4, 6, or 8 hours of ischemia and 1 hour of reperfusion. The contralateral gracilis muscle served as a control. Technetium 99m pyrophosphate (99mTc-PYP), an agent which localizes in injured muscle cells, was used to quantitate canine skeletal muscle damage. After 6 hours of ischemia and 1 hour of reperfusion, there was a significant increase of 215% of 99mTc-PYP uptake in the experimental vs the control muscle. Experimental muscle uptake was 8% greater than control after 4 hours and 405% more after 8 hours of ischemia and reperfusion. Segmental distribution of 99mTc-PYP uptake showed localization to be greatest in the middle of the muscle at the entry site of the gracilis artery. Electron microscopic evaluation also documented this area to have undergone the most severe injury. Distal portions of the muscle did not show increased damage. Our results show that 99mTc-PYP effectively quantitates skeletal muscle ischemia and reperfusion injury. The pattern of 99mTc-PYP uptake suggests that considerable injury is caused during reperfusion.

Animals↗
PubMed2006

Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia.

SLC25A19 mutations cause Amish lethal microcephaly (MCPHA), which markedly retards brain development and leads to alpha-ketoglutaric aciduria. Previous data suggested that SLC25A19, also called DNC, is a mitochondrial deoxyribonucleotide transporter. We generated a knockout mouse model of Slc25a19. These animals had 100% prenatal lethality by embryonic day 12. Affected embryos at embryonic day 10.5 have a neural-tube closure defect with ruffling of the neural fold ridges, a yolk sac erythropoietic failure, and elevated alpha-ketoglutarate in the amniotic fluid. We found that these animals have normal mitochondrial ribo- and deoxyribonucleoside triphosphate levels, suggesting that transport of these molecules is not the primary role of SLC25A19. We identified thiamine pyrophosphate (ThPP) transport as a candidate function of SLC25A19 through homology searching and confirmed it by using transport assays of the recombinant reconstituted protein. The mitochondria of Slc25a19(-/-) and MCPHA cells have undetectable and markedly reduced ThPP content, respectively. The reduction of ThPP levels causes dysfunction of the alpha-ketoglutarate dehydrogenase complex, which explains the high levels of this organic acid in MCPHA and suggests that mitochondrial ThPP transport is important for CNS development.

Anemia↗
PubMed1982

Thiamin-responsive maple-syrup-urine disease: decreased affinity of the mutant branched-chain alpha-keto acid dehydrogenase for alpha-ketoisovalerate and thiamin pyrophosphate.

The biochemical basis for the therapeutic effects of thiamin in thiamin-responsive maple-syrup-urine disease (MSUD) was investigated in intact and disrupted fibroblast cultures from normals and patients with various forms of MSUD. Decarboxylation of alpha-keto[1-14C]isovalerate (KIV) by intact cells from a thiamin-responsive MSUD patient was at 30-40% of the normal rate with or without thiamin in the incubation medium. Under similar conditions, intact classical MSUD fibroblasts failed to decarboxylate KIV. Branched-chain alpha-keto acid (BCKA) dehydrogenase activity measured in disrupted cells from the thiamin-responsive subject showed sigmoidal kinetics in the absence of thiamin pyrophosphate (TPP), with an increased concentration of substrate needed for half-maximal velocity (K0.5 for KIV = 7 mM vs. 0.05 mM in normal cells). When assayed with 0.2 mM TPP present, the mutant enzyme showed (i) a shift in kinetics to near Michaelis-Menten type as observed with the normal BCKA dehydrogenase and (ii) a lower K0.5 value of 4 mM for KIV, suggesting a TPP-mediated increase in the mutant enzyme's affinity for substrate. By contrast, TPP increased only the Vmax and was without effect on the apparent Km for KIV of the BCKA dehydrogenase from cells of normals and patients with classical MSUD and variant thiamin-responsive MSUD (grade 3). Measurement of the apparent Km for TPP of the BCKA dehydrogenase from thiamin-responsive mutant MSUd cells showed a 16-fold increase in the constant to 25 microM compared to enzymes from normal or classical MSUD cells. These findings demonstrate that the primary defect in the thiamin-responsive MSUD patient is a reduced affinity of the mutant BCKA dehydrogenase for TPP that results in impaired oxidative decarboxylation of BCKA.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1997

Phosphocitrate inhibits a basic calcium phosphate and calcium pyrophosphate dihydrate crystal-induced mitogen-activated protein kinase cascade signal transduction pathway.

