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PubMed1987

Nervous tissue thiamine metabolism in vivo. III. Influence of ethanol intake on the dynamics of thiamine and its phosphoesters in different brain regions and sciatic nerve of the rat.

The effects of chronic ethanol administration on different steps of the metabolism of thiamine (T), thiamine mono- (TMP) and thiamine pyrophosphate (TPP) in the cerebellum, brainstem, cerebral cortex and sciatic nerve were evaluated in vivo. The radioactivity of T and its phosphoesters was determined in plasma and in the selected nervous structures under steady-state conditions and at fixed time intervals (0.5-192 h) after an i.p. injection of [14C]T (30 micrograms: 1.25 microCi) to rats chronically (35 days) ethanol-treated (daily dose of 4.7 g X kg-1 b.wt. by gastric gavage) and pair-fed controls similarly treated with a sucrose solution isoenergetic with ethanol. All rats were given a nutritionally adequate diet supplying an excess of thiamine, which produced a virtually steady content of thiamine compounds in the tissues. By using a compartmental mathematical model, fractional rate constants, turnover rates and turnover times were calculated. Ethanol caused a reduction of the rate of thiamine compound enzymatic transformations (T phosphorylation to TPP, TPP dephosphorylation to TMP and TMP to T), and a facilitation of the regional uptake of T and TMP, associated to a less relevant influence on their release. Isoenergetic sucrose prevailingly caused an increased rate of thiamine metabolic steps (except phosphorylation in the brainstem and cerebral cortex), with negligible modifications of T and TMP uptake and release. Thus the changes induced by ethanol were virtually opposite to those caused by sucrose.

Animals↗

PubMed1981

Elevation of blood keto acids in cerebrocortical necrosis.

Values of various alpha-keto acids in whole blood were determined from cases of cerebrocortical necrosis (CCN), a thiamine deficiency disease, and were compared with those from normal animals. Thiamine pyrophosphate is an essential cofactor in the decarboxylation of many alpha-keto acids and this was reflected in elevated values not only of pyruvic acid but of glyoxylic, alpha-keto glutaric, phenyl pyruvic and hydroxyphenyl pyruvic acids in the CCN cases.

Animals↗

PubMed2000

Outcome of thiamine treatment in a child with Leigh disease due to thiamine-responsive pyruvate dehydrogenase deficiency.

We describe a child with severe psychomotor retardation, peripheral neuropathy and bilateral abnormal signal in basal ganglia on magnetic resonance imaging, consistent with Leigh disease. Fibroblast pyruvate dehydrogenase assayed with routine method was normal. However, because of neurological improvement after treatment with thiamine, pyruvate dehydrogenase activity was studied again with thiamine pyrophosphate concentration adjusted to the normal human tissue level and found to be deficient. We report here on diagnostic difficulties and clinical follow-up of this patient.

Child↗

PubMed2006

Crystal structure of 1-deoxy-D-xylulose 5-phosphate synthase, a crucial enzyme for isoprenoids biosynthesis.

Isopentenyl pyrophosphate (IPP) is a common precursor for the synthesis of all isoprenoids, which have important functions in living organisms. IPP is produced by the mevalonate pathway in archaea, fungi, and animals. In contrast, IPP is synthesized by a mevalonate-independent pathway in most bacteria, algae, and plant plastids. 1-Deoxy-D-xylulose 5-phosphate synthase (DXS) catalyzes the first and the rate-limiting step of the mevalonate-independent pathway and is an attractive target for the development of novel antibiotics, antimalarials, and herbicides. We report here the first structural information on DXS, from Escherichia coli and Deinococcus radiodurans, in complex with the coenzyme thiamine pyrophosphate (TPP). The structure contains three domains (I, II, and III), each of which bears homology to the equivalent domains in transketolase and the E1 subunit of pyruvate dehydrogenase. However, DXS has a novel arrangement of these domains as compared with the other enzymes, such that the active site of DXS is located at the interface of domains I and II in the same monomer, whereas that of transketolase is located at the interface of the dimer. The coenzyme TPP is mostly buried in the complex, but the C-2 atom of its thiazolium ring is exposed to a pocket that is the substrate-binding site. The structures identify residues that may have important roles in catalysis, which have been confirmed by our mutagenesis studies.

