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Bioscience Reports Feb 2018Thiamine plays a very important coenzymatic and non-coenzymatic role in the regulation of basic metabolism. Thiamine diphosphate is a coenzyme of many enzymes, most of... (Review)
Review
Thiamine plays a very important coenzymatic and non-coenzymatic role in the regulation of basic metabolism. Thiamine diphosphate is a coenzyme of many enzymes, most of which occur in prokaryotes. Pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes as well as transketolase are the examples of thiamine-dependent enzymes present in eukaryotes, including human. Therefore, thiamine is considered as drug or diet supplement which can support the treatment of many pathologies including neurodegenerative and vascular system diseases. On the other hand, thiamine antivitamins, which can interact with thiamine-dependent enzymes impeding their native functions, thiamine transport into the cells or a thiamine diphosphate synthesis, are good propose to drug design. The development of organic chemistry in the last century allowed the synthesis of various thiamine antimetabolites such as amprolium, pyrithiamine, oxythiamine, or 3-deazathiamine. Results of biochemical and theoretical chemistry research show that affinity to thiamine diphosphate-dependent enzymes of these synthetic molecules exceeds the affinity of native coenzyme. Therefore, some of them have already been used in the treatment of coccidiosis (amprolium), other are extensively studied as cytostatics in the treatment of cancer or fungal infections (oxythiamine and pyrithiamine). This review summarizes the current knowledge concerning the synthesis and mechanisms of action of selected thiamine antivitamins and indicates the potential of their practical use.
Topics: Amprolium; Antimetabolites; Biological Transport; Drug Design; Humans; Oxythiamine; Pyrithiamine; Thiamine; Thiamine Pyrophosphate
PubMed: 29208764
DOI: 10.1042/BSR20171148 -
Metabolism: Clinical and Experimental Jul 2023Thiamine (vitamin B1) is an essential cofactor in glucose metabolism, but it remains unclear whether thiamine status is lower in individuals with diabetes compared to... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Thiamine (vitamin B1) is an essential cofactor in glucose metabolism, but it remains unclear whether thiamine status is lower in individuals with diabetes compared to individuals with normal glucose metabolism.
AIMS
We conducted a systematic review and meta-analysis to study whether the circulating concentrations of various thiamine analytes differ between people with and those without diabetes.
METHODS
PubMed and the Cochrane Central Register of Controlled Trials were searched according to the study protocol. The standardized mean difference (SMD) and 95 % confidence intervals (CI) of thiamine markers between individuals with and without diabetes were used as effect size (random effects model). Subgroup analysis considered albuminuria as an additional variable.
RESULTS
Out of the 459 articles identified, 24 full-texts were eligible for the study, 20 of which qualified for the data analysis and four were evaluated for coherence. Compared to controls, individuals with diabetes showed lower concentrations of thiamine (pooled estimate SMD [95 % CI]: -0.97 [-1.89, -0.06]), thiamine monophosphate (-1.16 [-1.82, -0.50]), and total thiamine compounds (-1.01 [-1.48, -0.54]). Thiamine diphosphate (-0.72 [-1.54, 0.11] and erythrocyte transketolase activity (-0.42 [-0.90, 0.05]) tended to be lower in persons with diabetes than in controls without reaching statistical significance. Subgroup analysis showed that individuals with diabetes and albuminuria had lower thiamine levels than the controls (-2.68 [-5.34, -0.02]).
CONCLUSIONS
Diabetes is associated with lower levels of various thiamine markers, suggesting that individuals with diabetes may have higher thiamine requirements than those without diabetes, but well-designed studies are required to confirm these findings.
Topics: Humans; Thiamine; Albuminuria; Diabetes Mellitus; Thiamine Pyrophosphate; Glucose
PubMed: 37094704
DOI: 10.1016/j.metabol.2023.155565 -
Identification and characterisation of thiamine pyrophosphate (TPP) riboswitch in Elaeis guineensis.PloS One 2020The oil palm (Elaeis guineensis) is an important crop in Malaysia but its productivity is hampered by various biotic and abiotic stresses. Recent studies suggest the...