Calcium deposition diseases caused by calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystals are a significant source of morbidity in the elderly. We have shown previously that both types of crystals can induce mitogenesis, as well as metalloproteinase synthesis and secretion by fibroblasts and chondrocytes. These responses may promote degradation of articular tissues. We have also shown previously that both CPPD and BCP crystals activate expression of the c-fos and c-jun proto-oncogenes. Phosphocitrate (PC) can specifically block mitogenesis and proto-oncogene expression induced by either BCP or CPPD crystals in 3T3 cells and human fibroblasts, suggesting that PC may be an effective therapy for calcium deposition diseases. To understand how PC inhibits BCP and CPPD-mediated cellular effects, we have investigated the mechanism by which BCP and CPPD transduce signals to the nucleus. Here we demonstrate that BCP and CPPD crystals activate a protein kinase signal transduction pathway involving p42 and p44 mitogen-activated protein (MAP) kinases (ERK 2 and ERK 1). BCP and CPPD also cause phosphorylation of a nuclear transcription factor, cyclic AMP response element-binding protein (CREB), on serine 133, a residue essential for CREB's ability to transactivate. Treatment of cells with PC at concentrations of 10(-3) to 10(-5) M blocked both the activation of p42/p44 MAP kinases, and CREB serine 133 phosphorylation, in a dose-dependent fashion. At 10(-3) M, a PC analogue, n-sulfo-2-aminotricarballylate and citrate also modulate this signal transduction pathway. Inhibition by PC is specific for BCP- and CPPD-mediated signaling, since all three compounds had no effect on serum-induced p42/P44 or interleukin-1beta induced p38 MAP kinase activities. Treatment of cells with an inhibitor of MEK1, an upstream activator of MAPKs, significantly inhibited crystal-induced cell proliferation, suggesting that the MAPK pathway is a significant mediator of crystal-induced signals.

Calcium Phosphates↗
PubMed1998

thiBPQ encodes an ABC transporter required for transport of thiamine and thiamine pyrophosphate in Salmonella typhimurium.

In Salmonella typhimurium, thiamine pyrophosphate (TPP) is a required cofactor for several enzymes in central metabolism. Herein we identify a new thi operon, thiBPQ (designated sfuABC in Escherichia coli), required for the transport of thiamine and TPP into the cell. Insertions in the operon result in strains that are phenotypically and biochemically defective in thiamine and TPP transport. Data presented herein show that this operon is transcriptionally repressed in the presence of exogenous thiamine, with TPP the likely regulatory molecule. This work represents the first identification of thiamine transport genes in bacteria and demonstrates the function of a proposed ABC transporter in E. coli.

ATP-Binding Cassette Transporters↗
PubMed2001

Tumoral calcium pyrophosphate dihydrate crystal deposition disease. A clinicopathologic analysis of five cases.