Amino Acid Sequence↗

PubMed1992

Thiamin and Alzheimer's disease.

Because of clinical and neuropathological overlap between the characteristics of dementia of the Alzheimer type (DAT) and of a human thiamin deficiency syndrome (Wernicke-Korsakoff syndrome), thiamin pyrophosphate (TPP) dependent processes have been studied in DAT brain and other tissues. The activities of 3 TPP-dependent enzymes are reduced in DAT brain: transketolase (TK), the pyruvate dehydrogenase complex (PDHC), and the alpha-ketoglutarate dehydrogenase complex (KGDHC). Quantitatively, the most marked reductions are in KGDHC (to less than 20% of normal). In cultured skin fibroblasts, KGDHC activity is reduced to 50-60% of normal, TK activity to 80-90% of normal, and PDHC is normal. Structural and molecular studies of the DAT and non-DAT enzymes are in process. A lesion of KGDHC may be related to the pathogenesis of DAT. Treatment with large doses of thiamin has not been beneficial, but the data are not totally negative. Further studies of thiamin-dependent mechanisms in DAT seem justified.

Alzheimer Disease↗

PubMed1988

Sites of action of gossypol studied by autoradiography and enzyme histochemistry.

The distribution of 14C-gossypol acetate was studied by autoradiography in male rats after intraperitoneal or intratesticular injection. Accumulation of radioactivity was found in testis, kidney and liver, while there was little in brain, pituitary and epididymis. In testis, high accumulation occurred in interstitial cells, with low levels in Sertoli cells, spermatogonia and spermatocytes. In addition, the chronic effect of gossypol was assessed by enzyme histochemistry with thiamine pyrophosphate, alpha-glycerophosphate dehydrogenase, and by lipid stain. In the treated animals an increased number of luminal exfoliated cells (Sertoli cells, germ cells and spermatids) was noted, which showed positive reactions. The results suggest both direct and indirect effects of gossypol on testicular functions.

Animals↗

PubMed1997

Biochemical and molecular analysis of an X-linked case of Leigh syndrome associated with thiamin-responsive pyruvate dehydrogenase deficiency.

We report molecular analysis of thiamin-responsive pyruvate dehydrogenase complex (PDHC) deficiency in a patient with an X-linked form of Leigh syndrome. PDHC activity in cultured lymphoblastoid cells of this patient and his asymptomatic mother were normal in the presence of a high thiamin pyrophosphate (TPP) concentration (0.4 mmol/L). However, in the presence of a low concentration (1 x 10(-4) mmol/L) of TPP, the activity was significantly decreased, indicating that PDHC deficiency in this patient was due to decreased affinity of PDHC for TPP. The patient's older brother also was diagnosed as PDHC deficiency with Leigh syndrome, suggesting that PDHC deficiency in these two brothers was not a de novo mutation. Sequencing of the X-linked PDHC E1 alpha subunit revealed a C-->G point mutation at nucleotide 787, resulting in a substitution of glycine for arginine 263. Restriction enzyme analysis of the E1 alpha gene revealed that the mother was a heterozygote, indicating that thiamin-responsive PDHC deficiency associated with Leigh syndrome due to this mutation is transmitted by X-linked inheritance.

DNA↗

PubMed2004

The biosynthesis of the thiazole phosphate moiety of thiamin (vitamin B1): the early steps catalyzed by thiazole synthase.

Thiazole synthase (ThiG) catalyzes an Amadori-type rearrangement of 1-deoxy-d-xylulose-5-phosphate (DXP) via an imine intermediate. In support of this, we have demonstrated enzyme-catalyzed exchange of the C2 carbonyl of DXP. Borohydride reduction of the enzyme DXP imine followed by top-down mass spectrometric analysis localized the imine to lysine 96. On the basis of these observations, a new mechanism for the biosynthesis of the thiazole phosphate moiety of thiamin pyrophosphate in Bacillus subtilis is proposed. This mechanism involves the generation of a ketone at C3 of DXP by an Amadori-type rearrangement of the imine followed by nucleophillic addition of the sulfur carrier protein (ThiS-thiocarboxylate) to this carbonyl group.