The oil palm (Elaeis guineensis) is an important crop in Malaysia but its productivity is hampered by various biotic and abiotic stresses. Recent studies suggest the importance of signalling molecules in plants in coping against stresses, which includes thiamine (vitamin B1). Thiamine is an essential microelement that is synthesized de novo by plants and microorganisms. The active form of thiamine, thiamine pyrophosphate (TPP), plays a prominent role in metabolic activities particularly as an enzymatic cofactor. Recently, thiamine biosynthesis pathways in oil palm have been characterised but the search of novel regulatory element known as riboswitch is yet to be done. Previous studies showed that thiamine biosynthesis pathway is regulated by an RNA element known as riboswitch. Riboswitch binds a small molecule, resulting in a change in production of the proteins encoded by the mRNA. TPP binds specifically to TPP riboswitch to regulate thiamine biosynthesis through a variety of mechanisms found in archaea, bacteria and eukaryotes. This study was carried out to hunt for TPP riboswitch in oil palm thiamine biosynthesis gene. Riboswitch detection software like RiboSW, RibEx, Riboswitch Scanner and Denison Riboswitch Detector were utilised in order to locate putative TPP riboswitch in oil palm ThiC gene sequence that encodes for the first enzyme in the pyrimidine branch of the pathway. The analysis revealed a 192 bp putative TPP riboswitch located at the 3' untranslated region (UTR) of the mRNA. Further comparative gene analysis showed that the 92-nucleotide aptamer region, where the metabolite binds was conserved inter-species. The secondary structure analysis was also carried out using Mfold Web server and it showed a stem-loop structure manifested with stems (P1-P5) with minimum free energy of -12.26 kcal/mol. Besides that, the interaction of riboswitch and its ligand was determined using isothermal titration calorimetry (ITC) and it yielded an exothermic reaction with 1:1 stoichiometry interaction with binding affinities of 0.178 nM, at 30°C. To further evaluate the ability of riboswitch to control the pathway, exogenous thiamine was applied to four months old of oil palm seedlings and sampling of spear leaves tissue was carried out at days 0, 1, 2 and 3 post-treatment for expression analysis of ThiC gene fragment via quantitative polymerase chain reaction (qPCR). Results showed an approximately 5-fold decrease in ThiC gene expression upon application of exogenous thiamine. Quantification of thiamine and its derivatives was carried out via HPLC and the results showed that it was correlated to the down regulation of ThiC gene expression. The application of exogenous thiamine to oil palm affected ThiC gene expression, which supported the prediction of the presence of TPP riboswitch in the gene. Overall, this study provides the first evidence on the presence, binding and the functionality of TPP riboswitch in oil palm. This study is hoped to pave a way for better understanding on the regulation of thiamine biosynthesis pathway in oil palm, which can later be exploited for various purposes especially in manipulation of thiamine biosynthesis pathways in combating stresses in oil palm.
Topics: Arecaceae; Ligands; Malaysia; Palm Oil; Protein Binding; Riboswitch; Thiamine; Thiamine Pyrophosphate
PubMed: 32726320
DOI: 10.1371/journal.pone.0235431 -
Microbial Physiology 2023Polyphosphate kinases (PPKs) catalyze the reversible transfer of the γ-phosphate moiety of ATP (or of another nucleoside triphosphate) to a growing chain of...