We describe five cases of tumoral calcium pyrophosphate dihydrate crystal deposition disease (CPPDCD) and discuss the clinical, radiological and pathological features. Patients included 4 males and 1 female, ranging in age from 49 to 70 years (median, 63 yrs). The wrist was involved in two patients. The thumb, palmar aspect of the proximal phalanx of the middle finger and dorsum of the carpal bone of the hand were involved in one patient each. In one patient, a preoperative diagnosis of chondrosarcoma had been made. Macroscopically, the lesion was a circumscribed whitish-gray mass with a more or less chalky appearance, measuring between 1.0 to 6.2 cm (median, 2.5 cm). Histologically, all five lesions contained areas of calcification with crystal deposits and chondroid metaplasia. The majority of crystals were rhomboid in shape, characteristic of CPPD, but some needle-shaped crystals were also identified, which resembled urate crystals. A review of the 54 reported cases of tumoral CPPDCD including our series indicated that they could be divided into two categories based on anatomic location: central (head and neck) type (n = 33) and distal (extremity) type (n = 21). Patients of these two groups were not different with respect to age and gender, but those with the central type often presented with a painful mass (15 patients, 46%), or neurological disturbances (11 patients, 33%). Patients with the distal type presented with a painless mass or swelling (12 patients, 57%), but none had neurological signs, although 8 (38.1%) presented with acute attack similar to tophaceous gout. Tumoral CP-PDCD should be differentiated from tophaceous gout, tumoral calcinosis, and malignant or benign tumors.

Aged↗
PubMed1984

Turnover of [14C]thiamin and activities of thiamin pyrophosphate-dependent enzymes in tissues of mice with Ehrlich ascites carcinoma.

Turnover of [14C]thiamin was studied in mice with Ehrlich ascites carcinoma fed a thiamin-deficient diet and injected with 5 or 2 micrograms/mouse of the labeled vitamin. The process of conversion of [14C]thiamin to thiamin pyrophosphate (TPP) was monitored by measuring the activities of transketolase, pyruvate dehydrogenase, and oxoglutarate dehydrogenase. The amount of coenzyme-unsaturated apotransketolase was assessed by measuring the TPP effect--determining transketolase activity with and without the addition of TPP in vitro. Tumor growth was accompanied by thiamin deficiency, manifested in an increase in [14C]thiamin incorporation into the host tissues and the absence of saturation of the tissues with the labeled vitamin over 13 days. Increased values for the turnover coefficients, reduction of thiamin-dependent enzyme activities, elevation of the TPP effect, and a decrease in urinary excretion of the radioactive products also provided evidence for a disturbance in thiamin metabolism. The severity of the disturbance in thiamin metabolism during malignant tumor growth was directly related to the dose of the exogenous vitamin.

Animals↗
PubMed1994

Thiamin status of the elderly: dietary intake and thiamin pyrophosphate response.

OBJECTIVE: The present study was undertaken to investigate the relationship between thiamin intake and its biochemical status in 60 free-living (30 male, 30 female) elderly subjects (> or = 65 years). DESIGN: Dietary intake was estimated using a 3-nonconsecutive-day food record. Biochemical status was assessed by measuring the stimulating effect of thiamin pyrophosphate (TPP) on transketolase activity (TPP effect) in hemolyzed erythrocytes, which is a functional test indicative of metabolic availability of thiamin. RESULTS: Average daily thiamin intake was above the recommended requirement (> 0.4 mg/1000 Kcal) for each gender; however, almost half of the total study population had TPP effect > 14%, suggesting thiamin deficiency. There was no correlation between thiamin intake and TPP effect. CONCLUSION: These findings raise questions about the reliability of dietary intake in assessing metabolic availability of thiamin in the elderly.

Aged↗
PubMed2004

Modulation of glycogen phosphorylase activity affects 5-phosphoribosyl-1-pyrophosphate availability in rat hepatocyte cultures.

The effect of modulation of the rate of glycogenolysis on the availability of 5-phosphoribosyl-1-pyrophosphate (PRPP) was investigated in rat hepatocyte cultures. Dibutyryl cyclic AMP (dbcAMP), forskolin and glucagon, activating glycogen phosphorylase through activation of protein kinase A (PKA), were found to raise PRPP availability by 44%-56%. Arg-vasopressin and phenylephrine, activating glycogen phosphorylase through the phosphoinositide cascade, did not affect PRPP availability. dbcAMP, but not phenylephrine, increased the degradation of pre labeled glycogen by 57%. Caffeine and CP-91149, inhibitors of glycogen phosphorylase, decreased PRPP availability by 33% and 43%, respectively. The finding that induction of glycogenolysis enhances, and inhibition of glycogenolysis decelerates PRPP generation suggests that glycogenolysis is a major contributor to PRPP generation in liver tissue in the basal (postabsorptive) state.