Amino Acid Sequence↗

PubMed1968

Distribution of phosphatases in the golgi region and associated structures of the thoracic ganglionic neurons in the grasshopper, Melanoplus differentialis.

The neuronal perikarya of the grasshopper contain sudanophilic lipochondria which exhibit an affinity for vital dyes. These lipochondria are membrane-delimited and display acid phosphatase activity; hence they correspond to lysosomes. Unlike those of most vertebrates, these lysosomes also hydrolyze thiamine pyrophosphate and adenosine triphosphate. Like vertebrate lysosomal "dense bodies," they are electron-opaque and contain granular, vesicular, or lamellar material. Along with several types of smaller dense bodies, they are found in close spatial association with the Golgi apparatus. The Golgi complexes are frequently arranged in concentric configurations within which these dense bodies lie. Some of the smaller dense bodies often lie close to or in association with the periphery of dense multivesicular bodies. Further, bodies occur that display gradations in structure between these multivesicular bodies and the dense lysosomes. Acid phosphatase activity is present in the small as well as the larger dense bodies, in the multivesicular bodies, and in some of the Golgi saccules, associated vesicles, and fenestrated membranes; thiamine pyrophosphatase is found in both the dense bodies and parts of the Golgi complex. The close spatial association of these organelles, together with their enzymatic similarities, suggests the existence of a functional or developmental relationship between them.

Acid Phosphatase↗

PubMed2004

Mutational analysis of ThiH, a member of the radical S-adenosylmethionine (AdoMet) protein superfamily.

Thiamine pyrophosphate (TPP) is an essential cofactor for all forms of life. In Salmonella enterica, the thiH gene product is required for the synthesis of the 4-methyl-5-beta hydroxyethyl-thiazole monophosphate moiety of TPP. ThiH is a member of the radical S-adenosylmethionine (AdoMet) superfamily of proteins that is characterized by the presence of oxygen labile [Fe-S] clusters. Lack of an in vitro activity assay for ThiH has hampered the analysis of this interesting enzyme. We circumvented this problem by using an in vivo activity assay for ThiH. Random and directed mutagenesis of the thiH gene was performed. Analysis of auxotrophic thiH mutants defined two classes, those that required thiazole to make TPP (null mutants) and those with thiamine auxotrophy that was corrected by either L-tyrosine or thiazole (ThiH* mutants). Increased levels of AdoMet also corrected the thiamine requirement of members of the latter class. Residues required for in vivo function were identified and are discussed in the context of structures available for AdoMet enzymes.

Alleles↗

PubMed1999

Dynamic changes in glucose metabolism induced by thiamine deficiency and its replenishment as revealed by a positron autoradiography technique using rat living brain slices.

Dynamic changes in the cerebral glucose metabolic rate (CMRglc) before and after thiamine replenishment were investigated in living brain slices obtained from pyrithiamine-treated (PT) and pair-fed control rats by use of a positron autoradiography technique. Fresh rat brain slices (300 microm thick) were incubated with [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) in oxygenated Krebs-Ringer solution at 36 degrees C, during which serial two-dimensional images of [18F]FDG uptake in the slices were constructed on the imaging plates. The net influx constant (=K) of [18F]FDG was determined by a Patlak graphical method of the image data. Prior to thiamine pyrophosphate (TPP)-loading, the K value in the neurologically symptomatic PT was higher in all brain regions except the thalamus and mammillary body than the control, suggesting compensatory enhanced glycolysis. The rapid decrease in this heightened net influx constant immediately after TPP-loading was surmised to be due to activation of pyruvate oxidation with lactate as the substrate, with this inhibiting the glycolysis. From > or = 150 min after TPP-loading, the K value continued to show low values in the thalamus and mammillary body, which are regarded as the responsible sites for Korsakoff syndrome, whereas in all other sites recovery to control values was observed. These findings suggest that using this technique the quantitative evaluation of serial local changes in CMRglc from thiamine deficiency to after its replenishment may be useful in elucidating the pathophysiology and prognosis of Wernicke's encephalopathy.