Polyphosphate kinases (PPKs) catalyze the reversible transfer of the γ-phosphate moiety of ATP (or of another nucleoside triphosphate) to a growing chain of polyphosphate (polyP). In this study, we describe that PPKs of various sources are additionally able to phosphorylate thiamine diphosphate (ThP2) to produce thiamine triphosphate (ThP3) and even thiamine tetraphosphate in vitro using polyP as phosphate donor. Furthermore, all tested PPK2s, but not PPK1s, were able to phosphorylate thiamine monophosphate (ThP1) to ThP2 and ThP3 although at low efficiency. The predicted masses and identities of the mono- and oligo-phosphorylated thiamine metabolites were identified by high-performance liquid chromatography tandem mass spectrometry. Moreover, the biological activity of ThP2, that was synthesized by phosphorylation of ThP1 with polyP and PPK, as a cofactor of ThP2-dependent enzymes (here transketolase TktA from Escherichia coli) was confirmed in a coupled enzyme assay. Our study shows that PPKs are promiscuous enzymes in vitro that could be involved in the formation of a variety of phosphorylated metabolites in vivo.
Topics: Thiamine Monophosphate; Polyphosphates; Nucleotides; Thiamine; Thiamine Pyrophosphate
PubMed: 36041408
DOI: 10.1159/000526662 -
International Journal of Molecular... Jul 2023Thiamine (vitamin B1) is essential for the brain. This is attributed to the coenzyme role of thiamine diphosphate (ThDP) in glucose and energy metabolism. The synthetic... (Review)
Review
Thiamine (vitamin B1) is essential for the brain. This is attributed to the coenzyme role of thiamine diphosphate (ThDP) in glucose and energy metabolism. The synthetic thiamine prodrug, the thioester benfotiamine (BFT), has been extensively studied and has beneficial effects both in rodent models of neurodegeneration and in human clinical studies. BFT has no known adverse effects and improves cognitive outcomes in patients with mild Alzheimer's disease. In cell culture and animal models, BFT has antioxidant and anti-inflammatory properties that seem to be mediated by a mechanism independent of the coenzyme function of ThDP. Recent in vitro studies show that another thiamine thioester, O,S-dibenzoylthiamine (DBT), is even more efficient than BFT, especially with respect to its anti-inflammatory potency, and is effective at lower concentrations. Thiamine thioesters have pleiotropic properties linked to an increase in circulating thiamine concentrations and possibly in hitherto unidentified open thiazole ring derivatives. The identification of the active neuroprotective metabolites and the clarification of their mechanism of action open extremely promising perspectives in the field of neurodegenerative, neurodevelopmental, and psychiatric conditions. The present review aims to summarize existing data on the neuroprotective effects of thiamine thioesters and give a comprehensive account.
Topics: Animals; Humans; Neurodegenerative Diseases; Thiamine; Thiamine Pyrophosphate; Coenzymes
PubMed: 37511056
DOI: 10.3390/ijms241411296 -
Advances in Clinical and Experimental... Feb 2022Cyclophosphamide is a drug used in various types of cancer. It can cause oxidative and inflammatory ovarian damage and infertility. Thiamine pyrophosphate (TPP) to be...
BACKGROUND
Cyclophosphamide is a drug used in various types of cancer. It can cause oxidative and inflammatory ovarian damage and infertility. Thiamine pyrophosphate (TPP) to be investigated for its effect on cyclophosphamide-induced ovarian damage and reproductive dysfunction in the present study is the active metabolite of thiamine. It has been shown that TPP protects organs and tissues from oxidative stress and proinflammatory cytokine damage.
OBJECTIVES
To investigate the effect of TPP against the ovarian damage and reproductive dysfunction caused by cyclophosphamide in rats.
MATERIAL AND METHODS
Albino Wistar type female rats were divided into healthy control (HG), cyclophosphamide (CYC) and TPP + cyclophosphamide (TPPC) groups (for each group, n = 12). Thiamine pyrophosphate at a dose of 25 mg/kg was injected intraperitoneally (ip.) in the TPPC group, and 0.9% NaCI solution was injected ip. in the CYC and HG groups. One hour after the injection, 75 mg/kg of cyclophosphamide was administered ip. in the TPPC and CYC groups. This procedure was repeated once a day for 30 days. At the end of this period, 6 rats from each group were euthanized with a high dose of anesthetic (50 mg/kg of sodium thiopental). Biochemical and histopathological examinations were performed on the extracted ovarian tissue. The remaining animals were kept in the laboratory with mature male rats for 2 months for reproduction.