Amides↗
PubMed1983

A study of cold cardioplegic myocardial protection in rats: an experimental model using the uptake of technetium 99m pyrophosphate and enzyme activity as parameters of injury.

This study compares the use of St Thomas' cardioplegia and cold saline cardioplegia at 4 degrees C for protection against global myocardial ischaemia in a model of heterotopic cardiac transplantation in rats of isogeneic strain. The parameters of myocardial injury applied were the uptake of Technetium 99m pyrophosphate (Tc 99m Pyp) in the transplanted heart and the measurement of serum total creatine kinase (CK) and creatine kinase MB (CK:MB) isoenzyme activity. The findings indicate that St Thomas' cardioplegic solution confers improved myocardial protection compared with normal saline as judged by statistically significant differences between: (a) the uptake of Tc 99m Pyp between the two solutions at 30 min storage: and (b) the peak total serum creatine kinase enzyme activity at 90 min storage. Excellent correlation was present between the uptake of Tc 99m Pyp and peak total serum creatine kinase activity. Further application of this model is described.

Animals↗
PubMed2002

Identification and reconstitution of the yeast mitochondrial transporter for thiamine pyrophosphate.

The genome of Saccharomyces cerevisiae contains 35 members of a family of transport proteins that, with a single exception, are found in the inner membranes of mitochondria. The transport functions of the 15 biochemically identified mitochondrial carriers are concerned with shuttling substrates, biosynthetic intermediates and cofactors across the inner membrane. Here the identification of the mitochondrial carrier for the essential cofactor thiamine pyrophosphate (ThPP) is described. The protein has been overexpressed in bacteria, reconstituted into phospholipid vesicles and identified by its transport properties. In confirmation of its identity, cells lacking the gene for this carrier had reduced levels of ThPP in their mitochondria, and decreased activity of acetolactate synthase, a ThPP-requiring enzyme found in the organellar matrix. They also required thiamine for growth on fermentative carbon sources.

Carbon↗
PubMed1978

The determination of thiamin pyrophosphate in blood and other tissues, and its correlation with erythrocyte transketolase activity.

A sensitive method for the specific measurement of thiamin pyrophosphate (TPP) has been developed using the apoenzyme recombination concept. Yeast pyruvic decarboxylase apoenzyme can be reconstituted by the addition of TPP or samples containing TPP, yielding the holoenzyme with activity proportionate to the amount of TPP added. Using this technique, reaction mixtures containing 0.2 to 1.5 ng TPP can be assayed. Normal human erythrocyte TPP ranges from 50 to 150 ng per ml packed cells. When rats are fed a thiamin deficient diet, the erythrocyte TPP level falls more rapidly than the erythrocyte transketolase activity. After 8 days, the level of TPP in the erythrocytes of deficient animals was 10% of the level in pair-fed controls. At this time, however, there was no appreciable decrease in their respective transketolase activities. The level of TPP in the liver also is decreased drastically after 8 days. Therefore it appears that erytyrocyte and liver TPP stores have begun to be depleted and suggest that erythrocyte TPP levels are a more sensitive indicator of thiamin status.

Animals↗
PubMed1996

Thiamine pyrophosphate-requiring enzymes are altered during pyrithiamine-induced thiamine deficiency in cultured human lymphoblasts.

The most common of the severe complications of thiamine deficiency are beriberi and Wernicke-Korsakoff syndrome. To help clarify the biochemical basis for these disorders, a cell culture system has been established in which pyrithiamine, a potent thiamine transport inhibitor, was used to mimic different degrees of thiamine deficiency within human lymphoblasts. Activities of both transketolase and alpha-ketoglutarate dehydrogenase (alpha-KGDH) decreased at the same rate and to roughly the same levels in response to thiamine deficiency within a given cell line. However, variation in sensitivity to thiamine deficiency, as judged by the relative percentage of loss of enzymatic activities, was found when different cell lines were compared. When exogenous thiamine pyrophosphate was added to the activity assays, differences between transketolase and alpha-KGDH became readily apparent. Only 25% of the lost transketolase activity was present as apo-enzyme, whereas 70% of the lost alpha-KGDH activity was present in the apo-enzyme form. For transketolase, the non-recoverable activity was due mainly to a decrease in the synthesis rate of the protein during thiamine deficiency, suggesting that thiamine has a direct effect on the expression of the transketolase gene and/or protein.