Animals↗

PubMed1976

[Malabsorption and vitamin B1 deficiency in familial acrodystrophic neuropathies (author's transl)].

9 members of 4 families with familial acrodystrophic neuropathies were investigated. Lowered levels of vitamin B1 (thiamine pyrophosphate) were found in all cases except one. In this patient, as in 10 healthy control persons, normal values were obtained. The D-xylose test, which was carried out in 4 patients from 3 families, revealed intestinal malabsorption in all cases. It is suggested that malabsorption and deficiency of vitamin B1 as demonstrated in this report play a role in the development of these familial disorders.

Adult↗

PubMed1985

Preclinical left ventricular abnormalities in alcoholics are independent of nutritional status, cirrhosis, and cigarette smoking.

M mode echo recordings of the left ventricle (LV) were performed in 33 patients with alcoholic liver disease, 26 patients with various non-alcoholic liver diseases, and in 18 non-alcoholic controls. Groups were well matched for age and overall nutritional status (as assessed by anthropometry) and none of the subjects studied had cardiorespiratory symptoms. Alcoholics had significantly increased LV free wall thickness and LV cavity dimension at end diastole (EDD). Multiple regression analysis of the data identified alcohol abuse as the most important variable affecting EDD, and this relation could not be explained by differences in age, sex, overall nutrition, cigarette smoking, thiamine status (total blood thiamine and thiamine pyrophosphate concentration), presence of liver disease, or severity of liver disease (cirrhotic vs non-cirrhotic). The increase in LV free wall thickness was not significantly related to alcohol abuse. These results suggest that chronic alcohol abuse is an important independent risk factor for cardiac dilatation, and that increase in EDD may be an early marker of alcoholic cardiomyopathy.

Adult↗

PubMed1982

The Golgi apparatus of rat small intestinal absorptive cells. I. Morphology and cytochemical staining pattern in proximal and distal small intestinal regions.

Comparative studies on the Golgi apparatus of rat small intestinal absorptive cells from duodenal, jejunal and ileal segments showed that the characteristic polarity of Golgi stacks is apparent along the entire small intestine; dilated cisternae containing lipoprotein particles are preferably localized at one Golgi side (cis face); narrow, regular cisternae predominate at the other side (trans face). Osmium deposits after prolonged osmification are restricted to cis Golgi cisternae. Pronounced differences between proximal and distal small intestinal regions exist in the cytochemical staining pattern of Golgi stacks after localization of thiamine pyrophosphatase, inosine diphosphatase and acid phosphatase. In duodenal and proximal jejunal absorptive cells demonstration of thiamine pyrophosphatase and inosine diphosphatase causes heavy deposits of reaction product over all Golgi cisternae; in the distal jejunum and in the ileum only 1-3 cisternae at the trans Golgi side are reactive. Similarly, the number of acid phosphatase-positive cisternae decreases from proximal to more distal small intestinal regions. Thiamine pyrophosphate, nucleoside diphosphatase and acid phosphatase are assumed to be active in glycosylation being involved in the removal of uridine diphosphate and other nucleoside phosphates (Tartakoff, 1980; Farquhar and Palade, 1981; Roth and Berger, 1982). Accordingly, the differences in the Golgi apparatus staining pattern after localization of these enzymes between proximal and distal small intestinal segments may reflect regional differences in the glycosylation of apoproteins in lipoprotein particles and in the kinetics of glycosylated plasma membrane and lysosomal constituents.

Acid Anhydride Hydrolases↗

PubMed1978

[Distribution of enzymes in the stereocilia of the ductus epididymis of rats (author's transl)].