RESULTS
Thiamine pyrophosphate significantly decreased the cyclophosphamide-induced increase in the levels of the oxidant parameter malondialdehyde (MDA), proinflammatory nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), and interleukin 1 beta (IL-1β). In addition, TPP decreased the severe histopathological damage associated with cyclophosphamide in the ovarian tissue and prevented infertility.
CONCLUSIONS
Our experimental results have suggested that TPP could be beneficial in the treatment of cyclophosphamide-induced ovarian injury and infertility.
Topics: Animals; Antioxidants; Cyclophosphamide; Female; Glutathione; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Wistar; Thiamine Pyrophosphate
PubMed: 35156781
DOI: 10.17219/acem/142535 -
Basic & Clinical Pharmacology &... Jan 2016The aim of this study was to investigate whether thiamine pyrophosphate (TPP) has biochemical and histological preventive effects on oxidative liver damage induced by...
The aim of this study was to investigate whether thiamine pyrophosphate (TPP) has biochemical and histological preventive effects on oxidative liver damage induced by paracetamol (APAP). Rats were divided into the following groups: healthy control (HG), APAP (AG, 1500 mg/kg, orally), thiamine pyrophosphate (TPPG, 100 mg/kg, intraperitoneally), APAP+NAC (ANAC, 100 mg/kg, intraperitoneally), APAP+TPP (ATPG) and APAP+NAC+TPP (ANTG). Oxidant, antioxidant parameters, liver function tests and histological assessment were performed between groups. Malondialdehyde levels in the AG, HG, TPPG, ANAC, ATPG and ANTG groups were 0.470 ± 0.210, 0.213 ± 0.004, 0.194 ± 0.001, 0.197 ± 0.06, 0.199 ± 0.008 and 0.173 ± 0.010 μmol/g protein, respectively. Total glutathione levels were 7.787 ± 0.395, 14.925 ± 0.932, 13.200 ± 0.984, 13.162 ± 0.486, 13.287 ± 0.787 and 13.500 ± 0.891 μm/g protein, respectively. In the AG group, marked liver damage occurred with the elevation of liver function tests and oxidative stress markers, such as malondialdehyde, myeloperoxidase and nitric oxide (p < 0.05). Biochemical results were congruent with the histological changes of oxidative damage. Compared to the AG group (p < 0.05), TPP significantly reduced oxidant parameter levels in the ATPG group and simultaneously increased the antioxidant parameter levels of catalase and glutathione. The histological changes were improved to almost normal hepatic structure. Moreover, TPP had nearly the same hepatoprotective effect as NAC, and there was statistically no additional benefit with NAC co-treatment. There was no statistically significant difference (p > 0.05) among the ANAC, ANTG and ATPG groups in terms of oxidant/antioxidant levels. TPP proved to be as efficacious as standard therapy and may be beneficial in APAP-induced hepatotoxicity.