Cell Culture Techniques↗
PubMed1990

Detection of traumatic myocardial injury by means of simultaneous Tl-201/Tc-99m pyrophosphate tomography--report of three cases.

Trauma to the chest can result in cardiac damage, which may be missed by clinical examination because of associated injuries. Routinely performed non-invasive tests may also be non-diagnostic. Tc-99m pyrophosphate (PPi) tomography, in this study combined with Tl-201, is a promising addition to non-invasive evaluation. In three patients with cardiac injury, this technique successfully detected and localized myocardial necrosis.

Adult↗
PubMed1984

Assessment of myocardial necrosis immediately after intracoronary thrombolysis by intracoronary injection of technetium-99m pyrophosphate.

To assess myocardial necrosis immediately after intracoronary thrombolysis, thallium-201 (TL-201) and technetium-99m pyrophosphate (Tc-99m PYP) were injected simultaneously into the coronary artery in 25 patients with acute transmural myocardial infarction. In 17 of the 25 patients, the occluded coronary artery was reopened. Minutes after the intracoronary injection of Tc-99m PYP into the reopened coronary artery a localized accumulation was seen within the area of the Tl-201 defect in all patients. Control intravenous scintigraphy, which was performed in 8 of these 17 patients 1-6 days later, and in 2 patients 18 and 42 days after infarction, revealed a Tc-99m PYP spot similar to that of the acute intracoronary Tc-99m PYP scintigram in all 10 patients. In the 8 of the 25 patients, in whom intracoronary thrombolysis failed, no localized Tc-99m PYP accumulation was seen after injection into the infarct vessel. In 5 of these patients, a control intravenous scintigram, performed 1-8 days later, resulted in a Tc-99m PYP spot in the area of the Tl-201 defect. We conclude that, in the presence of therapeutic or spontaneous reperfusion, Tc-99m PYP scintigraphy may provide a useful method of assessing myocardial necrosis during the early stage of an acute myocardial infarction.

Adult↗
PubMed1988

Evidence for early mitogenic stimulation of metabolic flux through phosphoribosyl pyrophosphate into nucleotides in Swiss 3T3 cells.

Various mitogens activate purine and pyrimidine de novo biosynthesis and purine base phosphoribosylation as an early response in quiescent fibroblasts. Increased synthesis of 5-phosphoribosyl 1-pyrophosphate (PRPP) may precede or underlie these activations, but little direct evidence has been presented for this notion, due to lack of suitable analytical methods. To preferentially label intracellular ribose phosphate and quantitatively follow metabolic flux through PRPP into nucleotides, we prepared [ribosyl-14C]inosine and used it as a tracer. Evidence showed the validity of this method. Prior exposure of quiescent Swiss 3T3 cells in culture to epidermal growth factor plus insulin for 45-60 min enhanced approximately 2-fold the radioactivity incorporation from [ribosyl-14C]inosine into nucleotides, without increasing the specific radioactivity of intracellular free ribose 5-phosphate. [14C]Uracil incorporation into nucleotides, a measure of PRPP-independent ribose phosphate utilization for nucleotide synthesis, was not increased. These and other results indicate that epidermal growth factor plus insulin stimulates the metabolic flux through PRPP. Similar extents of stimulation were induced by bombesin and melittin in combination with insulin and by fibroblast growth factor alone, suggesting the presence of an unknown signaling pathway common to these mitogens. This system is highly useful for studies of the mechanisms that stimulate in situ activity of PRPP synthetase.

Animals↗