Thiamine and selected thiamine antivitamins — biological activity and methods of synthesis

Abstract

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.

Ascorbate and Thiamin: Metabolic Modulators in Plant Acclimation Responses

“…Through participation in the pentose phosphate pathway, transketolase has three important functions in the metabolism of the cells: (i) provision of pentoses for the synthesis of nucleotides; (ii) provision of metabolites for glycolysis or gluconeogenesis pathways; and (iii) indirectly influencing the synthesis of NADPH, required for the anabolic processes and antioxidants reduction (glutathione, ascorbate). Consequently, an appropriate activity of transketolase is essential for the proper functioning of lipid and carbohydrate metabolism [27].…”

“…Thiamin participates in the mitochondria central metabolism by functioning as a cofactor forpyruvate dehydrogenase (PDH), 2-oxoglutarate dehydrogenase (OGDH), and branched chain 2-oxoacid dehydrogenase (BCOADH, or branched chain ketoacid dehydrogenase, BCKDH). The PDH complex has a central role in bioenergetic processes, controlling the supply of acetyl-CoA into the TCA cycle and anabolic reactions, linking glycolysis and the TCA cycle via the oxidative decarboxylation of pyruvate [27,125]. PDH also produces acetyl-CoA from pyruvate in the chloroplast, which is used in the synthesis of fatty acids [27].…”

“…The term refers to the three vitamers forms, free thiamin; thiamin monophosphate (TMP); and thiamin pyrophosphate (TPP, or thiamin diphosphate, TDP), which is the active form. TPP works as an essential coenzyme for enzymes involved in photosynthesis in chloroplasts, in ATP synthesis in the participation in oxidative decarboxylation of pyruvate, and in the tricarboxylic acid cycle in mitochondrial central metabolism, as well as in the pentose phosphate pathway and alcoholic fermentation in cytoplasm [24][25][26][27]. Thiamin has also been shown to be involved in the acclimation responses to abiotic stresses and photoperiod [28][29][30][31][32].…”

Thiamine deficiency affects glucose transport and β‐oxidation in rats

“…It was shown in patients undergoing coronary surgery that thiamine treatment increased oxygen consumption suggesting adequate aerobic metabolism of patients receiving thiamine (Anderson et al, 2016). Additional factors affecting bioavailability of thiamine and its phosphates, besides anti-thiamine factors, were found, for example magnesium or pyrimidine deficiency (Baroncini, Annovazzi, Minonzio, Franzetti, & Zaffaroni, 2017;Tylicki, Łotowski, Siemieniuk, & Ratkiewicz, 2018).…”

ThiL is a valid antibacterial target that is essential for both thiamine biosynthesis and salvage pathway inPseudomonas aeruginosa

“…Microorganisms such as bacteria and fungi as well as plants produce TPP via de novo biosynthetic pathways that mammals lack (23,24). The TPP biosynthetic pathway of bacteria involves the separate biosynthesis of thiazole and pyrimidine moieties that are joined to form thiamine monophosphate (TMP) in a reaction catalyzed by thiamine phosphate synthase (ThiE) (25)(26)(27). Thiamine monophosphate kinase (ThiL) catalyzes the final step of the pathway by phosphorylating TMP to TPP, the biologically active form of the cofactor (28,29).…”