Topics: Acetaminophen; Acetylcysteine; Animals; Antioxidants; Catalase; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Glutathione; Liver; Liver Function Tests; Malondialdehyde; Nitric Oxide; Oxidative Stress; Peroxidase; Rats, Wistar; Thiamine Pyrophosphate
PubMed: 26432613
DOI: 10.1111/bcpt.12496 -
American Journal of Alzheimer's Disease... Dec 2011Alzheimer's disease (AD) is the most common form of dementia in elderly individuals and is associated with progressive neurodegeneration of the human neocortex. Thiamine... (Review)
Review
Alzheimer's disease (AD) is the most common form of dementia in elderly individuals and is associated with progressive neurodegeneration of the human neocortex. Thiamine levels and the activity of thiamine-dependent enzymes are reduced in the brains and peripheral tissues of patients with AD. Genetic studies have provided the opportunity to determine what proteins link thiamine to AD pathology (ie, transketolase, apolipoprotein E, α-1-antitrypsin, pyruvate dehydrogenase complex, p53, glycogen synthetase kinase-3β, c-Fos gene, the Sp1 promoter gene, and the poly(ADP-ribosyl) polymerase-1 gene). We reviewed the association between histopathogenesis and neurotransmitters to understand the relationship between thiamine and AD pathology. Oral thiamine trials have been shown to improve the cognitive function of patients with AD; however, absorption of thiamine is poor in elderly individuals. In the early stage of thiamine-deficient encephalopathy (Wernicke's encephalopathy), however, parental thiamine has been used successfully. Therefore, further studies are needed to determine the benefits of using parental thiamine as a treatment for AD.
Topics: Aged; Alzheimer Disease; Brain; Humans; Pyruvate Dehydrogenase Complex; Thiamine; Thiamine Deficiency; Thiamine Pyrophosphate; Transketolase
PubMed: 22218733
DOI: 10.1177/1533317511432736 -
Proceedings of the National Academy of... May 2022The transcriptome represents an attractive but underused set of targets for small-molecule ligands. Here, we devise a technology that leverages fragment-based screening...
The transcriptome represents an attractive but underused set of targets for small-molecule ligands. Here, we devise a technology that leverages fragment-based screening and SHAPE-MaP RNA structure probing to discover small-molecule fragments that bind an RNA structure of interest. We identified fragments and cooperatively binding fragment pairs that bind to the thiamine pyrophosphate (TPP) riboswitch with millimolar to micromolar affinities. We then used structure-activity relationship information to efficiently design a linked-fragment ligand, with no resemblance to the native ligand, with high ligand efficiency and druglikeness, that binds to the TPP thiM riboswitch with high nanomolar affinity and that modulates RNA conformation during cotranscriptional folding. Principles from this work are broadly applicable, leveraging cooperativity and multisite binding, for developing high-quality ligands for diverse RNA targets.
Topics: Base Pairing; Ligands; RNA Folding; Riboswitch; Small Molecule Libraries; Structure-Activity Relationship; Thiamine Pyrophosphate; Transcription, Genetic
PubMed: 35561226
DOI: 10.1073/pnas.2122660119 -
IUBMB Life Jul 2022Multiple mitochondrial matrix enzymes playing key roles in metabolism require cofactors for their action. Due to the high impermeability of the mitochondrial inner... (Review)
Review
Multiple mitochondrial matrix enzymes playing key roles in metabolism require cofactors for their action. Due to the high impermeability of the mitochondrial inner membrane, these cofactors need to be synthesized within the mitochondria or be imported, themselves or one of their precursors, into the organelles. Transporters belonging to the protein family of mitochondrial carriers have been identified to transport the coenzymes: thiamine pyrophosphate, coenzyme A, FAD and NAD , which are all structurally similar to nucleotides and derived from different B-vitamins. These mitochondrial cofactors bind more or less tightly to their enzymes and, after having been involved in a specific reaction step, are regenerated, spontaneously or by other enzymes, to return to their active form, ready for the next catalysis round. Disease-causing mutations in the mitochondrial cofactor carrier genes compromise not only the transport reaction but also the activity of all mitochondrial enzymes using that particular cofactor and the metabolic pathways in which the cofactor-dependent enzymes are involved. The mitochondrial transport, metabolism and diseases of the cofactors thiamine pyrophosphate, coenzyme A, FAD and NAD are the focus of this review.
Topics: Coenzyme A; Flavin-Adenine Dinucleotide; NAD; Thiamine Pyrophosphate; Vitamins
PubMed: 35304818
DOI: 10.1002/iub.2612