Using unfixed or cryostate sections from aldehyde fixed epididymides of adult rats gamma-glutamyl naphthylamides are hydrolysed in the stereocilia of the principal cells in zone 1A-4B and glycyl-prolyl naphthylamides in those of zone 1B-4A (nomenclature of Reid and Cleland, 1957); this is not the case when other amino acid and peptide naphthylamides are employed. Adenosine triphosphate (ATP) is metabolized by the stereocilia in zone 1a, 2, 3 and 4A and adenosine monophosphate (AMP) in the stereocilia of zone 3-6. With thiamine pyrophosphate (TPP) especially the Golgi apparatus of the principal cells in zone 1B and C, 2 and 3 reacts. In addition ATP, AMP and TPP stain the stereocilia of single epithelial cells outside the zones where all stereocilia react. The AMP pattern allows a further subdivision of zone 3 into 3 A and B. Substrates for the demonstration of alpha- and beta-D-glycosidases, non-specific esterases and alkaline phosphatases are either not hydrolyzed by the stereocilia or the rate of hydrolysis is low.

Adenosine Triphosphatases↗

PubMed2003

Structural and mechanistic studies on ThiO, a glycine oxidase essential for thiamin biosynthesis in Bacillus subtilis.

The thiO gene of Bacillus subtilis encodes an FAD-dependent glycine oxidase. This enzyme is a homotetramer with a monomer molecular mass of 42 kDa. In this paper, we demonstrate that ThiO is required for the biosynthesis of the thiazole moiety of thiamin pyrophosphate and describe the structure of the enzyme with N-acetylglycine bound at the active site. The closest structural relatives of ThiO are sarcosine oxidase and d-amino acid oxidase. The ThiO structure, as well as the observation that N-cyclopropylglycine is a good substrate, supports a hydride transfer mechanism for the enzyme. A mechanistic proposal for the role of ThiO in thiazole biosynthesis is also described.

Amino Acid Oxidoreductases↗

PubMed1988

Intestinal transport of thiamin and thiamin monophosphate in rat everted jejunal sacs: a comparative study using some potential inhibitors.

Rat everted jejunal sacs were incubated for 15 and 30 min at 37 degrees C in oxygenated Krebs-Henseleit buffer, pH 7.4, containing 0.2 microM [3H]-thiamin (3H-T) or [3H]-thiamin monophosphate (3H-TMP) with and without 10 mM 1-phenylalanine (PAL) or 2.5 mM levamisole (LEV). The concentrations of 3H-T and its phosphoesters in sac wall and serosal fluid were determined by a radiometric method after electrophoretic separation. In separate experiments, thiamin pyrophosphokinase (TPKase) and thiamin pyrophosphatase (TPPase) activities were determined in mucosal scrapings, with and without PAL or LEV, by using a radiometric and a colorimetric method, respectively. 3H-TMP was transported partly unchanged by an active mechanism similarly to 3H-T, but less efficiently. During transport, 3H-TMP was also enzymatically transformed to thiamin (T) and thiamin pyrophosphate, which accumulated in the tissue. In the serosal fluid, the concentration of 3H-TMP exceeded that of 3H-T. Presence of PAL or LEV with 3H-T or 3H-TMP in the incubation medium reduced the serosal transport and the tissue content of T compounds. LEV caused a dose-dependent inhibition of TPKase without affecting TPPase, whereas PAL inhibited both activities to about the same extent. These results indicate that the transport of TMP involves a number of different processes similar to those responsible for T transport. The effects of PAL and LEV underline the importance of phosphorylation-dephosphorylation coupling.

Animals↗

PubMed1998

Amprolium-induced cerebrocortical necrosis (CCN) in dromedary racing camels.

Amprolium was successfully used to induce cerebrocortical necrosis (CCN) in dromedary racing camels, only when they were fed on a barley diet. Camels which were fed on hay ad libitum did not suffer form CCN, although their thiamine pyrophosphate (TPP) reached similar levels as in camels fed on barley. The reason for this phenomenon is discussed. Five camels which suffered from CCN had TPP values of 80-115% and were euthanized on humane grounds when they were in lateral recumbency. Pathohistological investigations revealed a polioencephalomalacia of the dorsal cerebral cortex with oedema and status spongiosus. Cerebral autofluorescence was observed under ultraviolet light. The major clinicopathological changes were a slight anemia and a decreased potassium value whereas glucose, muscle enzymes, leucocyte counts and differential counts were elevated. A TPP effect of 12% was found during this study in healthy dromedary racing camels and symptoms were observed when TPP values reached 80-115%. The test is now being widely used during the camel racing season.

Amprolium↗